GENETICS BLOCK

Antibiotic-induced Hearing Impairment

A1555G in rRNA is StrepS Common in Spain & China Why? Drosophila mitochondrial mutants are hypersensitive to antibiotics

penetrance

Dominance relationships between alleles for a given trait can impact phenotypic ratios, but interactions between different genes can also impact phenotype. Such traits that result from the interaction among multiple genes and their environment are called complex traits. So, given a specific trait, how can we tell whether it is complex? One way to recognize a complex trait is through inconsistent inheritance patterns in successive generations. For example, a dominant trait might skip an entire generation yet be expressed in the subsequent generation. How is this possible? The answer to this question lies in the concepts of penetrance and expressivity When studying the relationships between genotype and phenotype, it is important to examine the statistical occurrence of phenotypes in a group of known genotypes. In other words, given a group of known genotypes for one trait, how many identical genotypes show the related phenotype? You might be surprised to learn that, for some traits, the phenotype might not occur as often as the genotype. For example, say everyone in population W carries the same allelecombinations for a certain trait, yet only 85% of the population actually shows the phenotype expected from those allele combinations. The proportion of genotypes that actually show expected phenotypes is called penetrance. Thus, in the preceding example, the penetrance is 85%. This value is calculated from looking at populations whose genotypes we know. In fact, large population studies are necessary for measuring penetrance, and studies of penetrance help us predict how likely it is that a trait will be evident in those who carry the underlying alleles. In general, when we know that the genotype is present but the phenotype is not observable, the trait shows incomplete penetrance. Basically, anything that shows less than 100% penetrance is an example of incomplete penetrance. Therefore, although the penetrance of a trait is a statistically calculated value based on the appearance of a phenotype among known genotypes, incomplete penetrance is simply a qualitative description about a group of known genotypes. A specific example of incomplete penetrance is the human bone disease osteogenesis imperfecta (OI). The majority of people with this disease have a dominant mutation in one of the two genes that produce type 1 collagen, COL1A1 or COL1A2. Collagen is a tissue that strengthens bones and muscles and multiple body tissues. People with OI have weak bones, bluish color in the whites of their eyes, and a variety of afflictions that cause weakness in their joints and teeth. However, this disease doesn't affect everyone who has COLIA1 and COLIA2 mutations in the same way. In fact, some people can carry the mutation but have no symptoms. Thus, families can unknowingly transmit the mutation from one generation to the next through someone who carries the mutation but does not express the OI phenotype. Incomplete penetrance examples such as OI demonstrate that even monogenic diseases do not have predictable expression patterns in a population. Is there a way to explain this unpredictability? Let's think about it. If two people have the same dominant mutation in COL1A1, why might only one of them actually display OI symptoms? Could it have to do with other genes that rescue the bad effect of a mutated collagen gene? Could it be that those who have OI simply express more mutated collagen than the person who is unaffected? To consider the possible explanations for incomplete penetrance, we have to remember how many steps there are between gene transcription and protein expression. Note that the expression of other genes, such as transcriptional or translational regulators, can influence the final effect of a gene product. Anything that interferes with the pathway from transcription to protein activation is known as an epigenetic factor. Indeed, there are multiple points at which another gene product can intervene in the stages prior to the production of a protein. Interference at these stages might stop production entirely, create an altered form of the protein that might never be active, or do any number of other things that renders the gene silent. So, the final stage of an active protein reflects many different processes that lead to the amino acid sequence and ultimate protein shape, all of which can be interfered with by other genes. Furthermore, some genes can up- or downregulate rates of transcription, which changes the total amount of protein produced. Thus, genes that affect the final form and expression amount of another gene can be influential in the formation of the phenotype derived from the regulated gene (Figure 1). So, if so many different possible modification points for a gene product exist, how can we narrow down the question of what causes incomplete penetrance? Interestingly, some scientists have actually tried to do this by observing how the genetic mutations that cause OI affect mice. These investigators inserted a mutated form of COL1A1 into mice and bred them so that they all contained this mutation. The mice were affected in similar ways to those with human OI: Many had severe bone weakness and multiple bone fractures, even at birth. In fact, when the researchers examined the mouse bones closely, they found that 70% of mice with the mutated COL1A1 gene showed evidence of OI (bone fractures); however, the remaining 30% appeared completely normal. In these mice with no OI phenotype, there was the same amount of COL1A1 expression as in those mice that did show the phenotype. Furthermore, the investigators used a purebred strain of mice that had little variability in their genomes to begin with. This means that the genetic context in which COL1A1 was expressed did not vary among the mice studied. Yet, despite the fact that all the mice had extremely similar genomes and all of them expressed the same amount of COL1A1, 30% of them did not show any OI phenotype. These results continue to be perplexing. Therefore, even the powerful experimental techniques currently available cannot explain penetrance. The two most popular explanations for incomplete penetrance, genetic background and variable expression levels, did not explain the lack of phenotype in 30% of the mice.

Angelman Syndrome

First described as 'puppet children' by Harry Angelman in Warrington in 1965. Symptoms:Developmental delaySpeech impairmentMovement or balance disorderapparent happy demeanor, easily excitable Associated with 15q11-q13 deletion Angelman syndrome or Angelman's syndrome[1][2] (AS) is a genetic disorder that mainly affects the nervous system.[7] Symptoms include a small head and a specific facial appearance, severe intellectual disability, developmental disability, speaking problems, balance and movement problems, seizures, and sleep problems.[7] Children usually have a happy personality and have a particular interest in water.[7] The symptoms generally become noticeable by one year of age.[7] Angelman syndrome is due to a lack of function of part of chromosome 15 inherited from a person's mother.[7] Most of the time, it is due to a deletion or mutation of the UBE3A gene on that chromosome.[7] Occasionally, it is due to inheriting two copies of chromosome 15 from a person's father and none from their mother.[7] As the father's versions are inactivated by a process known as genomic imprinting, no functional version of the gene remains. Angelman syndrome is typically due to a new mutation rather than one inherited from a person's parents.[7]Diagnosis is based on symptoms and possibly genetic testing.[8] No cure is available.[8] Treatment is generally supportive in nature.[8] Anti-seizure medications are used in those with seizures.[8] Physical therapy and bracing may help with walking.[8] Those affected have a nearly normal life expectancy.[7] AS affects 1 in 12,000 to 20,000 people.[7] Males and females are affected with equal frequency.[8] It is named after British pediatrician Harry Angelman, who first described the syndrome in 1965.[8][10] An older term, "happy puppet syndrome", is generally considered pejorative.[11]Prader-Willi syndrome is a separate condition, caused by a similar loss of the father's chromosome Angelman syndrome is caused by the loss of the normal maternal contribution to a region of chromosome 15, most commonly by deletion of a segment of that chromosome. Other causes include uniparental disomy, translocation, or single gene mutation in that region. A healthy person receives two copies of chromosome 15, one from the mother, the other from the father. However, in the region of the chromosome that is critical for Angelman syndrome, the maternal and paternal contribution express certain genes very differently. This is due to sex-specific epigenetic imprinting; the biochemical mechanism is DNA methylation. In a normal individual, the maternal allele of the gene UBE3A,[14]part of the ubiquitin pathway, is expressed and the paternal allele is specifically silenced in the developing brain. In the hippocampus and cerebellum, the maternal allele is almost exclusively the active one. If the maternal contribution is lost or mutated, the result is Angelman syndrome. (Some other genes on chromosome 15 are maternally imprinted, and when the paternal contribution is lost, by similar mechanisms, the result is Prader-Willi syndrome.) The methylation test that is performed for Angelman syndrome (a defect in UBE3A) looks for methylation on the gene's neighbor SNRPN (which is silenced by methylation on the maternal copy of the gene).[15] While Angelman syndrome can be caused by a single mutation in the UBE3A gene, the most common genetic defect leading to Angelman syndrome is a ~4Mb (megabase) maternal deletion in chromosomal region 15q11-13 causing an absence of UBE3A expression in the paternally imprinted brain regions. UBE3A codes for an E6-AP ubiquitin ligase, which chooses its substrates very selectively, and MAPK1, PRMT5, CDK1, CDK4, β-catenin, and UBXD8 have been identified as ubiquitination targets of this protein

Mitochondrial Gene Movement

Over evolutionary time protein-coding mitochondrial genes have tended to move from the mitochondrial genome to the nuclear genome. Endosymbiotic theory states that mitochondria originated as bacterial intracellular symbionts, the size of the mitochondrial genome gradually reducing over a long period owing to, among other things, gene transfer from the mitochondria to the nucleus. Such gene transfer was observed in more genes in animals than in plants, implying a higher transfer rate of animals. The evolution of gene transfer may have been affected by an intensity of intracellular competition among organelle strains and the organelle inheri- tance system of the organism concerned. This article reveals a relationship between those factors and the gene transfer rate from organelle to nuclear genomes, using a mathematical model. Mutant mitochondria that lose a certain gene by deletion are considered to replicate more rapidly than normal ones, resulting in an advantage in intracellular competition. If the competition is intense, heteroplasmic individuals possessing both types of mitochondria change to homoplasmic individuals including mutant mito- chondria only, with high probability. According to the mathematical model, it was revealed that the rate of gene transfer from mitochondria to the nucleus can be affected by three factors, the intensity of intra- cellular competition, the probability of paternal organelle transmission, and the effective population size. The gene transfer rate tends to increase with decreasing intracellular competition, increasing paternal organelle transmission, and decreasing effective population size. Intense intracellular competition tends to suppress gene transfer because it is likely to exclude mutant mitochondria that lose the essential gene due to the production of lethal individuals. ENDOSYMBIOTIC theory states that mitochondria originated as bacterial intracellular symbionts, their genome size having become gradually reduced over a long period of symbiosis. In animals, mitochondrial genome sizes are quite small (16-20 kb), with only 37 genes in general lacking introns, in which the coding regions constitute .90% of their size (Gray 1989, 1992; Boore 1999). On the other hand, the genome size of plant mtDNA varies among species (160-2000 kb in angiosperms), with coding regions constituting 10% of the total mitochondrial genome and with many introns present (Gray 1989, 1992; Brown 1999). For example, in Arabidopsis, mtDNA contains 57 genes with 366,924 nucleotides (Unseld et al. 1997). Either way, these mitochondrial genome sizes are 100-fold smaller than those of free-living bacteria (4000-6000 kb) (Selosse et al. 2001). One process resulting in reduced mtDNA size is gene transfer from the organelle to the nucleus (Thorsness and Weber 1996). In higher organisms, gene transfer has been implied by the various locations of certain genes coding mitochondrial proteins among different organisms. For example, the a-subunit of F1 ATPase exists in mitochondrial DNA in some eukaryotes but in nuclear DNA in others (Gray 1992), and the ribosomal protein gene rps10 exists in the mitochondrial genome in some angiosperm species, but in the nuclear genome in others (Wischmann and Schuster 1995; Adams et al. 2000). It has also been reported that the respiratory gene cox2, which is normally present in mitochondria, is variably involved in the nuclear genome in legume species. Some legume species possess the gene in both the mitochondrial and nuclear genomes, some in the mitochondrial genome only, and others in the nuclear genome only (Adams et al. 1999). A number of hypotheses have been proposed to ex- plain why and how gene transfer from mitochondria to the nucleus took place. If a mitochondrial genome lacks recombinations, its genetic information may be lost according to Muller's ratchet. Consequently, once a mitochondrial gene is copied to a nuclear genome, the original mitochondrion-based gene degenerates more rapidly, resulting in the gene persisting only in the nu- cleus (Blanchard and Lynch 2000; Selosse et al. 2001). Nevertheless, the efficacy of Muller's ratchet may depend upon mutation rates. When the mutation rate differs notably between genomes, the copy in the genome with the higher mutation rate is considered to degenerate more rapidly, even under Muller's ratchet. In plants, the rate of nuclear mutation is orders of mag- nitude greater than the mitochondrial mutation rate (Wolfe et al. 1987), resulting in a low expectation of any gene transfer. Nevertheless, in reality, many genes have been lost from mitochondrial genomes, the nuclear copies instead being active in these species. Such a strong selective force for gene transfer cannot be explained by Muller's ratchet only (Blanchard and Lynch 2000). Another hypothesis of gene transfer is that compact- ness of organelle genomes is advantageous in intracel- lular competition (Blanchard and Lynch 2000; Rand 2001; Selosse et al. 2001). If a mtDNA deletion mutant replicates faster than the wild-type full-length mtDNA, it will become more common in the cytoplasm. However, it can completely replace the wild-type mtDNA only if selection at the level of the cell allows the deletion mu- tant to persist without the functions encoded by the deleted region. On the basis of this concept, Albert et al. (1996) constructed a mathematical model of mito- chondrial genome dynamics. They considered a three- level selection process consisting of intermolecular, intermitochondrial, and intercellular selection. The intermolecular selection was assumed to favor mito- chondria with rapid replication, although both inter- mitochondrial and intercellular selection work against mitochondria lacking sufficient genetic information. There is no direct evidence for the intracellular selec- tion for the rapid replication of mitochondria, although it has been suggested by the dynamics of yeast mito- chondria involving good markers (respiration-deficient mutants, or petites). When heteroplasmic zygotes are produced by mating yeast strains that differ in one or more mitochondrial alleles, the majority of diploid progeny are homoplasmic after no more than 20 cell generations. In this case, the replication rate is consid- ered to be one of several important factors causing homoplasmy

Genetic Background

whenever you are studying anything, there are lots of ways that variation of other genes can affectt the mutant phenotype. the mutant phenotype is always there but its how much of it you can see full penetrance shows mutant phenotype, no penetrance doesn't show mutant phenotype, masked by all other variations Penetrance in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (the genotype) that also express an associated trait (the phenotype). In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms. For example, if a mutation in the gene responsible for a particular autosomal dominant disorder has 95% penetrance, then 95% of those with the mutation will develop the disease, while 5% will not. A condition, most commonly inherited in an autosomal dominant manner, is said to show complete penetrance if clinical symptoms are present in all individuals who have the disease-causing mutation. A condition which shows complete penetrance is neurofibromatosis type 1 - every person who has a mutation in the gene will show symptoms of the condition. The penetrance is 100%. Common examples used to show degrees of penetrance are often highly penetrant. There are several reasons for this: Highly penetrant alleles, and highly heritable symptoms, are easier to demonstrate, because if the allele is present, the phenotype is generally expressed. Mendelian genetic concepts such as recessiveness, dominance, and co-dominance are fairly simple additions to this principle. Alleles which are highly penetrant are more likely to be noticed by clinicians and geneticists, and alleles for symptoms which are highly heritable are more likely to be inferred to exist, and then are more easily tracked down In the preceding example, the genetic basis of the dependence of one gene on another is deduced from clear genetic ratios. However, only a small proportion of genes in the genome lend themselves to such analysis. One important property is that the mutation not exhibit decreased viability or fertility relative to wild type so that the frequency of recovery of mutant and wild-type classes are not skewed. Another property is that the difference in the norm of reaction (see Chapter 1) between mutant and wild type must be so dramatic that there is no overlap of the reaction curves for mutant and wild type, and hence we can reliably use the phenotype to distinguish mutant and wild-type genotypes with 100% certainty. In such cases, we say that this mutation is 100% penetrant. However, many mutations show incomplete penetrance. Thus penetrance is defined as the percentage of individuals with a given genotype who exhibit the phenotype associated with that genotype. For example, an organism may have a particular genotype but may not express the corresponding phenotype, because of modifiers, epistatic genes, or suppressors in the rest of the genome or because of a modifying effect of theenvironment. Alternatively, absence of a gene function may intrinsically have very subtle effects that are difficult to measure in a laboratory situation. Another measure for describing the range of phenotypic expression is called expressivity. Expressivity measures the extent to which a given genotype is expressed at the phenotypic level. Different degrees of expression in different individuals may be due to variation in the allelic constitution of the rest of the genome or to environmental factors. Figure 4-23 illustrates the distinction between penetrance and expressivity. Like penetrance, expressivity is integral to the concept of the norm of reaction.

Whay the sudden rise in BSE?

"In modern industrial cattle-farming, various commercial feeds are used, which may contain ingredients including antibiotics, hormones, pesticides, fertilizers, and protein supplements. The use of meat and bone meal, produced from the ground and cooked left-overs of the slaughtering process as well as from the cadavers of sick and injured animals such as cattle, sheep, or chickens, as a protein supplement in cattle feed was widespread in Europe prior to about 1987".

why females are more receptive?

- put 1000's of drosophila females together, males will chase anything their own size, sing a song , male chases female , vibrates wings nearest to her head and song tells her what species of fruit fly he is and the more singing he does the more intrested she gets. quality and quantity of song is important and pheromones around - mate for 20 mins - leave males and females together for 10 mins and work out how many of them mate Take two 3 day-old virgin flies, one male and one female Introduce them and they may, or may not, mateTheir ability to do this is GENETIC

mitochondrial gene therapy

- using adenovirus vector - mitochondria are impossible to genetically modify directly - strategies involve nuclear genes with mitochondrial targeting tags - adenovirus vector binds to cell membrane - vector packaged into vesicle - vesicle breaks down releasing vector - cell makes proteins using new gene introduce to nucleus and add protein tag in-front of protein so DNA knows where to go 1) direct in vivo administration of viral vectors, or the use of viruses to deliver the therapeutic genes into human cells; and 2) the transfer of genetically engineered blood or bone marrow stem cells from a patient, modified in a lab, then injected back into the same patient. Gene therapy is designed to introduce genetic material into cells to compensate for or correct abnormal genes. If a mutated gene causes damage to or spurs the disappearance of a necessary protein, for example, gene therapy may be able to introduce a normal copy of the gene to restore the function of that protein

yellow female mating behaviour

- yellow mutant females mate very quickly when compared to wild-type females. - Hypothesize that there is a biochemical issue here as pigmentation and neurotransmitter pathways are linked. - by chromosomal substitution, this enhanced receptivity has been localised to the X chromosome - yellow locus itself is responsible for the enhanced female receptivity ( changes in behaviour, sex specific reproduction) - WT fruit flies- yellow/brown/red eyes/ black rings across abdomen females become receptive to courting males about 8-12 hours after emergence yellow mutants= complete loss of pigmentation from the cuticle of adult flies yellow gene is responsible for changes in behaviour, sex-specific reproduction The D. melanogaster yellow gene encodes a protein hypothesized to act either structurally or enzymatically in the synthesis of dopamine melanin, and a Yellow homolog has been shown to bind dopamine and other biogenic amines in the sand fly Lutzomyia longipalpis . The interaction between Yellow and dopamine might explain the protein's effects on male mating success because dopamine acts as a modulator of male courtship drive in D. melanogaster . These effects of dopamine are mediated by neurons expressing the gene fruitless (fru) , which is a master regulator of sexually dimorphic behavior in D. melanogaster that can affect every component of courtship and copulation. fru has also been shown to regulate expression of yellow in the central nervous system (CNS) of male D. melanogaster larvae . These observations suggest that the pleiotropic effects of yellow on male mating success might result from effects of yellow in the adult CNS, particularly in fru-expressing neurons. Consistent with this hypothesis, functional links between the pigment synthesis pathway and behavior mediated by the nervous system have previously been reported for other pigmentation genes

tigon

A tigon (/ˈtaɪɡən/) or tiglon (/ˈtaɪɡlən/) is the hybrid offspring of a male tiger (Panthera tigris) and a female lion (Panthera leo) thus, it has parents with the same genus, but of different species. A pairing of a male lion with a female tiger is called a liger, also by portmanteau. The tigon's genome includes genetic components of both parents,[1] thus, they can exhibit visible characteristics from both parents: they can have both spots from the mother (lions carry genes for spots - lion cubs are spotted and some adults retain faint markings) and stripes from the father. Any mane that a male tigon may have will appear shorter and less noticeable than a lion's mane and is closer in type to the ruff of a male tiger. It is a common misconception that tigons are smaller than lions or tigers. They do not exceed the size of their parent species because they inherit growth-inhibitory genesfrom both parents, but they do not exhibit any kind of dwarfism or miniaturization; they often weigh around 180 kilograms (400 lb) Imprinting differences in Lions and Tigers reflects their different mating strategies Social female Lions mate multiple times, so competing males want fast growing embryos, but females do not so switch off the growth hormone gene of males. Solitary female Tigers male with just one male, so there is no competition between males for fast growing embryos.

Human Mitochondrial History - mitochondrial eve

All human mtDNA can be traced back to a single female living in Africa approximately 150,000 years ago. In human genetics, the Mitochondrial Eve (also mt-Eve, mt-MRCA) is the matrilineal most recent common ancestor (MRCA) of all living humans. In other words, she is defined as the most recent woman from whom all living humans descend in an unbroken line purely through their mothers and through the mothers of those mothers, back until all lines converge on one woman. In terms of mitochondrial haplogroups, the mt-MRCA is situated at the divergence of macro-haplogroup L into L0 and L1-6. As of 2013, estimates on the age of this split ranged at around 150,000 years ago,[note 3] consistent with a date later than the speciation of Homo sapiens but earlier than the recent out-of-Africa dispersal.[4][1][5] The male analog to the "Mitochondrial Eve" is the "Y-chromosomal Adam" (or Y-MRCA), the individual from whom all living humans are patrilineallydescended. As the identity of both matrilineal and patrilineal MRCAs is dependent on genealogical history (pedigree collapse), they need not have lived at the same time. As of 2013, estimates for the age Y-MRCA are subject to substantial uncertainty, with a wide range of times from 180,000 to 580,000 years ago[6][7][8] (with an estimated age of between 120,000 and 156,000 years ago, roughly consistent with the estimate for mt-MRCA.).[2][9] The name "Mitochondrial Eve" alludes to biblical Eve, which has led to repeated misrepresentations or misconceptions in journalistic accounts on the topic. Popular science presentations of the topic usually point out such possible misconceptions by emphasizing the fact that the position of mt-MRCA is neither fixed in time (as the position of mt-MRCA moves forward in time as mitochondrial DNA (mtDNA) lineages become extinct), nor does it refer to a "first woman", nor the only living female of her time, nor the first member of a "new species

Variable expressivity

Although some genetic disorders exhibit little variation, most have signs and symptoms that differ among affected individuals. Variable expressivity refers to the range of signs and symptoms that can occur in different people with the same genetic condition. For example, the features of Marfan syndrome vary widely— some people have only mild symptoms (such as being tall and thin with long, slender fingers), while others also experience life-threatening complications involving the heart and blood vessels. Although the features are highly variable, most people with this disorder have a mutation in the same gene (FBN1). As with reduced penetrance, variable expressivity is probably caused by a combination of genetic, environmental, and lifestyle factors, most of which have not been identified. If a genetic condition has highly variable signs and symptoms, it may be challenging to diagnose.

causes

BSE is an infectious disease believed to be due to a misfolded protein, known as a prion.[3][6] Cattle are believed to have been infected from being fed meat and bone meal (MBM) that contained the remains of other cattle who spontaneously developed the disease or scrapie-infected sheep products.[3] The outbreak increased throughout the United Kingdom due to the practice of feeding meat-and-bone meal to young calves of dairy cows.[3][8] Prions replicate by causing other normally folded proteins of the same type to take on their misfolded shape, which then go on to do the same, leading to an exponential chain reaction. Eventually, the prions aggregate into an alpha helical, beta pleated sheet, which is thought to be toxic to brain cells. The agent is not destroyed even if the beef or material containing it is cooked or heat-treated.[15] Transmission can occur when healthy animals come in contact with tainted tissues from others with the disease. In the brain, the agent causes native cellular prion protein to deform into the misfolded state, which then goes on to deform further prion protein in an exponential cascade. This results in protein aggregates, which then form dense plaque fibers. Brain cells begin to die off in massive numbers, eventually leading to the microscopic appearance of "holes" in the brain, degeneration of physical and mental abilities, and ultimately death.[citation needed] The British Government enquiry took the view that the cause was not scrapie, as had originally been postulated, but was some event in the 1970s that was not possible to identify

properties of drosophila balancer chromosomes

Balancer chromosomes are special, modified chromosomes used for genetically screening a population of organisms to select for heterozygotes. Balancer chromosomes can be used as a genetic tool to prevent crossing over (genetic recombination) between homologous chromosomes during meiosis. Balancers are most often used in Drosophila melanogaster (fruit fly) genetics to allow populations of flies carrying heterozygous mutations to be maintained without constantly screening for the mutations but can also be used in mice.[1] Balancer chromosomes have three important properties: they suppress recombination with their homologs, carry dominant markers, and negatively affect reproductive fitness when carried homozygously To suppress crossing over, balancer chromosomes are the products of multiple, nested chromosomal inversions so that synapsis between homologous chromosomes is disrupted. This construct is called a crossover suppressor.[7] If crossing over between a balancer chromosome and the balancer's homolog does occur during meiosis each chromatid ends up lacking some genes and carrying two copies of other genes. Recombination in inverted regions leads to dicentric or acentric chromosomes (chromosomes with two centromeres or no centromere). Progeny carrying chromosomes that are the products of recombination between balancer and normal chromosomes are not viable (they die). Dominant markers such as genes for green fluorescent protein or enzymes that make pigments allow researchers to easily recognize flies that carry the balancer chromosome.[8] By suppressing reproductive fitness when carried homozygously a balancer chromosome ensures that the population it is carried in does not become fixed for the balancer chromosome. Balancer chromosomes always contain a lethal recessive allele. This means that if an organism receives two copies of the balancer chromosome, one from the mother and one from the father, then the organism will not live. So any organism that is homozygous for that chromosome will not live to pass on its genes. However, offspring that only get one copy of one balancer chromosome and one copy of a wild type or mutant chromosome will live to pass on its genes. After only a few generations the population will be entirely heterozygous so that its genotype can be guaranteed on at least those two chromosomes. Balancer chromosomes also come with some sort of physical marker. This marker can be actually associated with the DNA in the chromosome such as the Green Fluorescent Protein that fluoresces in ultraviolet light, or it can be an easily distinguishable physical characteristic. These physical characteristics can be anything that is seen easily. In Drosophila melanogaster, for example, eye color and hair length are commonly used. This physical marker serves as a double check that there are indeed the heterozygous balancer chromosomes in the organism 1- multiple rearrangements that prevent recombination ( chromosomal inversions ) 2- one or more lethal recessive mutations 3- one or more dominant visible markers ( curly wings ) - once a lethal mutation is put over the right balancer it'll breed true indefinitely so many stocks can be kept cheaply and easily

imprinting

Because lions and mice have similar mating strategies, they probably have similarly imprinting strategies. Male lions want their offspring to be big, and female lions want their offspring to be medium-sized. A male lion's sperm has imprinted growth genes saying "grow really big!" This usually meets a female lion's egg that has imprinted genes saying "don't grow too much." This combination cancels each other out and makes an average sized lion. But because female tigers only mate with one male at a time, male tigers don't need to have big cubs. Tigers probably have not evolved similar imprinting strategies. Their eggs and sperm will just say "grow medium-sized." Lions and tigers have different DNA imprinting strategies. Male lions want their cubs to grow as big as possible! But a lioness wants all the cubs to be the same size, so her imprinting counteracts his. This means when a male lion's "grow really big!" sperm combines with a female tiger's "grow medium-sized" egg, the result is a really big liger. This imprinting also explains why a tigon is not nearly as big. If a male tiger's "grow medium-sized" sperm combines with a lioness's "don't grow too much"egg, the result is cat that isn't any bigger than its parents. There haven't been very many genetic studies on lions and tigers ... they're much harder to study than mice! They take much longer to grow and are much more difficult to take care of. Currently we do not know for sure which genes are imprinted in lions or tigers, or which of these genes make the biggest differences in terms of growth. There have been recent studies on big cats to compare genome sequences between tigers, lions and leopards. However, these studies do not give us information about imprinting. The technology exists to find methylation sites in DNA, so maybe in the future we will uncover more about imprinting differences between lions and tigers. But for now, scientists can infer a lot about these big cats based on evolutionary theories and what we know from mice.

anglemans/pws

Both associated with 15q11-q13 deletionSame deletion: 'opposite phenotypes' Dependent on parental origin of deletion Angelman associated with UB3A gene only expressed from maternal ch15 Prader-Willi associated with genes only expressed from paternal ch15

3: Bovine spongiform encephalopathy

Bovine spongiform encephalopathy (BSE), commonly known as mad cow disease, is a neurodegenerative disease of cattle.[2]Symptoms include abnormal behavior, trouble walking, and weight loss.[1] Later in the course of the disease the cow becomes unable to function normally.[1] The time between infection and onset of symptoms is generally four to five years.[2] Time from onset of symptoms to death is generally weeks to months.[2] Spread to humans is believed to result in variant Creutzfeldt-Jakob disease(vCJD).[3] As of 2018, a total of 231 cases of vCJD have been reported globally.[5] BSE is thought to be due to an infection by a misfolded protein, known as a prion.[3][6] Cattle are believed to have been infected by being fed meat-and-bone meal (MBM) that contained the remains of cattle who spontaneously developed the disease or scrapie-infected sheep products.[3][7] The outbreak increased throughout the United Kingdom due to the practice of feeding meat-and-bone meal to young calves of dairy cows.[3][8] Cases are suspected based on symptoms and confirmed by examination of the brain.[1] Cases are classified as classic or atypical, with the latter divided into H- and L types.[1] It is a type of transmissible spongiform encephalopathy(TSE).[9] Efforts to prevent the disease in the UK include not allowing any animal older than 30 months to enter either the human food or animal feed supply.[4] In Europe all cattle over 30 months must be tested if they will become human food.[4] In North America, tissue of concern, known as specified risk material, may not be added to animal feed or pet food.[10] About 4.4 million cows were killed during the eradication program in the UK.[11] Four cases were reported globally in 2017, and the condition has been deemed to be nearly eradicated.[1] In the United Kingdom, from 1986 to 2015, more than 184,000 cattle were diagnosed with the peak of new cases occurring in 1993.[3] A few thousand additional cases have been reported in other regions of the world.[1] It is believed that a few million cattle with the condition likely entered the food supply during the outbreak.[1]

Imprinting adds instructions to DNA sequences

But how do reproductive goals result in genetic differences? Mammals have evolved a way to pass on maternal or paternal goals to their offspring. They do this by imprinting. DNA is like an instruction manual. But instead of having the instructions for building a chair or a table, it has the instructions to build living things, like lions and tigers. While sperm and eggs are in the adults, prior to fertilization, their DNA can be modified. This can turn certain bits of the DNA "on" or "off". These modifications do not change the DNA sequence itself. It's just like if you were building a chair and you decided to underline or cross out certain instructions in order to make the chair you want.

Creutzfeldt-Jakob Disease (CJD)

Classic CJD is a human prion disease. It is a neurodegenerative disorder with characteristic clinical and diagnostic features. This disease is rapidly progressive and always fatal. Infection with this disease leads to death usually within 1 year of onset of illness. Creutzfeldt-Jakob disease (CJD) is a rapidly progressive, invariably fatal neurodegenerative disorder believed to be caused by an abnormal isoform of a cellular glycoprotein known as the prion protein. CJD occurs worldwide and the estimated annual incidence in many countries, including the United States, has been reported to be about one case per million population. Classic CJD is a human prion disease. It is a neurodegenerative disorder with characteristic clinical and diagnostic features. This disease is rapidly progressive and always fatal. Infection with this disease leads to death usually within 1 year of onset of illness. Creutzfeldt-Jakob disease (CJD) is a rapidly progressive, invariably fatal neurodegenerative disorder believed to be caused by an abnormal isoform of a cellular glycoprotein known as the prion protein. CJD occurs worldwide and the estimated annual incidence in many countries, including the United States, has been reported to be about one case per million population. The vast majority of CJD patients usually die within 1 year of illness onset. CJD is classified as a transmissible spongiform encephalopathy (TSE) along with other prion diseases that occur in humans and animals. In about 85% of patients, CJD occurs as a sporadic disease with no recognizable pattern of transmission. A smaller proportion of patients (5 to 15%) develop CJD because of inherited mutations of the prion protein gene. These inherited forms include Gerstmann-Straussler-Scheinker syndrome and fatal familial insomnia. Physicians suspect a diagnosis of CJD on the basis of the typical signs and symptoms and progression of the disease. In most CJD patients, the presence of 14-3-3 protein in the cerebrospinal fluid and/or a typical electroencephalogram (EEG) pattern, both of which are believed to be diagnostic for CJD, have been reported. However, a confirmatory diagnosis of CJD requires neuropathologic and/or immunodiagnostic testing of brain tissue obtained either at biopsy or autopsy In 1972 one of Prusiner's patients died of Creutzfeldt- Jakob disease (CJD), within 2 months of first symptoms. Symptoms include: dementia memory loss personality changes hallucinations Progression weeks, months or years

What is the infective agent?

Curiously the infective agent is resistant to heat and radiation, so cannot be DNA. However, the infective agent is sensitive to procedures that hydrolyse or modify proteins.

courtship behaviour

Drosophila males display a complex repertoire of behaviors that have evolved to achieve reproductive success. This includes following the female, tapping her with his forelegs, contacting her genitalia with his mouthparts, singing a species-specific courtship song, and bending his abdomen to copulate [3]. It is presumed that Drosophila females assess a courting male by 'summating' sensory cues for species type and fitness before sanctioning mating [3]. A virgin female has the ability to be unreceptive to and resist the courtship of a Drosophila male by exhibiting rejection behaviors, which include extruding her ovipositor, kicking, or decamping [3-6]. If she decides to accept the male, she slows down, ceases rejection behaviors and opens her vaginal plate for copulation [3]. After successful copulation, mated females become temporarily sexually unreceptive to further copulatory attempts, increasing their rate of egg-laying Drosophila species present an ideal model system in which to investigate the genetic basis of sexual isolation. Several species pairs are only partially reproductively isolated, producing fertile hybrids that can be backcrossed to one of the parental species to generate segregating backcross mapping populations. Furthermore, Drosophila melanogaster is a model organism with excellent genetic and genomic resources that are ideal for genetically dissecting complex traits, including the ability to clone chromosomes, replicate genotypes, and rear large numbers of individuals under uniform environmental conditions; publicly available mutations and deficiency stocks useful for mapping; abundant segregating variation in natural populations that can readily be selected in the laboratory to produce divergent phenotypes a complete well annotated genome sequence; and several platforms for whole-genome transcriptional profiling. Courtship behavior of Drosophila is composed of sequential actions that exchange auditory, visual, and chemosensory signals between males and females, allowing for individual components of the behavior to be quantified and separated (4, 5). Courtship is initiated when the male aligns himself with the female, using visual and olfactory signals for orientation. He then taps the female's abdomen with his foreleg, using pheromonal cues for gender and species recognition, followed by wing vibration to produce a species-specific courtship song. After courtship initiation, the male again uses pheromonal cues by licking the female's genitalia, after which he will attempt to copulate. The female can accept the male or reject him by moving away. Successful copulation is accompanied by the transfer of sperm and seminal fluids that stimulate the release of oocytes by the ovary (6) and reduce female receptivity to other males (7, 8). Components of the seminal fluids are associated with the reduced lifespan of mated females (9), setting up an intersexual conflict 1- orientation 2- vibration 3- licking 4- curling 5- copulation - particularly in mornings less likely in afternoons it is a female decision

Drosophila melanogaster

Drosophila melanogaster males perform a series of courtship behaviors that, when successful,result in copulation with a female. For over a century, mutations in the yellow gene, named for its effects on pigmentation, have been known to reduce male mating success. Prior work has suggested that yellow influences mating behavior through effects on wing extension, song, and/or courtship vigor. Here, we rule out these explanations, as well as effects on the nervous system more generally, and find instead that the effects of yellow on male mating success are mediated by its effects on pigmentation of male-specific leg structures called sex combs. Loss of yellow expression in these modified bristles reduces their melanization, which changes their structure and causes difficulty grasping females prior to copulation. These data illustrate why the mechanical properties of anatomy, and not just neural circuitry, must be considered to fully understand the development and evolution of behavior.

Mitochondrial bottleneck

Entities undergoing uniparental inheritance and with little to no recombination may be expected to be subject to Muller's ratchet, the inexorable accumulation of deleterious mutations until functionality is lost. Animal populations of mitochondria avoid this buildup through a developmental process known as the mtDNA bottleneck. The bottleneck exploits stochastic processes in the cell to increase in the cell-to-cell variability in mutant load as an organism develops: a single egg cell with some proportion of mutant mtDNA thus produces an embryo where different cells have different mutant loads. Cell-level selection may then act to remove those cells with more mutant mtDNA, leading to a stabilisation or reduction in mutant load between generations. The mechanism underlying the bottleneck is debated,[6][7][8] with a recent mathematical and experimental metastudy providing evidence for a combination of random partitioning of mtDNAs at cell divisions and random turnover of mtDNA molecules within the cell.[9] The mitochondrial bottleneck concept refers to the classic evolutionary term, which is used to explain an event that reduces and specifies a population. It was developed to describe why mitochondrial DNA in an embryo might be drastically different from that of its mother. When a large population of DNA is subsampled, each sample population will receive a slightly different proportion of mitochondrial genotypes. Consequently, when paired with a high degree of replication, a rare or mutated allele can begin to proportionally dominate. In theory, this makes possible a single-generation shift of overall mitochondrial genotype Although it is not well characterized, selection can occur for organelle genomes in heteroplasmic cells. Intracellular ("within cells") selection occurs within individual cells. It refers to the selective segregation of certain genotypes in mitochondrial DNA that allows the favoured genotype to thrive. Intercellular ("between cells") selection occurs on a larger scale, and refers to the preferential growth of cells that have greater numbers of a certain mitochondrial genotype.[4] Selective differences can occur between naturally occurring, non-pathological mtDNA types when mixed in cells, and may depend on tissue type, age, and genetic distance.[10] Selective differences between naturally occurring mtDNA types may pose challenges for gene therapies.[11] In mitochondrial DNA, there is evidence for potent germline purifying selection, as well as purifying selection during embryogenesis. Additionally, there is a dose-dependent decrease in reproduction ability for females that have mutations in mitochondrial DNA. This demonstrates another selection mechanism to prevent the evolutionary preservation of harmful mutations There is a wide variety of mitochondrial DNA genotypes in the maternal pool, which is represented by the bottle. The two genotypes in this maternal pool are represented by blue and yellow. When generated, each oocyte receives a small subsampling of mitochondrial DNA molecules in differing proportions. This is represented by the conveyor belt with oocytes, each one unique, as they are produced

mitochondrial Heteroplasmy

Heteroplasmy is the presence of more than one type of organellar genome (mitochondrial DNA or plastid DNA) within a cell or individual. It is an important factor in considering the severity of mitochondrial diseases. Because most eukaryotic cells contain many hundreds of mitochondria with hundreds of copies of mitochondrial DNA, it is common for mutations to affect only some mitochondria, leaving most unaffected. Although detrimental scenarios are well-studied, heteroplasmy can also be beneficial. For example, centenarians show a higher than average degree of heteroplasmy.[1] Microheteroplasmy is present in most individuals. This refers to hundreds of independent mutations in one organism, with each mutation found in about 1-2% of all mitochondrial genomes Mitochondrial mutations are frequently lethal. However, a fertilised egg inherits a specific frequency of mutant mitochondria, that may differ profoundly from that in the mother. In order for heteroplasmy to occur, organelles must contain a genome and, in turn, a genotype. In animals, mitochondria are the only organelles that contain their own genomes, so these organisms will only have mitochondrial heteroplasmy. In contrast, photosynthetic plants contain mitochondria and chloroplasts, each of which contains plastid genomes. Therefore, plant heteroplasmy occurs in two dimensions while studying chloroplast genomes, Erwin Baur made the first observations about organelle inheritance patterns. Organelle genome inheritance differs from nuclear genome, and this is illustrated by four violations of Mendel's laws.[4] During asexual reproduction, nuclear genes never segregate during cellular divisions. This is to ensure that each daughter cell gets a copy of every gene. However, organelle genes in heteroplasmic cells can segregate because they each have several copies of their genome. This may result in daughter cells with differential proportions of organelle genotypes.[4] Mendel states that nuclear alleles always segregate during meiosis. However, organelle alleles may or may not do this.[4] Nuclear genes are inherited from a combination of alleles from both parents, making inheritance biparental. Conversely, organelle inheritance is uniparental, meaning the genes are all inherited from one parent.[4] It is also unlikely for organelle alleles to segregate independently, like nuclear alleles do, because plastid genes are usually on a single chromosome and recombination is limited by uniparental inheritance

In Sheep CJD is called Scrapie

High levels of CJD in Libyan Jews (30x normal): Why? fCJD implies a mutation segregating in a familyvCJD attributed to eating lightly cooked infected sheep brain CJD Can be Transmitted by Infection

Familial CJD Mutation in PrP Gene

Human prion diseases are composed of sporadic and familial forms as well as forms caused by infection.1,2 Five types of Creutzfeldt-Jakob disease (CJD) and fatal insomnia are the sporadic forms that can be distinguished based on the characteristics of the disease phenotype.3 Fifty-six mutations, including the recently reported substitution of histidine (H) for arginine (R) at codon 148 (R148H) of the prion protein gene (PRNP), are known to be associated with familial prion diseases.4-6 Furthermore, it has been shown that the common methionine/valine (M/V) polymorphism at codon 129 of PRNP may modify the features of the disease phenotype associated with a PRNP mutation, depending on which of the two polymorphic codons is coupled with the mutation.4,7 Of a total of 62 disease-associated PRNP haplotypes reported, 15 are associated with a phenotype that belongs to the group of CJD.4-6 Despite the high number of pathogenic haplotypes, the distinct phenotypes associated with the familial CJD (fCJD) are, surprisingly, relatively limited in number, and they often appear to mimic the phenotypes of sporadic CJD (sCJD).8,9This observation raises the important issue related to the pathogenesis of prion diseases as to how the disease phenotype is related to the molecular characteristics of the pathological prion protein (PrPSc), the only known component in the infectious pathogen.All prion diseases are thought to share the same pathogenic mechanism that involves a conformational transition of α-helix into β-sheet structure in prion protein (PrP).10 The normal or cellular PrP (PrPC) interacts with the pathological and infectious PrPSc and thus adopts the same conformation as the PrPSc.10When a sufficient amount of PrPSc is generated, the disease becomes symptomatic. In sporadic prion diseases, PrPSc is thought to form spontaneously and randomly due to a co- or posttranslational error in PrP processing. In familial prion diseases, the etiology is thought to be different; these diseases are believed to result from the conversion of the mutant PrP (PrPM), a molecule that is unstable because of the presence of the mutation.4 The PrPC to PrPSc conversion results in the formation of the PrPSc species with different physicochemical characteristics probably reflecting distinct conformations also identified as "prion strains."11-14 In familial prion diseases, distinct prion strains are seemingly determined by the PrP genotype and are expected to be associated with different disease phenotypes

Manipulating Heteroplasmy

If all patients are heteroplasmic, is it possible to skew the relative frequencies of 'good' and 'bad' mtDNAs in favour of 'good' mtDNA? A: Exercise increases muscle bulk, increasing number of 'good' mtB: If mtDNA mutation creates restriction site, target restriction enzyme C: Target oligomers to 'bad' mtDNA to inhibit 'bad' mtDNA replication D: Target modified Zinc-Finger proteins to methylate 'bad' mtDNA Some 'success' with A & B. C & D more speculative.

Who was Oetzi

In 1991, Oetzi's remains were found in a Glacier in the Italian alps. Analysis of his mtDNA suggests that: Died 5300 years ago Ethnically Central European (mitotype K: 9% Europeans) He may have been sterile (reduced sperm mobility) To Quote a Top Scientist"At first it was thought that Oetzi had died from exposure to cold but wounds on his hands and an arrowhead lodged in his back suggest a more violent death" In the human mtDNA database there is one living person who matches 16568 of 16569bp mtDNA with Oetzi Ötzi, also called Iceman, also spelled Ice Man, an ancient mummified human body that was found by a German tourist, Helmut Simon, on the Similaun Glacier in the Tirolean Ötztal Alps, on the Italian-Austrian border, on September 19, 1991. Radiocarbon-dated to 3300 BCE, the body is that of a man aged 25 to 35 who had been about 1.6 metres (5 feet 2 inches) tall and had weighed about 50 kg (110 pounds). Initially it was thought that he had fallen victim to exposure or exhaustion while crossing the Alps and died of freezing, but X-ray examination in 2001 showed that an arrowhead was lodged in the Iceman's left shoulder, suggesting that he had likely bled to death after being shot. The small rocky hollow in which he lay down to die was soon covered (and protected) by glacial ice that happened to be melting 5,300 years later when his body was discovered by modern humans. His nickname, Ötzi, stems from the Ötztal Alps, where he was found. It was at first believed that the Iceman was free of diseases, but in 2007 researchers discovered that his body had been infested with whipworm and that he had suffered from arthritis; neither of these conditions contributed to his death. He also at one time had broken his nose and several ribs. His few remaining scalp hairs provide the earliest archaeological evidence of haircutting, and short blue lines on his skin (lower spine, left leg, and right ankle) have been variously interpreted as the earliest known tattoos or as scars remaining from a Neolithic therapeutic procedure. The various clothes and accoutrements found with him are truly remarkable, since they formed the gear of a Neolithic traveler. The Iceman's basic piece of clothing was an unlined fur robe stitched together from pieces of ibex, chamois, and deer skin. A woven grass cape and a furry cap provided additional protection from the cold, and he wore shoes made of leather and stuffed with grass. The Iceman was equipped with a small copper-bladed ax and a flint dagger, both with wooden handles; 14 arrows made of viburnum and dogwood, two of which had flint points and feathers; a fur arrow quiver and a bow made of yew; a grass net that may have served as a sack; a leather pouch; and a U-shaped wooden frame that apparently served as a backpack to carry this gear. His scant food supply consisted of a sloeberry, mushrooms, and a few gnawed ibex bones. In the human mtDNA database there is one living person who matches 16568 of 16569bp mtDNA with Oetzi

yellow male mating behaviour

Inbred yellow strain - WT Male x WT female = 70% mating frequency - Yellow Male x WT female = 25 % - WT male x Yellow Female = 95 % - Yellow Male x Yellow female = 65 % outbred yellow strain - WT Male x WT female = 70% mating frequency - Yellow Male x WT female = 30 % - WT male x Yellow Female = 75 % - Yellow Male x Yellow female = 35 % The difference in behaviour is associated with 'genetic background' difference in behaviour due to smith else not the yellow mutation yellow male rubbish in courting due to genetic background yellow males are not very active, no high quality of courtship because not as active, as a consequence females mate more slowly with them but when you got a bottle flies, yellow mutants that all live in the same bottle together through generations by accident you're doing a selection. you're selecting for females that accept really poor courtship from males the threshold of when they can mate is lowered so when they meet a WT male they immediately mate as they're used to slow courtship when you keep stocks of organisms in a lab you need to be careful on how you keep them because you are always doing a selection experiment

Expressivity

Individuals with the same genotype can also show different degrees of the same phenotype. Expressivity is the degree to which trait expression differs among individuals. Unlike penetrance, expressivity describes individual variability, not statistical variability among a population of genotypes. For example, the features of Marfan syndrome vary widely; some people have only mild symptoms, such as being tall and thin with long, slender fingers, whereas others also experience life-threatening complications involving the heart and blood vessels. Although the features of Marfan syndrome are highly variable, all people with this disorder have a dominant mutation in the gene coding for fibrillin 1, FBN1. However, it turns out that the position of the mutation in the FBN1 gene is correlated with the severity of the Marfan phenotype. Researchers found that a mutation in one FBN1 position is prevalent in families with severe symptoms, whereas a mutation in another position is prevalent in families with less severe symptoms. These findings are an encouraging clue as to how specific defects in the fibrillin 1 protein can account for the variable expressivity in Marfan syndrome (Li et al., 2008). Another example of expressivity at work is the occurrence of extra toes, or polydactyly, in cats. The presence of extra toes on a cat's paw is a phenotype that emerges in groups of cats who have interbred for generations. In fact, there are several well-known groups of these cats, such as those on Key West Island (known as "Hemingway's cats"), as well as those in breeding clusters in the eastern U.S. and shores of the British Isles (Figure 2). The first to report on this phenomenon was C. H. Danforth, who studied the inheritance of polydactyly among 55 generations of cats. He observed that the polydactyly phenotype showed "good penetrance, but variable expression" because the gene always causes extra toes on the paw, but the number of extra toes varies widely from cat to cat. Through his breeding studies, Danforth found that although a dominant allele underlies the cause of polydactyly, the degree of polydactyly depends on the condition of adjacent layered tissues in the developing limb; that is, the expression of genes in tissues surrounding tissue that will become the toe determines the degree of polydactyly.

transmission

It has been recognized that prion diseases can arise in three different ways: acquired, familial, or sporadic.[75] It is often assumed that the diseased form directly interacts with the normal form to make it rearrange its structure. One idea, the "Protein X" hypothesis, is that an as-yet unidentified cellular protein (Protein X) enables the conversion of PrPC to PrPScby bringing a molecule of each of the two together into a complex.[76] The primary method of infection in animals is through ingestion. It is thought that prions may be deposited in the environment through the remains of dead animals and via urine, saliva, and other body fluids. They may then linger in the soil by binding to clay and other minerals.[77] A University of California research team has provided evidence for the theory that infection can occur from prions in manure.[78] And, since manure is present in many areas surrounding water reservoirs, as well as used on many crop fields, it raises the possibility of widespread transmission. It was reported in January 2011 that researchers had discovered prions spreading through airborne transmission on aerosol particles, in an animal testing experiment focusing on scrapie infection in laboratory mice.[79] Preliminary evidence supporting the notion that prions can be transmitted through use of urine-derived human menopausal gonadotropin, administered for the treatment of infertility, was published in 2011

kuru

Kuru is a very rare, incurable and fatal neurodegenerative disorder that was formerly common among the Fore people of Papua New Guinea. Kuru is a form of transmissible spongiform encephalopathy (TSE) caused by the transmission of abnormally folded proteins (prion proteins), which leads to symptoms such as tremors and loss of coordination from neurodegeneration. The term kuru derives from the Fore word kuria or guria ("to shake"),[2] due to the body tremors that are a classic symptom of the disease. Kúruitself means "trembling".[3] It is also known as the "laughing sickness" due to the pathologic bursts of laughter which are a symptom of the disease. It is now widely accepted that kuru was transmitted among members of the Fore tribe of Papua New Guinea via funerary cannibalism. Deceased family members were traditionally cooked and eaten, which was thought to help free the spirit of the dead.[4] Women and children usually consumed the brain, the organ in which infectious prions were most concentrated, thus allowing for transmission of kuru. The disease was therefore more prevalent among women and children. The epidemic likely started when a villager developed sporadic Creutzfeldt-Jakob disease and died. When villagers ate the brain, they contracted the disease, and it was then spread to other villagers who ate their infected brains.[5] While the Fore people stopped consuming human meat in the early 1960s, when it was first speculated to be transmitted via endocannibalism, the disease lingered due to kuru's long incubation period of anywhere from 10 to over 50 years.[6] The epidemic declined sharply after the tribe ended cannibalism, from 200 deaths per year in 1957 to no deaths from at least 2010 onwards, with sources disagreeing on whether the last known kuru victim died in 2005 or 2009

causes

Kuru is largely localized to the Fore people and people with whom they intermarried.[16] The Fore people ritualistically cooked and consumed body parts of their family members following their death to symbolize respect and mourning. Because the brain is the organ enriched in the infectious prion, women and children, who consumed brain and viscera, had much higher likelihood of being infected than men, who preferentially consumed muscles

Kuru is a neurodegenerative disorder

Kuru means 'to shake' in the Fore language. At it's height, between 1957 and 1968, over 1100 members of the South Fore, mostly women, died of kuru. At one point, there were hardly any women remaining in some Fore territories.

Lion and tiger parents want different things

Lions are social and live in small groups called prides. A lioness can mate with any number of male lions in the pride... and she can have a litter with cubs from multiple fathers! Because the cubs can have different fathers, there is an incentive for male lions to have the biggest offspring. He would want his cubs to do better than their littermates! On the other hand, the lioness is mother to all the cubs in the litter. She wants all her babies to have an equal chance at surviving! Ideally, she wants all the offspring to be medium size so that she will have a successful pregnancy and be able to care for the cubs once they are born. Tigers are different. Unlike lions, they are mostly solitary. Tigresses only mate with one male tiger at a time. All her cubs will have the same father. This means the reproductive goals of male and female tigers are the same. Both want all the cubs to have an equal chance at surviving, so there is no pressure on male tigers to have large offspring

mother / father

M - HETEROZYGOUS - ANGELMANS // maternal F-PWS- paternal

The origin of mitochondria and chloroplasts

Mitochondria and chloroplasts likely evolved from engulfed prokaryotes that once lived as independent organisms. At some point, a eukaryotic cell engulfed an aerobic prokaryote, which then formed an endosymbiotic relationship with the host eukaryote, gradually developing into a mitochondrion. Eukaryotic cells containing mitochondria then engulfed photosynthetic prokaryotes, which evolved to become specialized chloroplast organelles.There are currently two main, competing theories about the origin of mitochondria. They differ with regard to their assumptions concerning the nature of the host, the physiological capabilities of the mitochondrial endosymbiont, and the kinds of ecological interactions that led to physical association of the two partners at the onset of symbiosis. The traditional view posits that the host that acquired the mitochondrion was an anaerobic nucleus-bearing cell, a full-fledged eukaryote that was able to engulf the mitochondrion actively via phagocytosis (Figure 2). This view is linked to the ideas that the mitochondrial endosymbiont was an obligate aerobe, perhaps similar in physiology and lifestyle to modern Rickettsia species; and that the initial benefit of the symbiosis might have been the endosymbiont's ability to detoxify oxygen for the anaerobe host. Because this theory presumes the host to have been a eukaryote already, it does not directly account for the ubiquity of mitochondria. That is, it entails a corollary assumption (an add-on to the theory that brings it into agreement with available observations) that all descendants of the initial host lineage, except the one that acquired mitochondria, went extinct. The oxygen detoxification aspect is problematic, because the forms of oxygen that are toxic to anaerobes are reactive oxygen species (ROS) like the superoxide radical, O2-. In eukaryotes, ROS are produced in mitochondria because of the interaction of O2 with the mitochondrial electron transport chain. In that sense, mitochondria do not solve the ROS problem but rather create it; hence, protection from O2 is an unlikely symbiotic benefit. This traditional view also does not directly account for anaerobic mitochondria or hydrogenosomes, and additional corollaries must be tacked on to explain why anaerobically functioning mitochondria are found in so many different lineages and how they arose from oxygen-dependent forebears. An alternative theory posits that the host that acquired the mitochondrion was a prokaryote, an archaebacterium outright. This view is linked to the idea that the ancestral mitochondrion was a metabolically versatile, facultative anaerobe (able to live with or without oxygen), perhaps similar in physiology and lifestyle to modern Rhodobacteriales. The initial benefit of the symbiosis could have been the production of H2 by the endosymbiont as a source of energy and electrons for the archaebacterial host, which is posited to have been H2 dependent. This kind of physiological interaction (H2 transfer or anaerobic syntrophy) is commonly observed in modern microbial communities. The mechanism by which the endosymbiont came to reside within the host is unspecified in this view, but in some known examples in nature prokaryotes live as endosymbionts within other prokaryotes. In this view, various aerobic and anaerobic forms of mitochondria are seen as independent, lineage-specific ecological specializations, all stemming from a facultatively anaerobic ancestral state. Because it posits that eukaryotes evolved from the mitochondrial endosymbiosis in a prokaryotic host, this theory directly accounts for the ubiquity of mitochondria among all eukaryotic lineages. Eukaryotes are genetic chimeras. They possess genes that they inherited vertically from their archaebacterially related host. Genes for cytosolic ribosomes in eukaryotes, for example, reflect that origin. But eukaryotes also possess genes that they inherited vertically from the endosymbiont - for example, mitochondrially encoded genes for mitochondrial ribosomes. But even the largest mitochondrial genomes possess only about sixty protein-coding genes, while typical mitochondria harbor up to a thousand proteins or more that are encoded in the nucleus. During the course of mitochondrial genesis, many genes were transferred from the genome of the mitochondrial endosymbiont to the genome of the host. This kind of endosymbiotic gene transfer is nothing unusual; endosymbiosis very often entails gene transfers from the endosymbiont to the host. It happened during the origin of plastids too, and it is still ongoing in our own genome: Mitochondrial DNA constantly escapes from the organelle and becomes integrated as copies into nuclear DNA. The vast majority of mitochondrial proteins are encoded by nuclear genes, and many of these are endosymbiotic acquisitions from the mitochondrial ancestors

Mitochondrial Gene Therapy

Mitochondria are (perhaps) impossible to genetically-modify directly Strategies involve nuclear genes with mitochondrial targetting tags Mitochondrial disease is now thought to be the second most commonly diagnosed genetic disease worldwide, and, unfortunately, there are still no proven treatment strategies for those diagnosed. Scientists from the Max Planck Institute for Biology of Ageing in Cologne were involved in collaborations to apply gene-therapy approaches in mice to successfully treat an animal model of mitochondrial disease. This may pave the way for future therapeutic strategies for patients.Mitochondria play a central role in our metabolism and energy production. Consequently, mitochondrial dysfunction causes a remarkably diverse group of metabolic diseases with a broad range of symptoms leading to severe disability. "Since the 1980s it was known that mutations in the mitochondrial DNA can lead to disease" explains James Stewart, group leader at the Max Planck Institute for Biology of Ageing and continues "we have known of these patients for over 30 years and only now are we starting to develop treatments". A remarkable feature of mitochondria is that they contain their own DNA. Mutations in this mitochondrial DNA (mtDNA) can lead to mitochondrial diseases, but whether a person with a mutation develops disease or not is more complex. Many copies of mtDNA are present in each of our cells and, normally, disease-causing mutations are present in only a fraction of them. However, if the fraction of mutated mtDNA molecules rises above a certain threshold, mitochondrial function is compromised resulting in mitochondrial disease. Therefore, reducing the levels of mutated mtDNA molecules is a potential treatment strategy. However, this treatment strategy is not so straightforward as conventional gene-therapy approaches do not work in mtDNA. Scientists from the University of Cambridge, UK and the University of Miami, USA, developed an approach to specifically degrade mutated mtDNA molecules in cell culture. Using a modified virus, they delivered a gene into the cell nucleus that encodes a protein that works as molecular scissors. These molecular scissors are then produced by the cell and targeted to mitochondria, where they specifically cut the mutated mtDNA.They had generated a mouse model of mitochondrial disease that contains a specific disease-causing mutation in mtDNA which leads to disorders in cardiac and muscular tissue. They treated the animals with the virus that only infected the heart or the muscles. The virus delivered the molecular scissor to cut the mutated mtDNA in the targeted tissue. And in fact, the approach worked! The levels of mutated mtDNA were reduced and the disease symptoms were alleviated. "This is the first gene therapy to actually remove the cause of a mitochondrial disease in a living animal" a delighted Stewart tells us. Of course, before the therapy can be applied to human patients more detailed work and safety assessments must be done. Nevertheless, the scientists could prove that they found a way to remove the cause of these mitochondrial diseases. And since there is a link between mitochondrial dysfunction and other conditions like Alzheimer's disease, Parkinson's disease, diabetes, and perhaps some cancers, the approach will might even have a higher impact in fighting those disorders in the future.

genetic background

Mitochondria are the only cellular organelles known to have their own DNA (mitochondrial DNA or mtDNA), distinct from the nuclear DNA (nDNA). Genetic testing (mutation analysis) for mitochondrial diseases is complicated by the complexity of the mitochondrion and mitochondrial respiratory chain itself, encoded by both mtDNA and nDNA. All up it takes about 1,500 genes to make an entire mitochondrion, and mtDNA encodes just 37 of those genes, the rest is encoded by the nDNA. Less than 10% of these 1,500 genes are actually allocated for making ATP with the rest involved in the specialised duties of the differentiated cell. Defects in nDNA can be inherited from either parent and in a Mendelian pattern, (that is, one copy of each gene comes from each parent). Also, most are autosomal recessive. Due to a quirk in the process of fertilisation, defects in the genes of the mtDNA are only maternally inherited. That's because during conception, when the sperm fuses with the egg, the sperm's mitochondria, and its mtDNA, are destroyed. Each human cell contains thousands of copies of mtDNA which at birth are usually all identical and called homoplasmy. By contrast, individuals with mitochondrial disorders resulting from mtDNA mutations may harbour a mixture of mutant (dysfunctional) and wild-type (normal) mtDNA within each cell and this is called heteroplasmy. The proportion of mutant mtDNA must exceed a critical threshold level, 'the threshold effect', before a cell expresses a biochemical abnormality of the mitochondrial respiratory chain10. The percentage level of mutant mtDNA may vary among individuals within the same family, and also among organs and tissues within the same individual11. Simplistically, a child conceived from a 'mostly healthy' ovum probably won't develop the disease, and a child conceived from a 'mostly mutant' ovum probably will. Therefore, the way that mtDNA and nDNA mutations interact with each other and with the environment, can help determine if disease occurs. So the link between genotype and phenotype in mitochondrial diseases has and will always be recognised as complex

3: Models of Mitochondrial Disease

Mitochondrial hearing impairment mutations: Maternally inherited Affect mt protein synthesis

mitochondrial replacement therapy

Mitochondrial replacement therapy (MRT, sometimes called mitochondrial donation) is the replacement of mitochondria in one or more cells to prevent or ameliorate disease. MRT originated as a special form of in vitro fertilisation in which some or all of the future baby's mitochondrial DNAcomes from a third party. This technique is used in cases when mothers carry genes for mitochondrial diseases. The therapy is approved for use in the United Kingdom.[1][2] A second application is to use autologous mitochondria to replace mitochondria in damaged tissue to restore the tissue to a functional state. This has been used in clinical research in the United States to treat cardiac-compromised newborns In in vitro fertilization and involves removing eggs from a woman, removing sperm from a man, fertilizing the egg with the sperm, allowing the fertilized egg to form a blastocyst, and then implanting the blastocyst. MRT involves an additional egg from a third person, and manipulating both the recipient egg and the donor egg. As of 2016 there were three MRT techniques: maternal spindle transfer (MST), pronuclear transfer (PNT), and more recently as of that date, polar body transfer (PBT). The original technique, in which cytoplasm taken from a donor egg and containing mitochondria, is simply injected into the recipient egg, is no longer used.[1]:46-47 Diagram of the meiotic phases, showing how the chromosomes look in metaphase II In MST, an oocyte is removed from the recipient, and when it is in the metaphase II stage of cell division, the spindle-chromosome complex is removed; some of cytoplasm comes with it, so some mitochondria are likely included. The spindle-chromosome complex is inserted into a donor oocyte from which the nucleus has already been removed. This egg is fertilized with sperm, and allowed to form a blastocyst, which can then be investigated with preimplantation genetic diagnosis to check for mitochondrial mutations, prior to being implanted in the recipient's uterus.[1]:47-48 In pronuclear transfer, an oocyte is removed from the recipient, and fertilized with sperm. The donor oocyte is fertilized with sperm from the same person. The male and female pronuclei are removed from each fertilized egg prior to their fusing, and the pronuclei from the recipient's fertilized egg are inserted into the fertilized egg from the donor. As with MST, a small amount of cytoplasm from the donor egg may be transferred, and as with MST, the fertilized egg is allowed to form a blastocyst, which can then be investigated with preimplantation genetic diagnosis to check for mitochondrial mutations, prior to being implanted in the recipient's uterus.[1]:50 The process of fertilization in the ovum of a mouse, showing pronuclei. In polar body transfer, a polar body (a small cell with very little cytoplasm that is created when an egg cell divides) from the recipient is used in its entirety, instead of using nuclear material extracted from the recipient's normal egg; this can be used in either MST or PNT. This technique was first published in 2014 and as of 2015 it had not been consistently replicated, but is considered promising as there is a greatly reduced chance for transmitting mitochondria from the recipient because polar bodies contain very few mitochondria, and it does not involve extracting material from the recipient's egg

Mitochondrial Genome Evolution

Nuclear-encoded mitochondrial genes need several modifications to be functional. The human mitochondrial genome has only 13 coding genes. Nuclear- encoded genes account for 99% of proteins needed for mitochondrial morphology, redox regulation, and energetics. Mitochondrial diseases are chronic (long-term), genetic, often inherited disorders that occur when mitochondria fail to produce enough energy for the body to function properly. (Inherited means the disorder was passed on from parents to children.) Mitochondrial diseases can be present at birth, but can also occur at any age. Mitochondrial diseases can affect almost any part of the body, including the cells of the brain, nerves, muscles, kidneys, heart, liver, eyes, ears or pancreas. Mitochondrial dysfunction occurs when the mitochondria don't work as well as they should due to another disease or condition. Many conditions can lead to secondary mitochondrial dysfunction and affect other diseases, including Alzheimer's disease, muscular dystrophy, Lou Gehrig's disease, diabetes and cancer. Individuals with secondary mitochondrial dysfunction don't have primary genetic mitochondrial disease and don't need to be concerned about the ongoing development or worsening of symptoms.The key problems linked to mitochondrial disease are low energy, free radical production and lactic acidosis. This can result in a variety of symptoms in many different organs of the body. Most affected people have a specific subset of these common symptoms of mitochondrial disease. Many of these symptoms are very treatable.

What are other examples of imprinting?

One of the most well-studied cases of imprinting is in mice. Just like lions, female mice can have litters with pups from multiple fathers. Therefore, male mice want their offspring to be big, so that their pups survive best from the litter. Female mice want all their offspring to be of moderate size. The gene "Insulin-like growth factor 2", or Igf2, tells a developing embryo to grow. The version that is inherited from the father is underlined, telling the embryo to grow a lot. The version inherited from the mother is crossed out, telling the embryo not to grow too much. Therefore, only the Igf2 gene inherited from the father is active. The baby mouse still gets a version from both parents, but only the one from dad is turned "on". Imprinting does not change the DNA letters themselves. Instead, imprinting causes methylation. Methylation is a chemical change that adds a small molecule on top of the DNA sequence. This chemical change acts like a stop sign, and turns the gene off. Methylation near the Igf2 gene results in increased production of dad's version of the gene compared to mom's version.

eyeless mutant Drosophila

Pax6/eyeless is involved in the development of the eye and the brain of both invertebrates and vertebrates. In Drosophila melanogaster, the Pax6 homolog eyeless is initially expressed throughout the undifferentiated eye disc, where it persists until the cells differentiate with the progression of the morphogenetic furrow.eyeless is required for normal development of the Drosophila eye, as mutations in the eyeless gene result in irregular facets as well as in a reduction of eye size In the vertebrate eye, Pax6 is expressed in the optic vesicle/optic cup, lens and cornea and is required for normal development of each of these eye structures phenotype: no round eyes but a slit of eye instead hence, have difficulties seeing when kept as a homozygous stock for many generations eyeless mutant flies revert to wild type, but the underlying original mutation remains reason for that? flies with bigger eyes selected for, see better, higher fitness as they'll be able to get more food and mate more selecting for better sights, eyes grow bigger every generation, 25+ generations later with no different stock = phenotype reappears breaking up variations ( modifier genes ) you've selected for. When kept as a homozygous stock for many generations eyeless mutant flies 'revert' to wild-type, but the underlying original mutation remains

variable penetrance

Penetrance refers to the proportion of individuals with a certain allele of a gene that exhibits the phenotype of that gene. Complete penetrance is when any individual who has the allele will show the phenotype (or conditions) of that gene. Incomplete penetrance means the trait is expressed in only part of the population that has the allele. Penetrance refers to the probability of a gene or trait being expressed. In some cases, despite the presence of a dominant allele, a phenotype may not be present. One example of this is polydactyly in humans (extra fingers and/or toes). A dominant allele produces polydactyly in humans but not all humans with the allele display the extra digits. "Complete" penetrance means the gene or genes for a trait are expressed in all the population who have the genes. "Incomplete" or 'reduced' penetrance means the genetic trait is expressed in only part of the population. The penetrance of expression may also change in different age groups of a population. Reduced penetrance probably results from a combination of genetic, environmental, and lifestyle factors, many of which are unknown. This phenomenon can make it challenging for genetics professionals to interpret a person's family medical history and predict the risk of passing a genetic condition to future generations. some will show the mutant phenotype and some don't. all got the mutation but only some of them show the phenotype ( variation of other genes masks the phenotype ( YES/NO) 50/50 chance

Reduced penetrance

Penetrance refers to the proportion of people with a particular genetic change (such as a mutation in a specific gene) who exhibit signs and symptoms of a genetic disorder. If some people with the mutation do not develop features of the disorder, the condition is said to have reduced (or incomplete) penetrance. Reduced penetrance often occurs with familial cancer syndromes. For example, many people with a mutation in the BRCA1 or BRCA2 gene will develop cancer during their lifetime, but some people will not. Doctors cannot predict which people with these mutations will develop cancer or when the tumors will develop. Reduced penetrance probably results from a combination of genetic, environmental, and lifestyle factors, many of which are unknown. This phenomenon can make it challenging for genetics professionals to interpret a person's family medical history and predict the risk of passing a genetic condition to future generations.

PrPC

PrPC is a normal protein found on the membranes of cells. It has 209 amino acids (in humans), one disulfide bond, a molecular mass of 35-36 kDa and a mainly alpha-helical structure. Several topological forms exist; one cell surface form anchored via glycolipid and two transmembrane forms.[28] The normal protein is not sedimentable; meaning that it cannot be separated by centrifuging techniques.[29] Its function is a complex issue that continues to be investigated. PrPC binds copper (II) ions with high affinity.[30] The significance of this finding is not clear, but it is presumed to relate to PrP structure or function. PrPC is readily digested by proteinase K and can be liberated from the cell surface in vitro by the enzyme phosphoinositide phospholipase C (PI-PLC), which cleaves the glycophosphatidylinositol (GPI) glycolipid anchor.[31] PrP has been reported to play important roles in cell-cell adhesion and intracellular signaling in vivo, and may therefore be involved in cell-cell communication in the brain

prayer willi syndrome

Prader-Willi syndrome (PWS) is a genetic disorder caused by a loss of function of specific genes on chromosome 15.[3] In newborns, symptoms include weak muscles, poor feeding, and slow development.[3] Beginning in childhood, those affected become constantly hungry, which often leads to obesity and type 2 diabetes.[3] Mild to moderate intellectual impairment and behavioral problems are also typical of the disorder.[3] Often, affected individuals have a narrow forehead, small hands and feet, short height, light skin and hair, and are unable to have children.[3] About 74% of cases occur when part of the father's chromosome 15 is deleted.[3] In another 25% of cases, the affected person has two copiesof chromosome 15 from their mother and none from their father.[3] As parts of the chromosome from the mother are turned off through imprinting, they end up with no working copies of certain genes.[3] PWS is not generally inherited, but rather the genetic changes happen during the formation of the egg, sperm, or in early development.[3] No risk factors are known for the disorder.[7] Those who have one child with PWS have less than a 1% chance of the next child being affected.[7] A similar mechanism occurs in Angelman syndrome, except the defective chromosome 15 is from the mother, or two copies are from the father.[8][9] Prader-Willi syndrome has no cure.[4] Treatment may improve outcomes, especially if carried out early.[4] In newborns, feeding difficulties may be supported with feeding tubes.[6] Strict food supervision is typically required, starting around the age of three, in combination with an exercise program.[6] Growth hormone therapy also improves outcomes.[6] Counseling and medications may help with some behavioral problems.[6]Group homes are often necessary in adulthood.[6] PWS affects between 1 in 10,000 and 1 in 30,000 people.[3] The condition is named after Swiss physicians Andrea Prader and Heinrich Williwho, together with Alexis Labhart, described it in detail in 1956.[1] An earlier description was made in 1887 by British physician John Langdon Down WS is caused by an epigenetic phenomenon known as imprinting, caused by the deletion of the paternal copies of the SNRPN and NDN necdin genes along with clusters of snoRNAs: SNORD64, SNORD107, SNORD108 and two copies of SNORD109, 29 copies of SNORD116 (HBII-85) and 48 copies of SNORD115 (HBII-52). These are on chromosome 15 located in the region 15q11-13.[26][27][28][29] This so-called PWS/AS region may be lost by one of several genetic mechanisms, which in the majority of instances occurs through chance mutation. Other, less common mechanisms include uniparental disomy, sporadic mutations, chromosome translocations, and gene deletions. Due to imprinting, the maternally inherited copies of these genes are virtually silent, and only the paternal copies of the genes are expressed.[30][31] PWS results from the loss of paternal copies of this region. Deletion of the same region on the maternal chromosome causes Angelman syndrome (AS). PWS and AS represent the first reported instances of imprinting disorders in humans. The risk to the sibling of an affected child of having PWS depends upon the genetic mechanism which caused the disorder. The risk to siblings is <1% if the affected child has a gene deletion or uniparental disomy, up to 50% if the affected child has a mutation of the imprinting control region, and up to 25% if a parental chromosomal translocation is present. Prenatal testing is possible for any of the known genetic mechanisms. A microdeletion in one family of the snoRNA HBII-52 has excluded it from playing a major role in the disease.[32] Studies of human and mouse model systems have shown deletion of the 29 copies of the C/D box snoRNA SNORD116 (HBII-85) to be the primary cause of PWS First described by Andrea Prader and Heinrich Willi in Switzerland in1956. Associated with 15q11- q13 deletion Symptoms:Low muscle tone, short stature, incomplete sexual development, cognitive disabilities, problem behaviors, and a chronic feeling of hunger that can lead to excessive eating and life-threatening obesity

function of prion

Prion Protein has a neuroprotective function It may act as part of a signalling cascade that promotes normal neuronal function

Kuru

Prion disease suffered by the Fore due to consuming humans through cannibalism specifically by consuming the brains/nervous system of the dead. Symptoms include insomnia, lack of coordination/balance, eventually death. Kuru is a very rare disease. It is caused by an infectious protein (prion) found in contaminated human brain tissue. Kuru is found among people from New Guinea who practiced a form of cannibalism in which they ate the brains of dead people as part of a funeral ritual. This practice stopped in 1960, but cases of kuru were reported for many years afterward because the disease has a long incubation period. The incubation period is the time it takes for symptoms to appear after being exposed to the agent that causes disease. Kuru causes brain and nervous system changes similar to Creutzfeldt-Jakob disease. Similar diseases appear in cows as bovine spongiform encephalopathy (BSE), also called mad cow disease. The main risk factor for kuru is eating human brain tissue, which can contain the infectious particles

PrPres

Protease-resistant PrPSc-like protein (PrPres) is the name given to any isoform of PrPc which is structurally altered and converted into a misfolded proteinase K-resistant form in vitro.[33] To model conversion of PrPC to PrPSc in vitro, Saborio et al. rapidly converted PrPC into a PrPres by a procedure involving cyclic amplification of protein misfolding.[34] The term "PrPres" has been used to distinguish between PrPSc, which is isolated from infectious tissue and associated with the transmissible spongiform encephalopathy agent.[35] For example, unlike PrPSc, PrPres may not necessarily be infectious.

mitochondrial

Schematic representation of variable mitochondrial DNA heteroplasmy transmission in mitochondrial disease. Mitochondrial DNA (mtDNA) transmission to offspring occurs through the maternal germline. A mixture of wild-type (healthy) and mutant mtDNA genomes may be present among the more than 100,000 mitochondrial copies within an oocyte. The bottleneck that occurs in the early embryo effectively reduces the total number of mitochondria to several hundred copies and the total mtDNA quantity to several thousand copies. Through this process, the percentage of mutant to wild-type mtDNA (heteroplasmy level) in the cells of the early embryo that emerges from the bottleneck may vary substantially from that in either the oocyte or the mother's somatic cells. As fetal development progresses, stochastic variation may lead to widely different mutant heteroplasmy levels within different organs of the same individual. The higher the mutation heteroplasmy level in given organ(s), the more likely the resulting child will develop a severe and early onset clinical phenotype. These factors underlie both the wide phenotypic variability characteristic of mtDNA diseases, as well as the complex recurrence risk for future children of mothers who carry pathogenic mtDNA mutations

material inheritance

Some of the traits inherited by the offspring can be solely attributed to the genetic material transmitted by the mother to her offspring. It is because during the union of gametes the ovum retains its mitochondria. Mitochondria are organelles that contain their own set of genes. It is a popular notion that most of the mitochondria acquired by the offspring are of maternal origin. When a sperm fertilizes an ovum, only its nuclear genetic material contained within the head is allowed to combine with that of the ovum while its midpiece and tail (with comparatively fewer mitochondria) are lost or disintegrated. Hence, hereditary diseases associated with faulty mitochondrial DNA are said to be inherited solely from the mother. These traits are also described as maternal effects. However, recent studies indicate that paternal mitochondrial DNA somehow gets into the ovum and thus a faulty paternal mitochondrial DNA can also be passed on to the offspring, debunking the precept that mitochondrial DNA (and therefore mitochondrial diseases) are solely maternal in origin. Synonym: matroclinous inheritance.

Three types of CJD

Sporadic (sCJD): random Variant (vCJD): acquired Familial (fCJD): inherited

Prion replication

The first hypothesis that tried to explain how prions replicate in a protein-only manner was the heterodimer model.[46] This model assumed that a single PrPScmolecule binds to a single PrPC molecule and catalyzes its conversion into PrPSc. The two PrPSc molecules then come apart and can go on to convert more PrPC. However, a model of prion replication must explain both how prions propagate, and why their spontaneous appearance is so rare. Manfred Eigenshowed that the heterodimer model requires PrPSc to be an extraordinarily effective catalyst, increasing the rate of the conversion reaction by a factor of around 1015.[47] This problem does not arise if PrPSc exists only in aggregated forms such as amyloid, where cooperativity may act as a barrier to spontaneous conversion. What is more, despite considerable effort, infectious monomeric PrPSc has never been isolated. An alternative model assumes that PrPSc exists only as fibrils, and that fibril ends bind PrPC and convert it into PrPSc. If this were all, then the quantity of prions would increase linearly, forming ever longer fibrils. But exponential growth of both PrPSc and of the quantity of infectious particles is observed during prion disease.[48][49][50] This can be explained by taking into account fibril breakage.[51]A mathematical solution for the exponential growth rate resulting from the combination of fibril growth and fibril breakage has been found.[52] The exponential growth rate depends largely on the square root of the PrPCconcentration.[52] The incubation period is determined by the exponential growth rate, and in vivo data on prion diseases in transgenic mice match this prediction.[52] The same square root dependence is also seen in vitro in experiments with a variety of different amyloid proteins.[53] The mechanism of prion replication has implications for designing drugs. Since the incubation period of prion diseases is so long, an effective drug does not need to eliminate all prions, but simply needs to slow down the rate of exponential growth. Models predict that the most effective way to achieve this, using a drug with the lowest possible dose, is to find a drug that binds to fibril ends and blocks them from growing any further.[54] Researchers at Dartmouth College discovered that endogenous host cofactor molecules such as the phospholipid molecule (e.g phosphaditylethanolamine) and polyanions (e.g. single stranded RNA molecules) are necessary to form PrPSc molecules with high levels of specific infectivity in vitro, whereas protein-only PrPSc molecules appear to lack significant levels of biological infectivity

PrPSc

The infectious isoform of PrP, known as PrPSc, or simply the prion, is able to convert normal PrPC proteins into the infectious isoform by changing their conformation, or shape; this, in turn, alters the way the proteins interconnect. PrPSc always causes prion disease. Although the exact 3D structure of PrPSc is not known, it has a higher proportion of β-sheet structure in place of the normal α-helix structure.[36] Aggregations of these abnormal isoforms form highly structured amyloid fibers, which accumulate to form plaques. The end of each fiber acts as a template onto which free protein molecules may attach, allowing the fiber to grow. Under most circumstances, only PrP molecules with an identical amino acid sequence to the infectious PrPSc are incorporated into the growing fiber.[29] However, rare cross-species transmission is also possible

Lions are big. Tigers are bigger. Lion-tiger hybrids are biggest. Why?

The liger, a lion-tiger hybrid is bigger than both lions and tigers. How is this possible? It turns out that it's not just your genes that matters, but who you got them from! Ligers are the offspring of a female tiger and a male lion. They are the biggest of all the big cats. Tigons are the opposite. They are the offspring of a female lion and a male tiger, and are about the same size as the average lion. If ligers and tigons are both lion/tiger hybrids, why are they different sizes? Scientists have not yet done complete genetic analyses of lion/tiger hybrids, so we don't know the exact answer. Currently, the prevailing explanation for this difference in size is due to a phenomenon called imprinting. Imprinting is a process where the DNA in sperm and eggs are modified even before fertilization. This can switch parts of the DNA "on" and other parts "off". Lions and tigers imprint their DNA differently. These differences have most likely evolved due to their different lifestyles and reproductive habits

When and How Often Did Mitochondria Arise?

The oldest undisputedly eukaryotic microfossils go back 1.45 billion years in the fossil record. Given the coincidence of mitochondria with the eukaryotic state, this can also be seen as a minimum age for mitochondria and a rough best-guess starting date for eukaryotic evolution. According to newer geochemical views, this date of origin corresponds to a protracted phase in Earth history when the oceans were mostly anoxic — from 1.8 billion years ago until about 580 million years ago — because of the workings of marine, H2S-producing bacteria. Eukaryotes thus arose and diversified in an environment where anoxia was commonplace. Accordingly it is hardly surprising that many independent eukaryotic lineages have preserved anaerobic energy-producing pathways in their mitochondria (Figure 3). Like eukaryotes themselves, mitochondria appear to have arisen only once in all of evolution. The best evidence for the single origin of mitochondria comes from a conserved set of clearly homologous and commonly inherited genes preserved in the mitochondrial DNA across all known eukaryotic groups. In the case of hydrogenosomes (which usually lack DNA) and mitosomes (which so far always lack DNA), the strongest evidence for their common ancestry with mitochondria is twofold. First, aspects and components of the mitochondrial protein import process are conserved in hydrogenosomes and mitosomes, arguing strongly for common ancestry with mitochondria. Second, all known lineages of eukaryotes that possess hydrogenosomes or mitosomes branch as sisters to mitochondrion-bearing lineages.

Pathogenesis

The pathogenesis of BSE is not well understood or documented like other diseases of this nature. Even though BSE is a disease that results in neurological defects, its pathogenesis occurs in areas that reside outside of the nervous system.[20]There was a strong deposition of PrPSc initially located in the Ileal Peyer's patches of the small intestine.[21] The lymphatic system has been identified in the pathogenesis of scrapie. It has not, however, been determined to be an essential part of the pathogenesis of BSE. The Ileal Peyer's patches have been the only organ from this system that has been found to play a major role in the pathogenesis.[20] Infectivity of the Ileal Peyer's patches has been observed as early as 4 months after inoculation.[21] PrPSc accumulation was found to occur mostly in tangible body macrophages of the Ileal Peyer's patches. Tangible body macrophages involved in PrPSc clearance are thought to play a role in PrPSc accumulation in the Peyer's patches. Accumulation of PrPSc was also found in follicular dendritic cells; however, it was of a lesser degree.Six months after inoculation, there was no infectivity in any tissues, only that of the ileum. This led researchers to believe that the disease agent replicates here. In naturally confirmed cases, there have been no reports of infectivity in the Ileal Peyer's patches. Generally, in clinical experiments, high doses of the disease are administered. In natural cases, it was hypothesized that low doses of the agent were present, and therefore, infectivity could not be observed.

Normal function PrP

The physiological function of the prion protein remains poorly understood. While data from in vitro experiments suggest many dissimilar roles, studies on PrP knockout mice have provided only limited information because these animals exhibit only minor abnormalities. In research done in mice, it was found that the cleavage of PrP proteins in peripheral nerves causes the activation of myelin repair in Schwann cells and that the lack of PrP proteins caused demyelination in those cells

prions

The protein that prions are made of (PrP) is found throughout the body, even in healthy people and animals. However, PrP found in infectious material has a different structure and is resistant to proteases, the enzymes in the body that can normally break down proteins. The normal form of the protein is called PrPC, while the infectious form is called PrPSc - the C refers to 'cellular' PrP, while the Sc refers to 'scrapie', the prototypic prion disease, occurring in sheep.[27] While PrPC is structurally well-defined, PrPSc is certainly polydisperse and defined at a relatively poor level. PrP can be induced to fold into other more-or-less well-defined isoforms in vitro, and their relationship to the form(s) that are pathogenic in vivo is not yet clear.

heteroplasmy and forensics

The specific genetic markers and procedures employed for DNA testing of specimens in forensics currently depend primarily upon the quality and quantity of DNA present, and additionally on the known samples available for comparison. Though not a unique identifier, mitochondrial DNA (mtDNA) has long offered advantages for certain forensic genetic analyses. MtDNA is abundant relative to nuclear DNA in most human cells, with each cell containing hundreds to thousands of copies of the mitochondrial genome (mtGenome) [1]. For aged specimens in which the DNA may be highly fragmented and damaged [2,3], the high copy number of the mtGenome often means that mtDNA data can be reliably generated even when attempts to type nuclear DNA markers fail to produce a profile. MtDNA is also generally present in abundance in samples that may contain little or no intact nuclear DNA, such as hair shafts [4] and aged fingernails [5]. As a result, mtDNA has been the historical marker of choice for these sample types [6-10]. Additional benefits of mtDNA in forensic casework relate to the inheritance of the molecule, which permits the use of maternal relatives as references for unknown samples

Drosophila technical knockout Model

The tko L85H mutation: Alters mitoribosome S12 protein shape Affects efficiency of ribosome assembly A point mutation in the Drosophila gene technical knockout (tko), encoding mitoribosomal protein S12, was previously shown to cause a phenotype of respiratory chain deficiency, developmental delay, and neurological abnormalities similar to those presented in many human mitochondrial disorders, as well as defective courtship behavior. The gene name in Drosophila reflects the so-called bang-sensitive phenotype of the canonical allele, tko25t, which suffers paralytic seizures induced by mechanical stress, This phenotype is shared with other mutants affecting mitochondrial bioenergy supply, e.g. in genes such as sesB, the adenine nucleotide translocase [16], or knockdown, citrate synthase [17]. Null alleles of tko are larval-lethal, but the tko25t phenotype is relatively mild, and thus constitutes an animal model for mitochondrial disorders. In addition to seizure sensitivity, tko25t exhibits delayed larval development, antibiotic sensitivity, hearing impairment, locomotor hyporeactivity, and defective courtship [18]. It carries a point mutation, L85H, at a conserved amino acid of mRpS12, which leads to the destabilization or defective assembly of the small mitoribosomal subunit [14], [18]. The resulting insufficiency of mitochondrial translational capacity entrains a substantially reduced activity of the major OXPHOS complexes to which the mtDNA-encoded polypeptides contribute, both in larvae and in adults, which is believed to underlie the developmental and behavioural phenotype [18], [19]. All aspects of the mutant phenotype are restored to wild-type by expression of a transgenic copy of the wild-type tko gene under the control of its natural promoter [18]. The severity of the tko25t phenotype varies according to nuclear background [18] and gene dosage [20], indicating that compensatory mechanisms can partially alleviate the effects of this stress.

Genetic Basis of Kuru Resistance

Why are there survivors? Mead and colleagues collected DNA samples from archival samples plus patients with Kuru and people from exposed and unexposed villages. Each person was assigned an 'exposure-index'. Two missense SNPs were found almost exclusively in exposed survivors: G127V and M129V M129V probably arose 200 years ago (10 generations ago) in Waisa

Spread of Kuru via Cannibalism

Why does Kuru primarily affect women and children? Kuru is spread through the consumption of infected brains. It spread its way through the Fore tribe, killing at least 2500 members in the twentieth century until its cause was discovered in the 1960s, and the brain-eating practice was finally abandoned. Kuru was first described in official reports by Australian officers patrolling the Eastern Highlands of Papua New Guinea in the early 1950s.[28] Some unofficial accounts place kuru in the region as early as 1910.[7] In 1951, Arthur Carey was the first to use the term 'kuru' in a report to describe a new disease afflicting the Fore tribes of Papua New Guinea. In his report, Carey noted that kuru mostly afflicted Fore women, eventually killing them. Kuru was noted in the Fore, Yate and Usurufa people in 1952-1953 by anthropologists Ronald Berndt and Catherine Berndt. [7] In 1953, kuru was observed by patrol officer John McArthur who provided a description of the disease in his report. McArthur believed that kuru was merely a psychosomatic episode resulting from the sorcery practices of the tribal people in the region.[28]After the disease had festered into a bigger epidemic the tribal people asked Charles Pfarr, a Lutheran Medical Officer to come to the area to report the disease to Australian authorities.[7] Initially, the Fore people believed the causes of kuru to be sorcery or witchcraft.[29] The Fore people also thought that the magic causing kuru was contagious. It was also called negi-nagi, which meant foolish person as the victims laughed at spontaneous intervals.[30] This disease, the Fore people believed, was caused by ghosts because of the shaking and strange behaviour that comes with kuru. Attempting to cure this, they would feed victims pork and casuarinas bark. When the Kuru disease had become an epidemic, Daniel Carleton Gajdusek, a virologist, and Vincent Zigas, a medical doctor, started research on the disease. In 1957, Zigas and Gajdusek published a report in the Medical Journal of Australia that suggested that Kuru had a genetic origin, and that "any ethnic-environmental variables that are operating in kuru pathogenesis have not yet been determined." [31] Cannibalism was suspected as a possible cause from the very beginning but wasn't formally put forth as a theory until 1967 by Glasse and more formally in 1968 by Mathews, Glasse, & Lindenbaum. [30] Even before cannibalism had been linked to kuru, it was banned by the Australian administration, and the practice was nearly eliminated by 1960. While the number of cases of kuru was decreasing, those in medical research were able to properly investigate kuru, which eventually led to the modern understanding of prions as the cause.[32] In an effort to understand the pathology of Kuru disease, Gajdusek established the first experimental tests on chimpanzees for Kuru at the National Institutes of Health (NIH). The method of the experiments was to introduce kuru brain material to the closest human relative, the chimpanzee, and to document the behaviors of the animal until death or a negative outcome occurred.[7] Michael Alpers, an Australian doctor, collaborated with Gajdusek by providing samples of brain tissues he had taken from an 11-year-old Fore girl who had died of Kuru. In his work, Gajdusek was also the first to compile a bibliography of the Kuru disease.[33][citation needed] Joe Gibbs joined Gajdusek to monitor and record the behavior of the apes and conduct autopsies. Within two years, one of the chimps, Daisy, had developed kuru, demonstrating that an unknown disease factor was transmitted through infected biomaterial and that it was capable of crossing the species barrier to other primates. After Elisabeth Beck confirmed that this experiment brought about the first conducted transmission of Kuru, the finding was deemed a very important advancement in human medicine leading to the award of the Nobel Prize in Physiology or Medicine to Daniel Carleton Gajdusek in 1976.[7] Subsequently, E. J. Field spent large parts of the late 1960s and early 1970s in New Guinea investigating the disease,[34] connecting it to scrapie and multiple sclerosis.[35] He noted similarities in the diseases interactions with glial cells, including the critical observation that the infectious process may depend on structural rearrangement of the host's molecules.[36] This was an early observation of what was to later become the prion hypothesis

why yellow mutant female Drosophila are highly receptive

Yellow mutant females of Drosophila melanogaster are more receptive to yellow males than are wild-type females. By chromosomal substitution, this enhanced receptivity has been localized to the X chromosome. Repeated backcrossing between a yellow and wild-type inbred line, with the yellow locus maintained segregating, allows the conclusion that the yellow locus itself is responsible for the enhanced female receptivity yellow femalesare more receptive than wild-type females to yellow males and that this enhancemenot f receptivityhas beenselectedin the yellow stock to counter the deficient courtship of yellow males. As the advantages-of sex-linked courtship behaviour and/or complementary effects in the sexes are not restricted to song characteristicsi,t is of interest to examine the basis of the receptivity of yellow females to yellow males

How do Prions cause infection

defective protein causes normal protein to take on abnormal shape, causing it to lose normal function

using balancer chromosomes

differ for pretty small region around yellow mutation but rest is exactly the same - WT Male x WT female = 70% mating frequency - Yellow Male x WT female = 30 % - WT male x Yellow Female = 75 % - Yellow Male x Yellow female = 35 % yellow female mate more frequently cut they have adapted to unsuccessful yellow males

evolution of mitochondria

endosymbiosis - came into eukarytoic from preeukaryotic surronded anarobic prokaryotic bacteria mitochondria has 2 membranes 1. prokaryotic cell 2. host eukaroytic cell - dependent on the host cell to provide proteins for its function and the host cell depends on it to supply the energy How did a situation evolve in which an organelle contains genetic information for some of its functions, while others are coded in the nucleus? Figure 3.41 shows the endosymbiosis model for mitochondrial evolution, in which primitive cells captured bacteria that provided the functions that evolved into mitochondria and chloroplasts. At this point, the proto-organelle must have contained all of the genes needed to specify its functions.Sequence homologies suggest that mitochondria and chloroplasts evolved separately, from lineages that are common with eubacteria, with mitochondria sharing an origin with a-purple bacteria, and chloroplasts sharing an origin with cyanobacteria. The closest known relative of mitochondria among the bacteria is Rickettsia (the causative agent of typhus), which is an obligate intracellular parasite that is probably descended from free-living bacteria. This reinforces the idea that mitochondria originated in an endosymbiotic event involving an ancestor that is also common to Rickettsia (for review see 981). .. Two changes must have occurred as the bacterium became integrated into the recipient cell and evolved into the mitochondrion (or chloroplast). The organelles have far fewer genes than an independent bacterium, and have lost many of the gene functions that are necessary for independent life (such as metabolic pathways). And since the majority of genes coding for organelle functions are in fact now located in the nucleus, these genes must have been transferred there from the organelle. .. Transfer of DNA between organelle and nucleus has occurred over evolutionary time periods, and still continues. The rate of transfer can be measured directly by introducing into an organelle a gene that can function only in the nucleus, for example, because it contains a nuclear intron, or because the protein must function in the cytosol. In terms of providing the material for evolution, the transfer rates from organelle to nucleus are roughly equivalent to the rate of single gene mutation. DNA introduced into mitochondria is transferred to the nucleus at a rate of 2 × 10-5 per generation. Experiments to measure transfer in the reverse direction, from nucleus to mitochondrion, suggest that it is much lower, <10-10 (3691). When a nuclear-specific antibiotic resistance gene is introduced into chloroplasts, its transfer to the nucleus and successful expression can be followed by screening seedlings for resistance to the antibiotic. This shows that transfer occurs at a rate of 1 in 16,000 seedlings, or 6 × 10-5 (3690). .. Transfer of a gene from an organelle to the nucleus requires physical movement of the DNA, of course, but successful expression also requires changes in the coding sequence. Organelle proteins that are coded by nuclear genes have special sequences that allow them to be imported into the organelle after they have been synthesized in the cytoplasm (see Posttranslational membrane insertion depends on leader sequences). These sequences are not required by proteins that are synthesized within the organelle. Perhaps the process of effective gene transfer occurred at a period when compartments were less rigidly defined, so that it was easier both for the DNA to be relocated, and for the proteins to be incorporated into the organelle irrespective of the site of synthesis. .. Phylogenetic maps show that gene transfers have occurred independently in many different lineages. It appears that transfers of mitochondrial genes to the nucleus occurred only early in animal cell evolution, but it is possible that the process is still continuing in plant cells (1399). The number of transfers can be large; there are >800 nuclear genes in Arabidopsis whose sequences are related to genes in the chloroplasts of other plants (1403). These genes are candidates for evolution from genes that originated in the chloroplast

technical knockout (tko) drosophila

genetic background is defined as the genotype of all other related genes that may interact with gene of interest and therefore influence specific phenotype // can also affect more subtle behaviours. tko mutants were originally isolated in a screen for bang-sensitive mutations tko encodes a mitroribosomal unit s12 tko is a model of human mitochondrial disease if you take a tube of flies and you vortex them they normally get very angry however with tko mutants they have a seizure and fall over. mutation on X chromosome vortex 30 seconds - WT flies angry - Angry vortex 30 seconds- tko mutants - still and fall over leave for 5 mins and they will recover, have mutation , no phenotype ( subtle behaviour ) , out cross to WT, phenotype re appeared if you keep homozygous flies together for many generations and you get selection against phenotype that's why you'd want to keep them as heterozygotes to avoid that problem. cross heterozygotes together- get mutant phenotypes in F1 can identify genes that suppress the phenotype lots of genes can interact with genes you're working with if you are doing an experiment and you don't use the appropriate controls, you can get complications The Drosophila mutant technical knockout (tko), affecting the mitochondrial proteinsynthetic apparatus, exhibits respiratory chain deficiency and a phenotype resembling various features of mitochondrial disease in humans (paralytic seizures, deafness, developmental retardation). We initially characterized the phenotype of the tko mutant in further detail, having confirmed that it carries a point mutation (L85H) in the gene for mitoribosomal protein S12, which converts a phylogenetically conserved leucine residue to histidine [14]. Genetic background can also affect more subtle behaviours:- tko mutants were originally isolated in a screen for bang-sensitive mutations tko encodes a mitoribosomal subunit S12tko is a model of human mitochondrial disease However, when we first received the strain....

Use Appropriate Controls

if you think you've got a strain that shows a phenotype with an insertion ( p element), to prove a mutation is caused by a transposon, jump the transposon out the strain should revert to WT. when indy mutation was out-crossed and ' mutants' treated with tetracycline, the longevity phenotype disappeared mothers have an infection, pass through cytoplasm the longevity phenotype is linked to intracellular wolbachia infection ( bacteria) To prove a mutation is caused by a transposon, jump the transposon out.

variable expressivity

individuals with the same genotype have related phenotypes that vary in intensity amount of severity of the phenotype behaviour masked someway, selected against some aspect of phenotype. everyones got the mutation but severity can be from no effect to very severe. GRADIENT Expressivity on the other hand refers to variation in phenotypic expression when an allele is penetrant. Back to the polydactyly example, an extra digit may occur on one or more appendages. The digit can be full size or just a stub. Hence, this allele has reduced penetrance as well as variable expressivity. Variable expressivity refers to the range of signs and symptoms that can occur in different people with the same genetic condition. As with reduced penetrance, variable expressivity is probably caused by a combination of genetic, environmental, and lifestyle factors, most of which have not been identified. If a genetic condition has highly variable signs and symptoms, it may be challenging to diagnose.

Prions

infectious protein particles that do not have a genome A prion is a type of protein that can trigger normal proteins in the brain to fold abnormally. Prion diseases can affect both humans and animals and are sometimes spread to humans by infected meat products. The most common form of prion disease that affects humans is Creutzfeldt-Jakob disease (CJD).

Mummy Tiger + Daddy Lion = Liger

largest of all big cats Their size is due to the failure of imprinting controlling the growth hormone gene. In a developing pure lion foetus, the father's growth hormone gene is silenced by genes from the mother The liger is a hybrid offspring of a male lion (Panthera leo) and a female tiger (Panthera tigris). The liger has parents in the same genus but of different species. The liger is distinct from the similar hybrid called the tigon, and is the largest of all known extant felines.[1][2] They enjoy swimming, which is a characteristic of tigers, and are very sociable like lions. Notably, ligers typically grow larger than either parent species, unlike tigons The liger is often believed to represent the largest known cat in the world.[1] Males reach a total length of 3 to 3.6 m (9.8 to 11.8 ft),[7][8] which means that they rival even large male lions and tigers in length.[9] Imprinted genes may be a factor contributing to the large size of ligers.[10] These are genes that may or may not be expressed on the parent they are inherited from, and that occasionally play a role in issues of hybrid growth. For example, in some dog breed crosses, genes that are expressed only when maternally-inherited cause the young to grow larger than is typical for either parent breed. This growth is not seen in the paternal breeds, as such genes are normally "counteracted" by genes inherited from the female of the appropriate breed

lecture 2 - mitochondria

mitochondria are essential energy-producing organelles - own DNA - consequence of gene function disease

Romanov mtDNA History

mtDNA samples were taken from the bodies and the D- loop sequenced. The D-loop sequence matches that of their surviving maternal relative Prince Philip, Duke of Edinburgh The specific genetic markers and procedures employed for DNA testing of specimens in forensics currently depend primarily upon the quality and quantity of DNA present, and additionally on the known samples available for comparison. Though not a unique identifier, mitochondrial DNA (mtDNA) has long offered advantages for certain forensic genetic analyses. MtDNA is abundant relative to nuclear DNA in most human cells, with each cell containing hundreds to thousands of copies of the mitochondrial genome (mtGenome) [1]. For aged specimens in which the DNA may be highly fragmented and damaged [2,3], the high copy number of the mtGenome often means that mtDNA data can be reliably generated even when attempts to type nuclear DNA markers fail to produce a profile. MtDNA is also generally present in abundance in samples that may contain little or no intact nuclear DNA, such as hair shafts [4] and aged fingernails [5]. As a result, mtDNA has been the historical marker of choice for these sample types [6-10]. Additional benefits of mtDNA in forensic casework relate to the inheritance of the molecule, which permits the use of maternal relatives as references for unknown samples mtDNA samples were taken from the bodies and the D- loop sequenced. The D-loop sequence matches that of their surviving maternal relative Prince Philip, Duke of Edinburgh.

imprinting

the process by which certain animals form attachments during a critical period very early in life Genomic imprinting is an epigenetic phenomenon that causes genes to be expressed in a parent-of-origin-specific manner.[1][2][3][4][5] Genes however, can also be partially imprinted. Partial imprinting happens when alleles from both parents are differently expressed rather than complete expression and complete suppression of one parents allele.[6] Forms of genomic imprinting have been demonstrated in fungi, plants and animals.[7][8] As of 2014, there are about 150 imprinted genes known in the mouse and about half that in humans.[9] In 2019, 260 imprinted genes have been reported in mice and 228 in humans.[10] Genomic imprinting is an inheritance process independent of the classical Mendelian inheritance. It is an epigenetic process that involves DNA methylation and histone methylation without altering the genetic sequence. These epigenetic marks are established ("imprinted") in the germline (sperm or egg cells) of the parents and are maintained through mitotic cell divisions in the somatic cellsof an organism.[11] Appropriate imprinting of certain genes is important for normal development. Human diseases involving genomic imprinting include Angelman syndrome, Prader-Willi syndrome and male infertility. Imprinting is a dynamic process. It must be possible to erase and re-establish imprints through each generation so that genes that are imprinted in an adult may still be expressed in that adult's offspring. (For example, the maternal genes that control insulin production will be imprinted in a male but will be expressed in any of the male's offspring that inherit these genes.) The nature of imprinting must therefore be epigenetic rather than DNA sequence dependent. In germline cells the imprint is erased and then re-established according to the sex of the individual, i.e. in the developing sperm (during spermatogenesis), a paternal imprint is established, whereas in developing oocytes (oogenesis), a maternal imprint is established. This process of erasure and reprogramming[42] is necessary such that the germ cell imprinting status is relevant to the sex of the individual. In both plants and mammals there are two major mechanisms that are involved in establishing the imprint; these are DNA methylation and histone modifications. Recently, a new study[14] has suggested a novel inheritable imprinting mechanism in humans that would be specific of placental tissue and that is independent of DNA methylation (the main and classical mechanism for genomic imprinting). This was observed in humans, but not in mice, suggesting development after the evolutionary divergence of humans and mice, ~80 Mya. Among the hypothetical explanations for this novel phenomenon, two possible mechanisms have been proposed: either a histone modification that confers imprinting at novel placental-specific imprinted locior, alternatively, a recruitment of DNMTs to these loci by a specific and unknown transcription factor that would be expressed during early trophoblast differentiation. Imprinting is caused by DNA MethylationMust occur before fertilisationCauses transcriptional silencingStably transmitted in somatic cellsReversible when passing through opposite parental germline

Gene Expression Complexity

variation at other genes influences expression at a specific gene geneticists exploits those in modifier screens and suppressor screens damaging one gene almost doubled the flys lifespan following p element ( transposon ) mutagenesis, flies with inherited extended life span were identified indy encodes a na+ di carboxylate transporter gene one mutant phenotype - lived 20 yrs longer ( 1 transposon inside 0 Variation at other genes influences expression at a specific gene Geneticists exploit these in modifier screens and suppressor screens