Genetics II

Answer 1

Question 2

Example: STATURE

Answer 2

Known to be influenced by genetic variations (~80-90%)
1st known genetic variation to affect height found in 2007
- Single nucleotide change in HMGA2 gene
- Homozygotes = 1cm taller (<1% variation)
Weedon, M. N. et al. Nature Genet. (2007)
* In 2008 genome-wide association study (GWAS)
identifies 20 loci that influence adult height (~3% variation -5cm)
Weedon, M. N. et al. Nature Genet. (2008)
* Allen, H.L. et al. Nature (2010)
- 180 loci explains ~10% of variation (n>100,000)
* GIANT study (Nature Genetics 2014)
- >400 loci explains ~20% of variation (n>250,000)
- Update on n=5.4M - >12,000 loci ~40% of variation (Nature
2022)

Question 3

Example: Coronary Artery Disease

Answer 3

(CAD) (polygenic/complex - discrete)
*
* Single largest killer (males and females) in
developed countries
* Multiple genetic and environmental influences and
interactions

• Risk factors also complex traits
• continuous and discrete
• Cholesterol
• Hypertension
• Obesity

Answer 3

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Question 5

For complex traits

Answer 5

• how much of the variation between people is due to
  genetic differences between them and how much is due to
  them experiencing different environments ?

Answer 5

Question 6

Key questions

Answer 6

• For a particular trait, is the observed variation influenced by genetic variation and/or by
  environmental factors?
• How important is genetic variation as a source of total phenotypic variation? (Heritability)
• How many genes are involved and where in the genome are they distributed? (Association studies, whole genome sequencing)
• If there is genetic variation, what is the phenotype of the various genotypes in different environments?
  (epigenetics)

Question 7

For complex traits

Answer 7

Answer 8

Question 9

Heritability

Answer 9

*H= h2
* H can take any value between 0 and 1
* His a feature of a population
The relative sizes of g and Ve tell us about the contribution of the variation in our genetics and environment to the differences between people (phenotypic variation)

Question 10

Measuring Heritability

Answer 10

Question 10

Heritability

Answer 10

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Question 12

H and resemblance
between relatives

Answer 12

As H increases, children tend to resemble more
closely their parents
*As H increases so does
the response to selection

Question 13

H and resemblance
between relatives

Answer 13

Question 14

Measuring Heritability

Answer 14

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Question 15

Complex traits can be continuous or discontinuous (discrete)

Answer 15

Continuous - shows a series of overlapping phenotypic
classes
- Height, weight
- Can estimate H using correlations

• Discontinuous - shows distinct phenotypes
• Cancer, Schizophrenia
• G + E combine to determine an underlying risk or liability toward trait (continuous)
• Estimate H from the frequency of the trait in relatives and in general
  population
• Examining difference in concordance rates between MZ and DZ twins

Answer 16

Question 17

complications

Answer 17

H is not a constant
— varies in space and time
Not the same in all populations or all generations (different gene variations; new variations; different environments)
*
* Shared environment can over-estimate H

• Genotype - Environment Interaction
• Assortative mating (ie non-random)
  ー
  Makes Vg appear larger
• H is overestimated

Answer 18

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Question 20

Assortative mating can affect genotype frequency and can lead to overestimates of H

Answer 20

How do we assess the effect of assortative mating on the expected genotype frequencies and r (coefficient of relationship)? NB: relates to earlier session on HWE

Answer 20

Question 20

Assortative mating can affect genotype frequency and can lead to overestimates of H

Answer 20

Coefficient of inbreeding (F) * For an individual * Probability that an individual has 2 genes at a locus that are identical by descent * F = 1/2 (r) of parents - "" is the coefficient of relationship * F = 0 if parents are unrelated

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Question 23

Polygenic inheritance model (Vc)

Answer 23

Each gene can have a small effect * The separate effect of each gene cannot be detected by observing the phenotype * Major or Minor genes * QTLs (Quantitative Trait Loci) - commonly used in agriculture and breeding * eQTLs (variants that affect expression)

Question 24

Polygenic inheritance model (Vc)

Answer 24

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Question 28

Re-evaluating the complexity

Answer 28

Polygenic (and pleotropic) a number of genotypes or mutations at different loci contribute to complex trait (polygenic inheritance) Locus heterogeneity (act independently) or Epistasis (gene interaction) * Gene X environment interactions * Developmental or time-dependent expression of genes * Gene has its most pronounced effect at a certain time or developmental stage (e.g., puberty). * General aging of the system * either through programmatic senescence or general wear and tear

Question 28

Linkage vs. Association

Answer 28

inkage = Seeks to identify chromosomal segments shared by affected (family) members * e.g. affected sib pairs * Results in large candidate regions

Answer 29

Question 30

Linkage vs. Association

Answer 30

Association = Measures preferential segregation of a particular allele with a phenotype across families * e.g. case control studies * Usually highlight smaller candidate regions

Answer 31

Question 31

Genome-wide Association Studies (GWAS)

Answer 31

Test 500K to 1M SNPs across the genome (tags >90% variation) * Test whether a particular allele occurs at higher/lower trequency among attected than unaffected individuals (case-control studies) disease cases controls * Involve population correlation, rather than co-segregation within a family

Question 32

Example: GWAS for common diseases/disorders

Answer 32

British Population * ~2000 individuals for each of 7 diseases * Bipolar, Crohn' s, T1D, CAD, T2D, Hypertension, RA * ~3000 shared controls * 50 Research Labs * Non-European ancestry excluded

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Question 41

Missing heritability - need to go beyond GWAS

Answer 41

Rare variants Need to use very large number of individuals to examine rare variants Some variants may be population specific - replication dificult * Exome Sequencing genome) Examine the few percent of genome that contain exons (~ 1% of * Whole genome sequencing still costly for large numbers

Answer 42

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Question 44

Adding to the complexity

Answer 44

Phenotypic plasticity (G-E interaction) - Variation, under environmental influence, in the phenotype associated with a genotype - Epigenetics

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