Statistical Genetics - week 7

Question 1

Hardy Weinberg equilibrium. When to use?

Answer 1

when you have 2 versions of a gene or 2 alleles – may be the normal and the affected or 2 alleles of a SNP

Question 2

what is hardy weinberg equilibrium?

Answer 2

p^2 + 2pq + q^2 = 1

p + q = 1

Question 3

p =

Answer 3

the normal allele

Question 4

q =

Answer 4

the affected allele

Question 5

p^2 =

Answer 5

represent the proportion of individuals homozygous for the normal allele

Question 6

2pq =

Answer 6

represents the number of heterozygous or carrier individuals

Question 7

q^2 =

Answer 7

• q2 represents the proportion of individuals homozygous for the disease allele, and affected with the disease

Question 8

If the genotype or allele frequencies are significantly different from what you’d expect (not in equilibrium) then it can be an indicator that

Answer 8

there’s a genotyping error with the technology so it’s one of the main reasons you use Hardy Weinberg equilibrium in genetic analysis.

Question 9

Defn of linkage disequilibrium

Answer 9

The non-random association of alleles at different loci

Question 10

What results in linkage disequilibrium in populations?

Answer 10

shared ancestral chromosome segments

Question 11

1. Imagine there’s an ancestral chromosome in yellow that picks up a mutation in a disease causing gene

Answer 11

This is a marker of the chromosome and it’s allele 2 of the marker locus. As the ancestral chromosome gets passed through many generations and the disease causing gene becomes prevalent in the population there’s recombination of this chromosome during meiosis. You no longer have a whole yellow chromosome, it gets broken up with the other chromosome in meiosis. So you might see a pattern like the image depending on recombination (if it occurs).

Question 12

2. If that marker locus with the allele 2 on it, is sufficiently close to the disease causing gene

Answer 12

then they will not be separated by recombination very often so will be inherited together. If inherited together more often that you’d expect by chance (i.e. equivalent to if they were on a different chromosome - 50/50 chance they’d be inherited together) then you say that the 2 variants are in linkage disequilibrium

Question 13

When is linkage disequilibrium useful?

Answer 13

Linkage disequilibrium is really useful for mapping genes

Question 14

Can think about how variation occurs within the genome i.e. SNPS

If everything segregated at random and if you assume that the allele frequency of each of these alleles is 50% then you’d expect to see the following pattern:

Answer 14

We’d expect for two SNPs with four alleles each at 50% frequency four “chromosomes” each at 25%

i.e. A-C, A-D, B-C, B-D
each at 25%

Question 15

Can think about how variation occurs within the genome i.e. SNPS

However in reality if 2 loci are in linkage disequilibrium what you see is:

Answer 15

2 options
1st option: A-C 33%, A-D 33% or B-C 33%

2nd option: A-C 50%, A-D 50%

Question 16

For two loci that are in linkage disequilibrium - option 1

Answer 16

only 3 haplotypes of 4 possible occur unless: recurrent mutation or recombination

Question 17

For two loci that are in linkage disequilibrium - option 2

Answer 17

only 2 haplotypes of 4 possible occur unless: recurrent mutation or recombination or selection drift

Question 18

Measuring linkage disequilibrium between alleles at two SNPS

Answer 18

D’ (D prime) and r^2

Question 19

another definition for linkage disequilibrium

Answer 19

Measures whether alleles occur together more or less frequently than expected by chance

Question 20

D’ =

Answer 20

measures linkage disequilibrium and is not affected by differences in allele frequencies of the 2 SNPs– value between 0 and 1.

Question 21

when does D’ = 1?

Answer 21

If you don’t see the recombination events happening between the 2 loci, so you see only 2 or 3 of the haplotypes (4 possible) always then you’ve got complete linkage disequilibrium so D’ = 1. • D’ = 1, complete LD, when 2/3 of the 4 possible haplotypes are present in a population, no recombination between loci.

Question 22

perfectly correlated?

Answer 22

If you also always see allele G of SNP 1 with allele T of SNP 2 and allele A of SNP 1 with allele C of SNP 2 – always the case they’re also perfectly correlated (only see 2 of the 4 haplotypes then that means that r2 = 1 (this depends on the allele frequency)

Question 23

r^2 =

Answer 23

correlation, 1 means perfect correlation between the alleles at the SNPs, when there are only 2 of the 4 possibly haplotypes present

Question 24

when do you have a high D’ and high r^2

Answer 24

if SNPS are of a similar allele frequency and there’s no recombination then you have a high D’ and a high r2

Question 25

Why is measuring linkage disequilibrium between alleles at two SNPS important?

Answer 25

Important in GWAS as the haplotype blocks means there’s lots of redundancies when you come to genotyping

Question 26

In populations non - random recombination causes

Answer 26

haplotype blocks

Question 27

haplotype blocks

Answer 27

within a block SNPs are in linkage disequilibrium and tag each other

Question 28

what is another option apart for genotyping all SNPS in GWAS?

Answer 28

For GWAS instead of genotyping all the SNPs in the genome we can capture many of them by using Tag SNPS:

Question 29

GWAS signals capture SNPs in linkage disequilibrium in the same haplotype block

Answer 29

If these 2 SNPS are in linkage disequilibrium together and they have a high r2 then you don’t need to genotype both of them because by genotyping 1 you will know the genotype of the 2nd. Some may capture 2 or 3 or 4 or 5 different SNPS.
In GWAS able to reduce the number of genotyping SNPS that you have to

Question 30

why do we only need to analyse a small proportion of SNPs?

Answer 30

We only need to analyse small proportion of SNPs because across 10’s – 100’s kb there is extensive linkage disequilibrium

Question 31

Take home message: Hardy Weinberg

Answer 31

Hardy Weinberg equilibrium is used to calculate allele and genotype frequencies

Question 32

Take home message: LD

Answer 32

Genetic variants in linkage disequilibrium tend to be inherited together on the same haplotype

Question 33

Take home message: how is LD measured?

Answer 33

Linkage disequilibrium is measured by D’

Question 34

Take home message: SNPs in LD

Answer 34

SNPs in linkage disequilibrium and of similar allele frequency are highly correlated (r2)

Question 35

Take home message: GWAS

Answer 35

In association studies (GWAS), can use tag SNPS that are in linkage disequilibrium with our genotype SNPS to include much of the variation within the whole genome (In association studies significant signals tag causal SNPs that may not have been included in the genotyped SNPs.)