GDC

3 things that inactivate/silence DNA (making it repressive heterochromatin) (e.g. when 1 X chromosome gets inactivated) *What is the heterochromatin of the inactivated X chromosome called?

1. DNA methylation 2. Low levels of histone acetylation 3. Presence of histone macroH2A *facultative heterochromatin

Name 2 ways a point mutation can occur

1. mistakes in DNA replication 2. DNA damage by chemical mutagens (or by radiation) and misrepair

Name 2 mutagens that can cause deamination of DNA base pairs

1. nitrous acid (HNO2) 2. heat 1. Deaminates nucleotides (NH2 groups are replaced with =O groups) Cytosine -> Uracil Adenine -> Hypoxanthine 2. Causes deamination of cytosine in a similar way to nitrous acid. Also converts guanine to cytosine.

How can microscopically visible deletion, translocation or inversion mutations occur? (2 mechanisms)

1. unequal crossing o ver 2. DNA damage by chemical mutagens (or by radiation) and misrepair

Name 4 ways a submicroscopic deletion or insertion mutation can occur

1. unequal crossing over 2. misalignment during DNA replication 3. insertion of mobile element 4. DNA damage by chemical mutagens (or by radiation) and misrepair

Splice site mutation

Mutation at a point where coding and non-coding regions meet in a section of DNA - alters a site where an intron is normally removed from mRNA = mutation in the coding region of a gene that alters splicing of the mRNA. (Introns removed from immature mRNA to produce mature mRNA)

Can you get genes within genes? Tell me about NF1 In the intron or exon part?

NF1 - Neurofibromin 1 gene OGMP & EVI2A+B are both in the ANTI-SENSE strand of the NF1 gene (in the INTRON part!!!) OGMP - Oligodendrocyte-Myelin glycoprotein gene EVI2A + B - Ecotropic Viral Integration Site with 2 - genes A+B

More than 21% of brain disabilities with known genetic causes map to which chromosome?

The x chromosome --> Women are more protected than men from non / reduced function alleles. • This could lead to males being less intelligent on average?????

Translocation mutation

mutation in which one part of one chromosome breaks off and attaches to another (usually a problem that arose during recombination (rearrangement of parts between nonhomologous chromosomes)

Sex linked DOMINANT conditions are extremely rare, but name 2: The pattern of inheritance will be similar to autosomal dominant. However......

o incontinentia pigmenti (IP2 gene - is usually lethal in males) o congenital generalized hypertrichosis (wolf man syndrome). ....all the daughters but none of the sons of affected males will be affected.

What is the most common cause of triploidy?

polyspermy (the fertilisation of an egg by more than 1 sperm) --> such embryos will usually spontaneously abort!

Transposition

section of DNA can excise itself from 1 part of DNA and insert itself dsomewherre else in the genome - can cause porbs

Genetic imprinting

selective expression of either the maternal or paternal copy of a gene occurs when genes have differing effects depending on whether they are inherited from the mother or the father

Microsatellite DNA

sequence of tandemly repetitive DNA, 10 to 100 base pairs long

What is a mechanism for insertion / deletion mutations? Is it always problematic? In that generation or more of an issue in the next?

unequal crossing over NB insertion isn't that big of a problem unless the junction contains an important gene-- but still an issue when passing on the genetic mutation - may have doubling up or lack of gene/chromsome

Epistasis

when the action of 1 gene masks the effects of another (genes are @ diff loci) - a gene at 1 locus alters the phenotypic expression of a gene at a second locus E.g: both genes produce enzymes which act in the same biochemical pathway. • Making it impossible to tell the genotype at the second gene. • If Gene 1 product is not present then it is not possible to tell the genotype of Gene 2.

Hydroxylamine (NH2OH) - effect on DNA?

Reacts with cytosine to produce N4-hydroxycytosine, which pairs with adenine. C-->T

Critical gene in sex determination? Where is SRY usually found?

SRY (also known as Testis Determining Factor, TDF) • SRY is usually on the Y chromosome. (•However XX men would typically have a copy of the SRY gene translocated onto their X chromosome • And XY women will often lack a functional SRY gene.) Default developmental programme is female - if you don't throw in a Y chromosome with the SRY gene you'll go down the female pathway!

Tautomeric shifts What kind of mutations can they generate?

The position of protons in BPs changes --> can change the bonding structure, allowing noncomplementary base pairing May lead to permanent base-pair changes and mutations TRANSITION mutations

What is "stratification" in personalised medicine? *What % of patients respond positively to drugs?

"Stratification" refers to the division of patients with a particular disease into subgroups, based on a specific characteristic, who respond more frequently to a particular drug or, alternatively, are at decreased risk of side effects in response to certain treatments *30-70% + sooo many ADRs (adverse drug reactions)

Transposons

(jumping genes) short strands of DNA capable of moving from one location to another within a cell's genetic material

What can alkylating agents do to DNA? (2) e.g. ethyl methane sulfonate (EMS), nitrosoguanidine (NG) What kind of mutations can they generate?

1. Introduce alkyl groups (CH3-, CH3CH2- etc = ethyl, methyl) into nucleotides at numerous positions - this attacks DNA & causes strand breaks 2. Can also trigger misrepair of DNA Usually: G -> A T -> C TRANSITION mutations (basically makes a thymine turn into a "pretend" cytosine -masks it)

Explain Mendel's 2 laws 1. Segregation 2. Independent assortment

1. SEGREGATION: Organisms (peas, humans etc!) have 2 copies of each gene but transmit only 1 to each offspring. Which one is transmitted is chosen at random. i.e. if you are heterozygous for 2 different alleles, the alleles will segregate from each other in your offspring. 2. INDEPENDENCE OF ASSORTMENT: Where alleles of more than 1 gene are segregating, segregation at each gene occurs independently of the others (exception = linkage)

1/3 of all x chromosomes are present in males - so if a condition is lethal, how many of those mutant x chromosomes are lost from the population each generation? But these disease frequencies are constant. So what does this suggests?

1/3 - will disappear - those males will fail to thrive & reproduce -> so that means the rate they are being lost is the same as the rate at which they are being replaced w new mutations --> this means the mutation rate of a lethal X linked recessive disease is 1/3 of the frequency of the allele (helps quickly estimate the rate of mutation of new disease alleles)

How much of the nuclear genome is coding vs non-coding DNA? What is in the non-coding DNA?

10% coding 90% non-coding = - pseudogenes - gene fragments - introns, untranslated sequences etc

If a child is affected w an autosomal recessive condition like cystic fibrosis, sickle cell disease & Tay Sachs disease, subsequent full siblings have a ??? chance of being affected.

25% NB Inbreeding increases the chance of observing an autosomal recessive condition. o Since we all carry a few deleterious recessive alleles, inbreeding often leads to autosomal recessive disease

Some traits are not sex-linked; they are sex-limited. E.g.?

Breast cancer, endometriosis

Human Genome Project

2003 - sequenced all 3.3billion bp of the human genome

How many genes in the nuclear genome vs mitochondrial genome?

3000 vs 37

At what stage/when does X inactivation occur?

Blastocyst stage of development • Each cell independently and randomly inactivates 1 X chromosome • All daughter cells will have the same X-chromosome inactivated.

E.g: Tumor suppressor genes - retinoblastoma: o 2 mutant alleles in a cell will result in unregulated cell growth (a tumor). o But if an individual inherits only 1 mutant allele then most cells will be protected against unregulated growth by the normal allele (recessive). How come even some of these individuals w only 1 mutant allele will still develop cancer?

A small number of cells will pick up somatic mutations in the normal allele - leading to unregulated growth. o Thus an individual inheriting only 1 mutant allele will develop tumors (dominant). This is an example of : dominance at the level of the organism, recessivity at the level of the cell.

Exceptions to clear cut Mendelian inheritance - phenocopies

An environmentally determined trait may mimic a genetic trait o E.g: heat shock delivered to Drosophila pupae may cause a variety of defects which mimic those caused by mutations in genes affecting wing or leg development. • In humans, the drug thalidomide taken during pregnancy caused phenocopies of the rare genetic disease - phocomelia. • Many cases of polydactyly are not inherited and may be environmentally induced phenocopies.

What is the long-standing theory of ageing?

Ageing as wear and tear, particularly at the molecular level, longevity assured by somatic maintenance (e.g. detoxification, repair, turnover mechanisms) = a dominant paradigm New idea is oxidative damage, but even that seems to be association rather than causation - we're still trying to discover the cause of ageing

The trade-off theory for the evolution of ageing George C Williams AKA "pleiotropy theory"

Ageing evolves as a side-effect of natural selection in favour of mutations that cause a benefit during youth Cause of ageing: late-life action of wild type genes (Mutations may be beneficial in youth, but at the price of a higher rate of ageing • More individuals will survive to express the early benefit than will survive to suffer the higher rate of ageing)

Imprinting can give a false impression of sex-linkage. Explain

Angelman syndrome and Prader-Willi syndrome are two different conditions both of which seem to be caused by very similar deletions of a small part of chromosome 15. • The Angelman gene (UBE3A) is inactivated on the paternal chromosome • The Prader-Willi gene is inactivated on the maternal chromosome. If this portion on your paternal chromosome is deleted, you will get Prader-Willi (the Prader-Willi gene is also inactivated on the maternal chromosome); if this portion on the maternal chromosome is deleted, you will get Angelman --> So different diseases can be caused by the same deletion

Why has natural selection not acted to remove the Huntington's mutation from populations? What principle does this establish? (Haldane)

Average age of onset of Huntington's 35.5 years • For much of the evolutionary history of mankind, most people did not live to be that old • The selective pressure to remove the Huntington's mutation is therefore weak Principle: Mutations with deleterious effects in late life are subject to a weaker force of natural selection ---> Mutations with late life deleterious effects will accumulate in populations. These accumulated mutations cause ageing

Genuine non-Mendelian inheritance - Mitochondrial inheritance What is heteroplasmy?

Can be complicated by heteroplasmy (when only a proportion of mitochondrial DNA molecules are defective), by interaction with nuclear coded genes and by somatic changes which may occur with age. - the % of mitochondria that may be mutated can change from cell to cell, tissue to tissue & generation to generation (-> may make it harder to determine the inheritance pattern of a disease)

IONIZING radiation (e.g. X-rays, gamma rays) - effect on DNA?

Cause formation of intracellular FREE RADICALS: molecules containing unpaired electrons. Cause damage to individual bases and single or double-strand breaks (cells usually kill themselves when they see breaks like this cos they're like f me this is not good) Broken ends can join with breaks on other chromosomes

DNA polymerase slippage

Caused by looping out of DNA Common in areas of repeated sequence Can lead to small insertions or deletions Overtime this loop will keep getting bigger & disease will get worse!

What can UV light do to DNA?

Causes dimerization of adjacent pyrimidines, particularly thymine residues. These distort the structure of DNA and prevent normal base pairing. --> Requires repair for normal replication Polymerase hits the thymine dimer & is like wtf is this i'm not gonna touch it & the polymerase stops. Can be repaired. If not, can cause problems.

Highly repetitive DNA forms 'satellite' bands in what procedure?

Centrifuging - the highly repetitive part is denser than normal DNA When whole genomic DNA is centrifuged at high speed in a high density solution (CsCl), it separates according to density.

What is the mechanism for short tandem repeat number variation?

DNA polymerase slippage AKA -slipped strand mispairing • An important source of variation in repeat regions. • Can occur in homoploymer tracts (e.g. CCCCCCCCCCC). • Most probable cause of repeat-number variation in microsatellites basically creates a short INSERTION

What are chromosomes made up of?

DNA wrapped around proteins

Give an example of dominance at the level of the organism, recessivity at the level of the cell.

E.g: Tumor suppressor genes - retinoblastoma: o 2 mutant alleles in a cell will result in unregulated cell growth (a tumor). o But if an individual inherits only 1 mutant allele then most cells will be protected against unregulated growth by the normal allele (recessive). o However, a small number of cells will pick up somatic mutations in the normal allele - leading to unregulated growth. o Thus an individual inheriting only 1 mutant allele will develop tumors (dominant).

All eukaryotic genes have introns. T/F? As a rule of thumb, the smaller the gene, the higher....

False - not all! Some small genes don't have any. Insulin is tiny (does have introns tho); dystrophin is masssssiiiveee As a rule of thumb, the smaller the gene, the higher the proportion of its length is exon.

Mitochondrial DNA is wrapped around histone proteins. T/F?

False - not associated w histones, unlike nuclear DNA! = naked! and CIRCULAR

Recessive X-linked. NO female to female transmission. T/F?

False NO MALE to MALE transmission

UGA codes for STOP in both nuclear & mitochondrial DNA. T/F?

False- it acc codes for tryptophan in mitochondrial genes! AGA & AGG code for STOP in mitochondrial DNA (but arginine in nuclear DNA)

Ageing evolved for the good of the species, to remove worn out individuals, and reduce competition for limited resources. T/F?

False. Ageing acc seems to be a side-effect of mutations that are beneficial in earlier life = "pleiotropy theory" (a.k.a. antagonistic pleiotropy, trade off theory) - George C. Williams

All genes on the inactivated X escape activation. T/F?

False. A very small number of genes on the inactivated X escape inactivation.

Intercalators (e.g. Ethidium bromide, acridine orange) - effect on DNA?

Flat molecules that fit into one of the groves of the DNA molecule. Can interfere with DNA replication and repair, and cause slipped-strand mispairing. Leads to: insertions & deletions

Hereditary Hemorrhagic Telangiectasia o Disease is caused by mutations in the Endoglin gene on chromosome 9. What is this condition an example of?

Haploinsufficiency

The dominant negative effect e.g.

Heterozygote produces a nonfunctional protein that prevents the functional normal allele from functioning also (this is usually because the protein needs to form a multimer to be active --> 1 defective component inserted into the multimer can destroy the activity of the whole complex!) e.g. Osteogenesis imperfecta o Due to mutated collagen type I gene

Trinucleotide expansion mutations

Huntington's disease

Exceptions to clear cut Mendelian inheritance - germline mosaicism In what kind of disorders is it most common? *Can you test it w a blood test?

If a new disease mutation occurs in one germ cell precursor out of the many non-mutant precursors, its descendent germ cells will be diluted by the many non-mutant germ cells also present. • This will result in offspring carrying the disease allele in non-Mendelian ratios!!! (some kids will have the disease; some won't) If someone has germline mosaicism this means that some of their egg or sperm cells are normal and some contain a specific genetic alteration or chromosome problem. • Most common with autosomal dominant and x-linked disorders E.g: osteogenesis imperfecta and Duchenne muscular dystrophy *No - the mutated gene is only present in germ cells (egg & sperm cells) NB We cannot test egg or sperm cells for mosaicism either.

Bulky adducts (e.g. aflatoxin B) - effect on DNA?

Large chemical groups that form covalent associations with DNA, particularly bases. These bases are then removed to leave apurinic sites.

Huntingtin gene is NEAR the micro-satellite marker and that's how we found it's location. What is this called?

Linkage analysis

AB dad and B mum have a baby, but the baby has O blood type. How can this be?

No H antigen (h/h) = O phenotype, even if individual carries A or B alleles. • In example, both parents are H/h for H antigen. • Daughter is h/h • She appears to be blood group O even though she must be carrying at least one A or B allele

Missense vs nonsense

Non-sense = when a point mutation causes a premature STOP NB frameshift can also lead to premature stop

Just how wrong is the ROS theory? Perhaps forms of ROS other than superoxide are important? Perhaps it is broad spectrum molecular damage that is important? Or (radical interpretation) perhaps damage is not important at all? Oxidative damage increases with increasing age, so there may just be an association (not causality). Explain

Pathology is typically accompanied by increased oxidative damage --> • Ageing entails extensive, severe pathology • Whatever the cause of ageing, one would expect to see increased levels of oxidative damage

SNPs - Single nucleotide polymorphisms

Positions in a genome where some individuals have one nucleotide (e.g. A) and others have a different nucleotide (e.g. G or T)

A segment of chromosome 15 is deleted on the paternal chromosome. What condition could the child get?

Prader Willi, because the Prader-willi gene is inactivated in the maternal chromosome, so the child will now has 2 copies of the Prader-Willi gene that don't work! Maternal deletion -> AngelMan Paternal deletion -> Prader-Willi

Satellite DNA

Short sequences of DNA that are tandemly repeated as many as 10 million times in the DNA; - located in the centromeres & telomeres - differs in density from most of its DNA - does not undergo transcription

The ABO gene codes for a glycosyl-transferase which modifies a molecule known as H antigen on the surface of red blood cells. What does the A form add vs what does the B form add to form antigens? What about the O allele?

The A form adds N-acetylgalactosamine, the B form adds D-galactose forming the A and B antigens respectively. • The O allele has a frameshift mutation

What does SRY (AKA TDF) do w the SF1 protein?

The SRY gene product, together with the SF1 protein, is a transcription factor that upregulates other transcription factors (most importantly, SOX-9) -- to determine sex -- what makes a male a male (women lack SRY and stay on default developmental path)

Pleiotropy

The ability of a single gene to have multiple apparently unrelated effect e.g. in Tourette's Pleiotropy can occur whenever a gene product is required in more than one tissue or organ

Risk estimation Mum is carrier of DMD (x-linked recessive). Dad is not. Son has DMD, sister doesn't. What is the chance that the sister of the affected boy is a carrier?

The obvious (wrong) answer is ½. This answer assumes that the mother must be a carrier. • However, because the affected boy may be the result of a new mutation (with a ⅓ chance), there is only a ⅔ chance left that his mother is a carrier and therefore only a ⅓ chance that his sister is a carrier. (1/3 is half of 2/3) • If however there had been two affected brothers or an affected maternal uncle as well as the affected brother then we could have been certain that the mother was a carrier and the first answer would have been correct.

Turner's syndrome - women can inherit their x either from their father or mother. Which ones have more social skills?

Those that inherit their X from their father Boys also inherit their X from their mother - so maybe that's why men suffer from more conditions associated w reduced social skills? Cos their mums are giving them shitty X chromosomes making them stupid

Transversions are more likely to occur than transitions. T/F? (both types of substitution mutation) Which is less problematiic?

Transitions (purine to purine/ pyrimidine to pyrimidine) = much more likely! e.g. A to G or C to T & also less of a problem! - might still code for the same amino acid!!! Usually the 1st 2 base pairs are the same for all the codons for an amino acid -- see genetic code redundancy Transversions - Between different families of nitrogenous base (Purine -> Pyrimidine , Pyrimidine -> Purine) e.g. A to T or G to C

transitions vs transversions (types of SUBSTITUTION mutation) Which are more likely to occur?

Transitions - Within same family of nitrogenous base (Purine -> Purine or Pyrimidine -> pyrimidine) MORE LIKELY e.g. A to G or C to T Transversions - Between different families of nitrogenous base (Purine -> Pyrimidine , Pyrimidine -> Purine) e.g. A to T or G to C

Mitochondrial DNA has a higher mutation rate than nuclear DNA. T/F?

True

Mitochondrial DNA is very gene rich and contains very little 'junk DNA'. T/F?

True - unlike nuclear DNA which is 90% non-coding o 13 protein-coding genes o 2 rRNA genes o 22 tRNA genes

Explain silent alleles Where do we see them? Name 3 conditions

Two common alleles: A and B. • One rare allele - O = no protein E.g: adenosine deaminase (associated with severe combined immunodeficiency, hemolytic anemia and possibly autism).

Norrmally w cystic fibrosis, both parents are carriers. But only 1 is. What can explain this? What does this arise from?

Uniparental disomy --look at DNA and notice that BOTH pairs of chromosomes for that gene come from the same parent - they are IDENTICAL! This arises during meiotic non-disjunction (failure of chromosomes to separate properly during meiosis) SO RARE

Haploinsufficiency

When 1 copy is not sufficient for organism to survive! You need 2 copies of the gene to get enough product to avoid a hereditary condition! e.g. Hereditary Hemorrhagic Telangiectasia - 1 copy means insufficient endolin --> prob w blood vessels --> the phenomenon in which a person has only a single functional copy of a gene, and that single functional copy does not produce a normal phenotype. Shows a dominant pattern of inheritance.

Serotonin syndrome Tx?

With any drug that increases 5-HT (e.g., MAO inhibitors, SNRIs, TCAs) --> hyperthermia, confusion, myoclonus, cardiovascular instability, flushing, diarrhea, seizures, hypERreflexia -Treatment: cyproheptadine (5-HT2 receptor antagonist).

o Duchenne muscular dystrophy (DMD) o Haemophilia: • A - factor VIII deficiency • B - factor IX deficiency o Colour blindness (red/green). o Lesch-Nyhan syndrome (HGPRT deficiency) oGlucose-6-phosphate dehydrogenase deficiency What is the pattern of inheritance of these conditions?

X linked recessive

Can ageing be suppressed and lifespan increased?

Yes. Life extending interventions include lowered insulin/IGF-1 and target of rapamycin (TOR) signalling, and dietary restriction. But by what mechanisms do these interventions act?

What is the problem of phase in genetics? "haplotypic phase" This mainly a prob w males.

You know where the sites are, but you don't know how the genes are arranged on the chromosome False - not a prob w male cos they only have 1 x chromosome

Mosaicism

a condition in which cells within the same person have a different genetic makeup. - happens in cells that undergo nondisjunction in mitosis during embryonic development; fraction of body cells have extra or missing chromosome

genetic heterogeneity

a condition which may be caused by mutations in more than 1 gene - both genes may act in the same biochemical or regulatory pathway (this is true in Tuberous sclerosis where the protein products of the two genes interact) Tuberous sclerosis: An identical disease phenotype is produced by mutations in either of two unrelated genes, TSC1 on chromosome 9 or TSC2 on chromosome 16, which code for hamartin and tuberin

homozygous lethal phenotype e.g. which condition?

a phenotype that arises from a homozygous recessive genotype, leading to the premature death of an organism e.g. Achondroplasia dwarfism in humans (probably). • Usually caused by a new mutation in fibroblast growth factor receptor gene 3 (FGFR3), which cause abnormal cartilage formation. • Is usually inherited from father and occurs during spermatogenesis.

Exceptions to clear cut Mendelian inheritance - codominance e.g.?

blood types The ABO gene codes for a glycosyl-transferase which modifies a molecule known as H antigen on the surface of red blood cells. • The A form adds N-acetylgalactosamine, the B form adds D-galactose forming the A and B antigens respectively. • The O allele has a frameshift mutation

variable expressivity (the degree to which a disease manifests itself) e.g.

e.g. polydactyly many different forms: o small extra bump on the side of the hand o a finger which widens to end in two fingertips o an extra finger which dangles by a thin cord from the hand o a hand which looks normal except that it has a thumb and five fingers o other variations

Exceptions to clear cut Mendelian inheritance - semi-dominance give an example

e.g.: Familial Hypercholesterolemia +/+ = normal +/- = death as young adult -/- = death in childhood •Gene codes cholesterol receptor in liver (LDLR); •LDLR detects cholesterol in blood and signals to absorb it into cells. •fewer receptors = more cholesterol in blood = greater risk of heart disease

No H antigen (h/h) = what phenotype? (Bombay phenotype)

h/h = O even if individual carries A or B alleles!

Bombay phenotype (epistasis)

hh, a rare variant of the ABO antigen system in which affected individuals do not have A or B antigens and thus appear to have blood type O, even though their genotype may carry unexpressed alleles for the A and/or B antigens! Persons with the rare homozygous recessive genotype, hh, do not produce the precursor antigen H

All autosomal monosomies are lethal, but males with only one X chromosome are normal. How is this accomplished? *What is a Barr body?

inactivation of one of the two X chromosomes in females! (lyonization) • This means that although females have 2 copies of each X chromosome gene, only one is usually functional in each cell (like males) • The inactive X chromosome is visible as a dark staining "Barr body".

Missegregation of chromosomes @ meiosis can lead to what kind of mutation? *Frequencey per cell division (of this mutation)?

loss of a whole chromosome 1 in 100

What is the mechanism for recurrent deletion mutations?

misalignment and recombination

Most mutations either have no effect or cause the loss of function, but occasionally mutation can cause the gain of an undesirable function... (gain of function mutations). Give an example

α-1-antitrypsin: o Normal role is to inhibit elastase in the lung, but A SINGLE nucleotide CHANGE can change its specificity from elastase to thrombin. So now it inhibits thrombin instd of elastin. o This results in serum thrombin being mopped up leading to a form of haemophilia

Genuine non-Mendelian inheritance - uniparental disomy

• Both copies of a single chromosome may be inherited from the same parent (along with no copies of the corresponding chromosome from the other parent). • Rare cases of cystic fibrosis (a common autosomal recessive disease) have occurred in which 1 parent was a heterozygous carrier of the disease but the second parent had 2 wild type alleles • The child had received 2 copies of the mutant chromosome 7 from the carrier parent and no chromosome 7 from the unaffected parent.

dominant negative mutations in collagen genes

• Collagen fibrils are built of arrays of triple-helical procollagen units. • The type I procollagen comprises two chains encoded by the COL1A1 gene and one encoded by COL1A2. • Mutant chains disrupt the whole fibril!!! • Null-mutants are less severe. e.g. Osteogenesis imperfecta o Due to mutated collagen type I gene

Exceptions to clear cut Mendelian inheritance - anticipation

• Genetic disease appears with earlier onset and / or increased severity in succeeding generations. • Caused by expansion of trinucleotide repeats within the coding regions of some genes. • E.g: Mytonic dystrophy, Huntingdon's disease, fragile X syndrome

Exceptions to clear cut Mendelian inheritance - incomplete penetrance % penetrance =

• In extreme cases of low expressivity, some individuals may show no symptoms, despite carrying a disease allele, but their parents and children might. • This can be see by looking directly at DNA (if the disease allele is known) • 20% penetrance = 20% of people carrying disease allele will get disease. • E.g. Mutations in BRCA1 and BRCA2 give a 80% lifetime risk of developing breast cancer

Exceptions to clear cut Mendelian inheritance - incomplete ascertainment

• Many families where both parents are carriers of an autosomal recessive mutation will not have any affected children and thus will not come to medical attention. • This BIASES our observations only to families with affected offspring. • If this ascertainment bias is not taken into account, we may imagine that we are dealing with a disease which is inherited in a way other than autosomal recessive

Females inactivate one of their X chromosomes, so why don't female carriers of sex-linked recessive diseases also suffer the disease?

• Sometimes they do (e.g. in Fabry disease most of female carriers show some disease manifestation, sometimes severe) --- sometimes carrying the disease in half your cells is sufficient to show symptoms • Sometimes they show milder but related symptoms (to those observed in males) • Diffusible gene products (e.g. Hemophilia A / factor VIII deficiency) --- only need some types of cells to produce the product e.g. the clotting factors • Some genes escape X-inactivation (up to 25% in humans, 3 - 15% in mice) • Preferential inactivation of one X chromosome (e.g. the paternal X chromosome)

Aflatoxin B

• Thought to be one of the major mutagens found in food in the developing world, particularly the tropics. • Produces by the fungus Aspergillus flavus oryzae, which grows on grain, peanuts etc. when stored in damp conditions. • Binds to guanine. • Results in the removal of the guanine residue

Recessive X linked inheritance - Males are HEMIZYGOUS ( they only have 1 x chromosome so they can't be homozygous obvs) Name some other patterns in this type of inheritance

• Usually only males affected • No cases of male to male transmission • All the affected males can be linked through unaffected carrier females • If the mutant gene is lethal (such as Duchenne Muscular Dystrophy) then it takes an very unusual event to produce an affected female (because the female gets 1 x from mother & 1 from father & obvs father can't pass on his x if it's a lethal condition cos he's dead!)

Arguments against the oxidative damage theory of ageing (Superoxide free radical, O2, e.g. from mitochondrial respiration causes molecular damage --> ageing)

•Treatment w antioxidants usually does not slow ageing •Over-expression of antioxidant enzymes typically does not slow ageing •Reduced antioxidant defence can increase oxidative damage without affecting ageing •Increased oxidative stress often increases lifespan