Genetics 2nd Block
Multifactorial disorders (Polygenic) Its most common and prevalent diseases. ____________________ influences act on a genetic predisposition to produce a liability to a disease. Influence of multiple genes + environmental factors. How many organ systems are affected? Person affected if liability above a threshold.
"Environmental" one
Nondisjunction Nondisjunction during meiosis can produce gametes with an extra or missing chromosome, or Aneuploidy. Homologous chromosomes may fail to separate during meiosis I or Sister chromatids may fail to separate during meiosis II. What is the result of the gametes in nondisjuction of homologous chromosomes in meiosis I? What is the result of the gametes in nondisjustion of sister chromatidsin meiosis II?
*n+1, n+1, n-1, n-1 *n+1, n-1, n, n
describe X-linked Recessive Inheritance. Do men or women generally pass this on? Are men or women usually affected? Give 3 or 4 examples of diseases.
-It is a type of recessive inheritance for genes on the X- chromosome. Males express the phenotype when they inherit 1 effected allele, while females need to inherit 2 effected alleles. -Males cannot pass the effected X allele onto sons, because a son must receive a Y from the father to be male. Women are very rarely affected and are primarily heterozygous carriers because they have the 2 X's to pass and the men only need to receive one. Example: Duchenne Muscular Dystrophy, Hemophilia, G6PD Deficiency, Bruton's Agammaglobinemia, etc.
Inclomplete Dominance Diseases Genotype ability to make LDL cholesterol receptors: HH Homozygous? Hh Heterozygous? hh Homozygous?
-Normal ability to make LDL cell receptors -Mild disease arthersclerotic plaques as young as 25 years -Sever disease artheroslerotic plaques as young as 15 slide 12 pp 1
Chromosomal abnormalities are two types: Abnormalities in number of chromosomes (Numerical). Aneuploidy - _____________________________________ Polyploidy - ______________________________________ Abnormalities in structure of chromosome. deletion duplication-_____________________________ inversion - ______________________________________ translocation- ________________________________________
-abnormal # of chromosomes 45 or 47 -too many 47 or 48 -duplicated extra genetic material - segments are reversed end to end -rearrangement of parts between nonhomologous chromosomes
Hardy - Weinberg equilibrium for Autosomal Recessive diseases Generally p the normal allele frequency in the population is very close to ____. In autosomal recessive condition, a large percentage of the disease producing allele is 'hidden' in heterozygous carriers who cannot be distinguished phenotypically (clinically) from homozygous normal individuals.
1 *use 1 for p in the mathematical equation for autosomal recessive diseases
When recessive and dominant characteristics form a zygote, Pp. That first generation will show the dominant phenotype, but the second generation will show the dominant:recessive phenotype at about a ______ ratio. PP, Pp, Pp, pp.
3:1
Numerical abnormalities fill in the blank with the numbers of n's Euploidy - normal ____ (____) Polyploidy (__________) - spontaneous abortion Aneuploidy: (Caused due to ______________) Trisomy (_________) = ____ (compatible with life) Monosomy (________) = 45 Autosomal - incompatible with life. Sex chromosomal - compatible with life. (turner's syndrome) Abnormalities of sex chromosomes are better tolerated than autosomal. Abnormalities of sex chromosomes sometimes symptomatic in adult age (e.g. __________).
46 (2n) 3n or 4n non-disjunction (2n+1) 47 (2n-1) 45 infertility
_____________________: Heterozygotes with one copy of the altered gene are affected. Example: Polycystic kidney disease, neurofibromatosis, Huntington disease, etc. _____________________: Homozygotes with two copies of the altered gene are affected. Example: Cystic fibrosis, Sickle-cell anaemia, Phenylketonuria, beta thalssaemia, etc. __________: Males with one copy of the altered gene on the X-chromosome are affected. Example: Hemophilia, Duchenne Muscular dystrophy, Rett syndrome, etc.
Autosomal dominant Autosomal recessive X-linked
Describe Incomplete Dominance. Is it hetero or homozygote? What will a first generation look like of a red and white flower in incomplete dominance? What will the second generation look like?
Both genes affect phenotype, and an Intermediate type is formed. Heterozygote phenotype Offspring is different from either homozygote phenotype. Example: P Generation: Red flowered × White flowered C^R C^R × C^W C^W F1 generation: All offspring C^R C^W second generation= 1 dominant: 2 pink : 1 recessive
If every generation has the disease what is the condition? What should the next question be? if yes, what is the condition? if no, what is the condition?
Dominant is there male to male transmission? autosomal dominant may be x- dominant. Ask if all daughter are affected. If yes, it is x-dominant. If no, it is autosomal dominant.
What are 7 or 8 Examples of Chromosomal aberrations. Tell me which ones are trisomy and which ones are monosomy
Down syndrome (trisomy) Edward syndrome (trisomy) Patau syndrome (trisomy) Klinefelter syndrome (monosomy) Turner syndrome (monosomy) Cri du chat syndrome Angelman syndrome Prader-willi syndrome
Reverse Banding Reversal of Giemsa staining. Stains ____ Rich Regions. Incubation of slides containing metaphase chromosomes in hot ______________ buffer/ heating and stained with ____________. Regions that stain poorly by G or Q banding are examined, R banding gives a pattern that is easier to analyse than that given by G or Q banding. Used to analyse __________ rich regions and sub-telomeric regions. *R banding can be used to verify if a deletion has occured when you can not see it in the lighter GC area of G banding
GC phosphate Giemsa gene *(G-C rich) will be dark
________________________________ Most common method of banding technique. Arrested Metaphase or prometaphase chromosomes are partially treated with __________ - certain non histone proteins are destroyed. Stained with Giemsa. Produces characteristic light and dark bands - around 400 in number.
Giemsa banding: G banding trypsin
describe Autosomal Dominant Inheritance. describe effect of homozygote and heterozygote. see image 22 pp1 for huntington's disease example
Heterozygotes with one copy of the altered gene are affected. Example: Polycystic kidney disease, neurofibromatosis, Huntington disease, etc. Homozygotes with both altered genes are generally die before reproductive age.
What is the first question you ask when reading a pedigree chart?
Is every generation suffering with the disease?
_____________ Disorders 1% of total live birth. Mutation in single gene. Follow Mendelian type of inheritance. Dominant/recessive pedigree patterns. High risks to the relatives. Some isolated cases due to new dominant mutations. Structural proteins, enzymes, receptors, transcription factors. Today about 5000 diseases.
Monogenic
______________________ 1% of total live birth. Mutation in single gene. Follow Mendelian type of inheritance. Dominant/recessive pedigree patterns. High risks to the relatives. Some isolated cases due to new dominant mutations. Structural proteins, enzymes, receptors, transcription factors. Today about 5000 diseases.
Monogenic disorders
__________________________ -__________________________ allows in one hybridization experiment distinguish according to different colour every pair of autosomes and sex chromosomes. (used for basic karyotyping) -Then it is possible to make analyses of the whole genome and every structural and numerical rearrangement. -FISH limits analysis to specific chromosomes or regions of chromosomes, and CGH (comparative genome hybridization) visualises only those changes that result in variations in copy number, SKY permits the visualisation of all chromosomes at one time, 'painting' each pair of chromosomes with different fluorescent colour.
Multicolor FISH -mFISH mFISH or Spectral karyotyping (SKY)
What are the 5 Factors responsible for genetic variation in/ among populations?
Mutation Natural selection Genetic drift Gene flow Consanguinity
If every generation is not suffering with the disease what is the condition? What is the next question to ask? what if the answer is yes? what if the answer is no?
Recessive All (or almost all) affected are males? x-linked recessive autosomal recessive
Human Traits _________________________ disorders follow Mendelian laws: Albinism (autosomal, recessive), webbed fingers (autosomal, dominant), short-limbed dwarfism (autosomal, dominant)
Single gene (Monogenic)
Classification of genetic disorders Chromosomal aberrations Multifactorial (Polygenic) Single gene (Monogenic) ____________________ (cancer) Atypical Inheritance
Somatic mutations
what is Reduced penetrance? what may be the cause of reduced penatrance (2 main things)?
Some people are carrying a disease that would normally show clinical symptoms, but they are healthy. -Certain autosomal dominant disorders in which some individuals show the sign and symptoms of the diseases while others are never clinically diagnosed, so-called reduced penetrance. -A person carry a faulty gene but it's not necessary that this person will express the disease due to reduced penetrance of the gene. -Reduced penetrance might be due to: * modifying effects of other genes *interaction of the gene with environmental factors 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.
Gene flow -More gradual change in gene frequency in larger population resulting from gene flow. -Gene flow refers to the _____________ of genes among population. -Because of gene flow, population located close to one another often tend to have similar gene frequencies.
exchange
A disease tends to either involve more of an enviromental factor, or more of a genetic factor. When disease has more of a genetic factor, Is it a more rare or common disease? Are the the genetics more slimple or complex? Are they Multifactorial or Unifactorial? Do they have a higher or lower recurrence rate? *enviromental diseases are the opposite of each other
rare simple unifactorial higher recurrence rate
Incomplete Dominance Diseases Tay-Sachs disease -Homozygote has serious symptoms (unable to metabolize certain lipids due to non-working enzyme, lipids accumulate in the brain and cause seizures, loss of mental and motor skill, death in a few years). -Heterozygote has no symptoms but has detectable biochemical effects (organism level = [dominant or recessive?], biochemical level = incomplete dominant).
recessive
Incomplete Dominance Diseases Sickle-cell disease Homozygote [dominant or recessive?] has sickle-cell disease. Heterozygote has milder sickle-cell __________.
recessive trait
circle and square with a line attached *see symbols for identical and non-identical twins, and example of mother and father with son and 2 daughters slide 26 pp1
sexual partners
What is Co-dominance? What is the example given during class in the human body where co-dominance is expressed? slide 14 pp1
Both genes are expressed separately. NOT intermediate. Example: human blood groups .
Structural Abnormalities ___________ followed by loss or rearrangement, deletion, translocation. Generally: ______ of chromosomal material is more dangerous than gain. abnormalities of sex chromosomes are better tolerated than _____________. abnormalities of sex chromosomes sometimes symptomatic in ___________ age (e.g. infertility). usually origin de novo (both parents and siblings are normal).
Breakage loss autosomal adult
Autosomal Recessive Inheritance describe the CC, Cc, and cc children of parents with this inheritance. Try to give 3 or 4 examples of autosomal recessive diseases from class.
CC homozygous manifests clinical symptoms Cc heterozygous manifests no clinical symptoms but is a carrier cc homozygous is unaffected Example: Cystic fibrosis, Sickle-cell anaemia, Phenylketonuria, beta thalssaemia, etc.
__________________________________________ -0.6% of total live birth. -Alterations in the number or structure of chromosomes. -Autosomes or Sex chromosomes. -Thousands of genes may be involved. -Multiple organ systems affected at multiple stages in gestation. -Usually de novo (trisomies, deletions, duplications) but can be inherited (translocations). -Studied by Cytogenetics -Cell cycle arrested in ________phase. -22 pairs of autosomes, 2 sex chromosomes (XX or XY) -Cytogenetic disorders are relatively frequent! (1:160 newborns; 50% of spontaneous abortions)
Chromosomal aberrations (cytogenetic disorders) metaphase
__________________________ They contain sequences from whole chromosomes or half chromosomal parts (partial probes). Determination of structural rearrangements (translocations and deletions of large extent), identification of origin of marker- chromosomes.
Chromosome Painting Probes
what is Multicolor banding with high resolution -mBAND useful for? (2 or 3 points)
Enables determination of 1. exact breakpoints of chromosomal 2. aberrations with much higher 3. resolution than classical banding.
How do you run a test cross, for example with flowers?
If you want to know if something is heterozygous or homozygous. Cross bread a flower a flower that you know a homozygous recessive genes. If the flower that you are testing is homozygous dominant then it will produce only Pp flowers of one color. If it was a heterozygous flower it will produce flowers of 2 colors Pp and pp. 1:1
__________________________ Mapping of genes on chromosomes, micro-detection or extra material from structural rearrangements (translocations, deletions). must view images to understand concept slide 26 pp 4
Locus specific DNA probes
Mitochondrial Inheritance *IS ONLY PASSED FROM THE ___________ mtDNA is a small circular double-stranded molecule containing 37 genes. (coding for 2 rRNA, 22 tRNA, and 13 proteins of the ___________). Each cell contains thousands of copies of mitochondrial DNA while it's content is more high energy requiring cells like, muscles and brain. In this type of disorder the defective gene is present in mitochondrial chromosome. It affects generally energy metabolism so those tissues which require constant supply of energy are affected most. Example: Lebers hereditary optic neuropathy (LHON); Rapid Optic nerve death -> blindness in young adult life
MOTHER electron transport chain
What is Pleiotropy? Give 3 or 4 examples
One gene, multiple symptoms. -It is common for many genetic disorders to manifest in different systems of the body in a variety of ways. -One gene control more than one phenotype. -A single gene that may give rise to two or more apparently unrelated effects. Example: Tuberous sclerosis, Cystic fibrosis, Phenyketonuria, Sickle cell anemia. -Tuberous sclerosis affected individuals can present with either learning difficulties, epilepsy, a facial rash, or, all features.
_______________________ Many genes determine. Many genes control just about every characteristic in humans. height, skin color. Environment plays a role. slide 17 pp 1 really helps in this 1
Polygenic inheritance
____________________________________ (only 2 generations given in chart) A woman homozygous for an autosomal recessive disorder, whose husband is heterozygous for the same disorder. Their children have a 1 in 2 (50%) chance of being affected i.e. homozygous). It is not dominant but it looks like dominant pattern. It happens in recessive case only. slide 19 pp 2 to see chart
Pseudo-dominant inheritance
_____________________ Banding First technique discovered Quinacrine mustard-Fluorescent Staining. Other fluorescent dyes: 1. DAPI - (4,6-diamidino-2-phenylndole), 2. Hoechst 33258 Examination by fluorescence microscopy. Specific pattern of bright (______ rich regions) and dim bands - (_______ rich regions). *dark regions are deleted regions
Quinacrine (Q) AT GC
Cytogenetics to determine the chromosomal aberrations -Conventional cytogenetics has a very powerful ability to scan the genome for __________________ that involve both gains and losses of portions of the genome, as well as rearrangements within and among chromosomes. -However, the staining patterns produced on the chromosomes by banding procedures are sometimes ambiguous, and the resolution is limited by the optical characteristics of microscopes and the complex manner in which ______ is packaged into chromosomes. -In some cases analysis can be improved by using ________ with probes for specific genetic loci, such as telomeres or sites of known gain or loss of sequence. -Aberrations that involve gain or loss of chromosome segments are particular important in medical cytogenetics.
aberrations DNA FISH (Fluorescence in situ hybridization)
-Karyotypes are prepared using standardized staining procedures that reveal characteristic structural features for each ______________________. -_____________ cytogenetics is the study of the relationship of chromosomal alterations and genetic diseases in human beings. -______________ cytogenetics is a study of genetic disorders using new technologies that combine cytogenetic and molecular techniques. -The medical cytogenetics concepts and techniques deals with the mechanism of chromosomal alterations, Chromosomal banding pattern, common cytogenetic disorders and _____________ of chromosomal disorders.
chromosome Clinical Molecular diagnosis
Hereditary = Familial = Congenital = *Not all genetical diseases are congenital - e.g. Huntington disease - 3rd to 4th decade of life.
derived from parents transmitted in the gametes through generations present at birth (not always genetically determined - e.g. congenital syphilis, toxoplasmosis).
circle square I, II, III
female male generation number
Pure breed means ______________ Impure breed means _______________
homozygous heterozygous
Banding Techniques -Dividing cells are arrested in the ____________ stage or __________________ stage with the help of _____________________. -Require the chromosome to undergo denaturation or enzymatic digestion, followed by exposure to a __________ specific dye. -Produce alternating light and dark bands in mitotic chromosome. -There are many Banding Techniques are available as follows, see slide 13 pp 4 and study types of chromosome bands:
metaphase or pro-metaphase Colchicine DNA
Atypical inheritance of single-gene disorders Maternal inheritance of _______________ mutations. Anticipation Atypical presentation for Autosomal Dominant defects: Pleotropy Variable expressivity Heterogeneity New mutation Unusual inheritance patterns due to Genomic Imprinting. Mosaicism: Somatic mosaicism Germline mosaicism
mitochondrial
Probes for Specific Chromosomal Structures -a-satellite DNA -centromeres. -Determination of ______________ aberrations, identification of the origin of centromeres in marker-chromosomes, could be performed on amniotic fluid cells when there is strong clinical indication for one of the trisomies. must view images to understand concept slide 25 pp 4
numerical
Consanguinity Consanguinity refers to the mating of individuals who are related to one another (____________ cousin or closer). Relatives are more likely to share the same disease-causing genes because of their mutual descent from common ancestors. It can disturb equilibrium by increasing the proportion of _________zygotes at the expense of ___________zygotes. In-breeding may expose recessive gene to selection and loss, thus permanently altering the gene frequencies. review slide 23 pp 3 probability table
second homo hetero
Centromeric (C) - Banding What are the main 2 usefulnesses of the C banding? see slide 19 pp 4 for image or more detail
tell us how many chromosomes are present, and where the centromere is located.
Hardy-Weinberg Equilibrium priciple used for?
used to predict genotype and allele frequencies in a population
are glycosaminoglycans and glycoproteins the same thing?
yes, i think they are
Mendel's 1st Law -Law of segregation: Two alleles of a gene separate as gametes. One gametes carries one allele, and and the other gamete carries the other allele (haploid) -Then two gametes fuse to produce a __________ that contains two alleles (diploid).
zygote
describe Anticipation. what is the reason that causes anticipation? give 3 or 4 examples of when it takes place.
-A pattern of inheritance in which individuals in the most recent generations of a pedigree develop a disease at an earlier age or with greater severity than do those in earlier generation. -The reason might be the gradual expansion of trinucleotide repeat within or near a coding gene. -Example: Huntington disease, CAG repeats at Chromosome 4; Myotonic dystrophy, CTG Repeats at chromosome 19.
what causes Genomic Imprinting? describe what it is exactly. name 3 or 4 conditions
-Imprinting is due to methylation and histone modifications in the chromosome. -Genomic imprinting is a genetic phenomenon by which certain genes are expressed in a parent-of-origin-specific manner. It is an inheritance process independent of the classical Mendelian inheritance. A chromosome which remembers the disease. The allele on that chromosome is normal (no mutation in the DNA). e.g. Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann syndrome, Silver-Russell syndrome.
What is Epistasis? If BbCc same mice breed what will the ratio of their breed be? B=black b= brown
-One gene affects another gene. -Simple di-hybrid cross ratio. B=black b=brown C=allows color to be expressed c= does not allow color to be expressed 9black:3brown:4white (because all cc, .../... are white
describe X-linked Dominant Inheritance Who is more affected by this, and why? Can a male pass this to his son's or daughters? name 2 examples
-Only one copy of allele required (X-chromosome) to have disease. -Both males and females can be affected, although males may be more severely affected than female as they carry only one copy of genes found on the X-chromosome. -When a male is affected, all his daughters will be affected, but none of his sons will be affected. Example: Fragile X Syndrome, Incontinentia Pigmenti, etc.
____________________________________________________ is only used when their is a change in of one single nucleotide. It only causes a disease 99.9% of the time, but we test for it because it predicts future susceptibility for disease. slide 37 of pp 4
Comparison of CGH array with Single nucleotide polymorphism (SNP) array
name 5 to 6 Examples of polygenic disorders. *Often familial occurrence - probability of disease is in 1st degree relatives about 5-10%; 2nd degree relatives - 0.5-1%.
Diabetes mellitus Hypertension Gout Schizophrenia (Psychiatry) Congenital heart disease - certain forms Some types of cancer (ovarian, breast, colon)
Nature and ___________: The Environmental Impact on Phenotype Another departure from Mendelian genetics: the phenotype for a character depends on environment as well as genotype. The norm of reaction is the phenotypic range of a genotype influenced by the environment. For example, hydrangea flowers of the same genotype range from blue-violet to pink, depending on soil acidity.
Nurture
What is Co-dominance What is the example given in class?
Two allelic traits that are both expressed in the heterozygous state. So basically it happens to the dominant alleles. Example: Blood group AB: the A and B blood groups are codominant.
Hardy - Weinberg equilibrium for _______________________ condition In X-linked dominant condition, the disorder is twice in the females than in males (XX vs XY). Males usually die (a genetic lethal) if they have faulty gene. In this condition female who receive the one faulty gene on X-chromosome have the disorder. If both faulty genes are present in females that is also generally lethal. WHAT EVER THE GIVEN RATIO IS OF SICK PEOPLE THAT IS THE ANSWER. NO MATH NEEDED!
X-linked Dominant
Somatic Mutations -Alterations in DNA that occur after _________________. Somatic mutations can occur in any of the cells of the body except the _________________________ and therefore are not passed on to children. *These alterations can (but do not always) cause cancer or other diseases. A change in the genetic structure that is neither inherited nor passed to offspring. Somatic mutations in embryonic cells can result in patches of tissues containing the mutation. Size of the patch depends on the timing of the mutation. Individual is a *genetic mosaic.
conception germ cells (sperm and egg)
Selection for heterozygotes: Sickle cell anemia is a classic example of a situation in which the heterozygotes is more __________ in a particular environment. How could the sickle cell disese mutation become so frequent, especially in Africa? Falciparum malaria has been common in much of Africa does not survive well in the erythyrocyte of sickle cell. These individuals who have no clinical sign of sickle cell disease (______________zygous) are thus protected against the lethal effects of malaria. Consequently, there is a heterozygote advantage for the sickle cell mutation and it maintains a relatively high frequency in some African population.
fit heterozygous
-only mutations that are not lethal are pass on on genetic diseases. -Like, we know that the tuberculosis is a microbial (environmental) disease but now it's also known that ___________________ susceptible people are prone for TB while others are not.
genetically
Natural Selection -Natural selection acts upon genetic variation, increasing the frequencies of alleles that promote survival or fertility (referred to as fitness) and decreasing the frequencies of alleles that reduce fitness. -The reduced fitness of most disease-producing alleles helps explain why most genetic diseases are relatively rare. -Dominant diseases in which the disease-causing allele is most readily exposed to the effects of natural selection, tend to have lower allele than do recessive diseases where the allele is typically hidden in _______________. -The effects of selection are more obvious and can be readily measured for ___________ than for _____________.
heterozygotes dominants recessive
Hardy - Weinberg equilibrium for Autosomal Dominant diseases Most of the affected individuals will be _________________. In this case prevalence is 2q (p more or less equal to 1). q² represents the prevalence of homozygous affected individuals who although much less commonly seen, they have more severe symptoms and generally die before reproductive age. ( remove __________ from H-W equations) In contrast, in Huntington disease (autosomal dominant) the number of triplet repeats correlates much more strongly with disease severity than heterozygous or homozygous status. Practical application: 1/500 people have LDL receptor deficiency and risk of CVS disease. 2q=1/500, then q= 1/2x500= 1/1000, q²=1/106 (1/1000 x 1/1000). These individuals have greatly elevated LDL levels and they have at very early age CVS disease *see slide 12 for problem example
heterozygous q^2 because they die before reproductive age
Genetic drift -Changes in gene frequencies often occur when new settlement are formed. The possible explanation, perhaps migrants are themselves a separate subpopulation, differing genetically from the population as a whole. The gene frequencies of the migrants will probably NOT be representative of the population from which they come. -Genetic drift make certain genetic diseases [more or less?] common in small, isolated populations than in the world at large. -A relatively large population in Hardy - Weinberg equilibrium for an allele or many alleles can be affected by population 'bottle neck' in which natural disaster or large scale genocide dramatically reduces the size of the population. -Genetic drift may then change allele frequencies and a new hardy-Weinberg equilibrium is reached.
more
-Chromosomes are the vehicles of inheritance that reside in the cell _______________. -What is a Chromosome? -The number of DNA in an individual chromosome is ___________, long molecule which is highly coiled and condensed. The total number of bases in all the chromosomes of a human cell is approximately six billion and individual chromosomes range from 50 to 250 million bases. -__________________: It the process of imaging the full chromosome sets of an organism, thus providing a genome-wide snapshot of an individual's chromosomes. -_______________: Arrangement of chromosomes in sets (Its easier way to show karyotype).
nucleus one Karyotyping Ideogram
Hardy-Weinberg equation?
p^2+2pq+q^2=1
Describe Hardy-Weinberg Equilibrium priciple. What are the 5 conditions that must be met?
-The Hardy-Weinberg principle states that both allele and genotype frequencies in a population remain constant-that is, they are in equilibrium-from generation to generation unless specific disturbing influences are introduced. -The disturbing influences include non-random mating, mutations, selection, random genetic drift, gene flow and meiotic drive. Genotype frequencies stay the same if five conditions are met. 1. very large population: no genetic drift. 2. no emigration or immigration: no gene flow. 3. no mutations: no new alleles added to gene pool. 4. random mating: no sexual selection. 5. no natural selection: all traits aid equally in survival.
___________________________________ -*this technique is more and more used in cancer detection use slide 29 to give further details pp 4 -CGH is a two colour FISH technique that allows the detection of _________ and ________ in DNA copy number variations (CNVs) across the entire genome without prior knowledge of specific chromosomal abnormalities. -Deletions and duplications of individual DNA segments (less than 1-2mb) to be seen in routine metaphase chromosome preparations are detected by CGH (comparative genome hybridization). -To detect deletions or duplications in unexplained malformations or mental retardation in apparently normal chromosome analysis by routine cytogenetic tests. -Use of DNA _______________ technique in conjunction with CGH techniques: Array CGH (aCGH). -aCGH: Similar to conventional CGH, but during hybridization, cloned chromosomal DNA fragments (about 200 kb in size) replace the metaphase chromosomes. This method offers greater sensitivity and ____________ than conventional CGH in detecting CNVs.
Comparative Genome hybridization losses and gains microarrays resolution
Numerical Abnormalities ___________ - normal 46 (2n) ______________ (3n or 4n) - spontaneous abortion _______________: (Caused due to non-disjunction) Two type: ____________ (2n+1) = 47 (compatible with life) _____________ (2n-1) = 45 _______________ - incompatible with life. ___________________ - compatible with life. Abnormalities of sex chromosomes are better tolerated than autosome. Abnormalities of sex chromosomes sometimes symptomatic in adult age (e.g. infertility).
Euploidy Polyploidy Aneuploidy Trisomy Monosomy Autosomal Sex chromosomal
_________________________________ -Just as nucleic acid hybridization probes are used to identify fragments of DNA in southern blots, cytogeneticists can hybridize probes labelled with fluorescent dyes to DNA contained within chromosomes immobilized on microscopic slides. -Performed by fixing and denaturing interphase or metaphase chromosomes (in situ) and hybridized with fluorescent probes. -Uses: Give 2 or 3 uses of this technique
Fluorescence in situ hybridization (FISH) -Examine the presence or absence of a particular DNA sequence; -evaluate the number or organization of a chromosome or chromosomal region. -Sub-microscopic mutations, deletions or duplications may be detected,
describe Variable expressivity.
The whole class room has a heterozygous disease, but everyone is expressing different symptoms of the same disease. -It refers to the range of signs and symptoms that can occur in different people with the same genetic condition, even in the same family. -If a genetic condition has highly variable signs and symptoms, it may be challenging to diagnose. Example: In autosomal dominant polycystic kidney disease, some individuals have renal dysfunction at early adulthood while others have not. The features of Marfan syndrome (Fibrillin-1 gene defect) vary widely - some people have only mild symptoms (such as being tall and thin with long, slender fingers), while others experience life threatening complications involving the heart and blood vessel.
Mutation -Although human population are typically in Hardy-Weinberg equilibrium for most loci, deviation from equilibrium can be produced by new mutations. -In general, mutation rate do not differ very much from population to population. The mutation rate of recessive genes is much more difficult to determine because it is usually impossible to know whether the gene in question is a new mutation or has been inherited from a _______________ parent. -New hereditary variation that arises by ___________ is the only source of the material for evolution upon which natural selection acts to preserve the fit and to eliminate the less fit. -___________________: in some cases, a new mutation can be introduced into population when someone carrying the mutation is one of the early founder of the community.
heterozygous mutations Founder effect
how many colors does mFish use? how many colors does CGH methodology use? slide 36 pp 4
mFISH = lots of colors CGH - 2 colors
-How to see chromosomes: -Chromosomes only visible as cells approach and pass through _____________ in cell cycle, what is seen in Duplicated chromosome. -Normal Karyotype: -Normal human karyotype has 46 chromosome. -22 pairs of _____________ and a pair of sex chromosome. -Female: 46, XX -Male: 46, XY
metaphase autosomes
-Comparative genomic hybridization (CGH) allows screening the entire genome for these aberrations. [compare one genome with a canerous one for example] -Using _______________, the resolution of CGH can be much greater than with standard cytogenetics. -Microarrays with dense coverage of the entire genome allow screening for aberrations at any location without the need to have prior knowledge about where to test. -Thus array CGH offers the ability to screen genomes of affected individuals to discover new aberrations, determine if apparently balanced translocations also involve gains or loses of DNA, establish ________________ _________________ relationships for conditions with variable aberrations, and provide comprehensive clinical diagnostic information. -In combination with techniques such as chromosome microdissection or chromosome sorting, array CGH can map translocation breakpoints with high precision.
microarrays phenotype-genotype relationships
p^2+2pq+q^2=1 What do the variable stand for? p^2? q^2? 2pq?
p = frequency of the dominant allele/most common allele in the population. q = frequency of the recessive allele/ least common in the population. p^2 = percentage of homozygous dominant (healthy individuals). q^2 = percentage of homozygous recessive individuals (having disease). 2pq = percentage of heterozygous individuals (?).
Pedigree symbols white symbol black symbol half black, half white symbol
person without condition person with condition recessive gene carrier
Hardy - Weinberg equilibrium for X-linked Recessive condition When considering X-linked recessive condition, most cases occur in HEMIZYGOUS MALES (XY). Therefore q = _____________________________________________ __________________________, 1/10000 males have hemophilia A also gives the allele frequency for the disease producing allele 1/10000. q² = ________________________________(1/100,000,000)=1/108 2q = ______________________________________ (1/5000) X linked recessive traits are seen much more commonly in males than in female. As with autosomal recessive traits, the majority of X-linked recessive genes are hidden in ____________ heterozygous carriers (although a considerable number of those genes are seen in affected males).
q= disease producing allele frequency equals the prevalence of affected males q² = prevalence of disease in female 2q = prevalence of female carriers female
