W5 variation maintenance + W6 complex traits

Question 1

How does mutation shape genetic variation?

Answer 1

• increases genetic variability
  need to consider;
  1. origin of the mutation- germline vs somatic (germline passed on)
  2. pop size and mutation rate- replication rate impacts mutation rate
  3. relationship to fitness- fitness consequences of the mutation, beneficial, neutral or deleterious

Question 2

How does selection shape genetic variation?

Answer 2

• trait variation and individual fitness relationship
• survival of the fittest- how selection impacts depends of the relationship bw trait variation and fitness
• natural selection is usually through decrease in genetic variation
• long term effect of directional and stabilising selection is to reduce variation- only few convincing examples of disruptive selection maintaining variation thus decrease

Question 3

How does drift shape genetic variation?

Answer 3

process that may cause gene variants to disappear completely thus reducing genetic variability by bottleneck and founder

Question 4

Types of selection that impact variation

Answer 4

1. Directional selection- fitness increases or decreases with trait value- shrinks variation
2. Stabilising selection- selection for intermediate trait values not extreme- shrinks variation
3. Disruptive selection- thought to maintain genetic variation

Question 5

Why is mutation unlikely to be the only factor maintaining genetic variation?

Answer 5

• contribution of deleterious variants to quantitative trait variation still unclear
• for mutation to persist and replace genetic variation is only in effective population size- unlikely yo be beneficial and persist

Question 6

How does antagonistic pleiotropy maintain genetic variation?

Answer 6

• pleiotropy= one gene multiple traits
• here the allele is beneficial for one trait and detrimental for another
  e. g. in male and female fitness

Question 7

How does context-dependent selection maintain variation?

Answer 7

• selection acts differently in diff environments- thus multiple alleles are maintained as they will provide fitness in different contexts
  1. Spatial- e.g. mice will variation in a-globin protein due to local adaptation to oxygen availability
  2. Temporal- e.g. beak size in finches related to available seeds
  3. frequency dependent- e.g. colour morphisms in grove snail, birds favour common colours (cycle)

Question 8

What are the characteristics of ageing?

Answer 8

• a decline in age-specific survival probability
• a decline in age-specific reproductive rate
• an increase in age-specific frailty or disease susceptibility

Question 9

How is ageing and evolutionary paradox? mutations

Answer 9

ageing= loss reproductive ability thus ageing traits not under selection

• mutation early in life= strong selection, late= under mutation shadow, many late acting mutations
• higher genetic load causes ageing
• changes in genetic variation with increased age

Question 10

How is ageing and evolutionary paradox? antagonistic pleiotropy

Answer 10

• selection can favour alleles that enhance survivorship and or rate at early reproductive ages that will be the expense of lower survivorship and higher reproductive age
• ageing is the result of pleiotropic effects of early and late fitness genes
• evidence= neg correlation bw fecundity and longevity

Question 11

what are private and public genes?

Answer 11

Public- evolutionarily conserved, can be oberved in lab then related to humans
Private- unique to each species

Question 12

Mendelian vs quantitative genetics in the context of complex traits

Answer 12

Mendelian
-focus following a single gene that can be directly scored, focus on discrete characters
- phenotype highly informative as to genotype 
Quantitative genetics (biometricians) 
-genetics as the statistical study of quantitative variation 
-focus on continuous variation and human inheritance 
-phenotype highly uninformative as to genotype

Question 13

What are QTLs?

Answer 13

Linkage between molecular markers and the genes that control the trait(s) of interest. Maps regions of chromosome that contains gene of interest rather than gene itself.
- then test for statistical association

Question 14

QTL mapping first step

Answer 14

Step 1; detection of QTL

• know the genotypes at multiple markers; scored at whether they have 1 none or both copies of alleles
• measure the phenotype of interest
• use linkage mapping LOD score to determine if there is significance
• Threshold testing Statistical tests are generally called significant if the p-value falls below 0.05.

Question 15

QTL mapping second step

Answer 15

Step 2; localization

• Once we get a signal not necessarily at the gene where we know- usually just at a region
• Finer resolution with GWAS but often not the casual SNP
• QTL estimated are the main estimates of the true number of loci

Question 16

What is the importance of setting a proper significance threshold?

Answer 16

-Thresholds are chosen to control for false positives AND false negatives
p < 0.05 is significant

Question 17

How pleiotropic are traits?

Answer 17

associated with reduction in adaptation rate as traits are not free to evolve independently

Question 18

Epistasis

Answer 18

one gene masks the effect of another or several genes work together

Question 19

Explain the problem of missing heritability

Answer 19

-Missing heritability= gap between what is predicted as heritability and what is discovered in GWAS
E.g. human height
- measurement; easy and accurate, heritability; 80-90%
- strategy; multistage (detection + validation)
- Sample size: 14,000 – 30,000 (detection) + 6,000 – 20,000 (validation)
- Cost: $30 million (actually 3 studies with many other phenotypes)
• Detected: 95 SNPs ,Validated: 54 SNPs
• Novel Loci: 40 previously unknown variants
• Effect size explained: only 5% of height’s heritability is explained by these 54 loci

Question 20

Common variant- common disease hypothesis for GWAS

Answer 20

• common alleles- lots of alleles out there with large effect
• Common diseases are attributable in part to allelic variants present in more than 1–5% of the population- could be proven to be wrong

Question 21

What is the infinitesimal model?

Answer 21

• many variants of small effect (notice scale)
• The infinitesimal model underpins quantitative genetic theory
• Empirical genetic data show that most alleles have small effects
• Common variants collectively capture “most” of the genetic variance in GWASs

Question 22

What is the rare allele model?

Answer 22

• Rare alleles- all have really small effect not detecting them

Question 23

What are the problems/benefits of GWAS?

Answer 23

GWAS (personal genomics problems/benefits)

1. For 23 of the 24 diseases, the majority of individuals will receive negative test results
2. these negative test results will, in general, not be very informative, as the risk of developing 19 of the 24 diseases in those who test negative will still be, at minimum, 50 - 80% of that in the general population
3. On the positive side, in the best-case scenario more than 90% of tested individuals might be alerted to a clinically significant predisposition to at least one disease.

Question 24

What is the future of personal genomics?

Answer 24

•more difficult to imagine predictive variants accounting for a sizeable proportion of disease risk without also explaining a sizeable proportion of heritability
•The limited incremental value in disease prediction of variants identified so far suggests that genetic prediction of complex diseases on a population basis will be challenging
- But, the identification of even many hundreds of risk variants of small effect should permit identification of the small proportion of a population at the highest genetically defined risk, in which targeted prevention strategies should be explored