L3, Genetic variation in populations

Question 1

Hardy Weinberg: - use, assumptions

Answer 1

• See FCs
• Applies only if mating is random and population is stable
• Able to use to predict genotype frequency based on known allele frequency in a population

Question 2

Assumptions of Hardy-Weingberg rule:

Answer 2

• Mating is random -> humans actually mate assortatively e.g. religion
• -> Likely not a major interference with H-W overall due to scale of populations
• No inbreeding (critical!)
• Allele frequencies remain constant across generations

Question 3

Why may allele frequencies vary across generations?

Answer 3

• Mutation -> take a long time to reach appreciable frequencies in populations
• Selection (e.g. heterozygote advantage)
• Genetic drift (particularly in small populations) -> random changes in population

Question 4

How is inbreeding quantified?

Answer 4

• Coefficient of relationship (R) = proportion of alleles shared by two people having common ancestors -> Sum of (1/2)^n where n = number of links through a common ancestor
• Coefficient of inbreeding (F) = proportion of loci at which individual is expected to be homozygous -> 1/2R of parents

Question 5

ROH:

Answer 5

• Runs of homozygosity
• Important when considering and fitness
• -> Researchers have calculated that first cousins are 55% less likely to have children; associated with ROH and not common variant homozygosity

Question 6

What factors determine persistence of new mutations?

Answer 6

• Type of mutation ( dominant, recessive, X-linked)
• Selection (positive, neutral, negative)
• Population effect

Question 7

Frequency of mutations in generation -> affected protein-coding genes?

Answer 7

• 1 per 30 million bps per generation
• Average of 1 protein-coding gene per generation

Question 8

What is heterozygote advantage?

Answer 8

• The case in which the heterozygous genotype has a higher relative fitness than either AA or aa
• e.g. Sickle cell trait protects against malaria in

Question 9

+ Heterozygote advantage example in wild horse populations:

Answer 9

• TRPM1 gene
• Heterozygote: Leopard complex spotting
• Homozygote: Congenital night blindness

Question 10

Describe the founder effect:

Answer 10

• Loss of genetic variation that occurs when a new population is established by a very small number of individuals from a larger one
• Also increases frequency of previously rare alleles e.g. Ashkenazi Jews with a high prevalence of particular rare diseases

Question 11

Heritability:

Answer 11

• How much of the observed variation in a trait is caused by genetics
• Highly penetrant, single gene disorders should have a heritability of 0 (no variation)

Question 12

How is heritability traditionally estimated?

Answer 12

• Plotting trait in offspring against parents (e.g. height), extrapolating slope gradient -> % heritability

Question 13

Current methods for estimating heritability:

Answer 13

• Calculating lambda values: risk to sibling / population risk
• Risk to sibling is calculated using proportion of affected probands in a study who have an affected sibling
• Twin concordance studies (monozygous vs dizygous)
• Adoption at birth (many complications; need a large number for estimating heritability)

Question 14

Pharmacogenetics:

Answer 14

• Side effects conferred by genetic factors
• Also includes sensitivity to particular drugs (e.g. warfarin - 20% variation in safe, effective dose)
• Pharmacodynamics
• Pharmacokinetics

Question 15

Examples of drugs with serious side effects conferred by genetics:

Answer 15

• Azathioprine -> immunosupressant that produces neutropenia in those with low TPMT activity
• Fluorouracil -> cancer drug which is toxic to nervous system in some individuals
• Succinylchloride -> muscle relaxant which produces prolonged apnea in those with low butyrylcholinesterase activity
• Warfarin -> anticoagulant that produces excessive bleeding in those with low CYP2C9 activity