Linkage analysis

Question 1

What does linkage analysis do?

Answer 1

estimates the recombination frequency hence the genetic distance

Question 2

linkage

Answer 2

Alleles of loci close on the same chromosome are co-segregating more often than expected from random segregation

Question 3

Which pedigrees are suitable for linkage analysis?

Answer 3

1. Multigenerational pedigrees, at least 3
2. critical meiosis must be informative
3. phase must be known

Question 4

What is needed if there is a high recombination fraction between 2 loci?

Answer 4

The more meioses are needed to obtain evidence that they are linked

Question 5

Why do we use the likelihood based method?

Answer 5

Because in most pedigrees it is not possible to conclusively count the recombinants

Question 6

What is the likelihood based method used for?

Answer 6

To estimate if the genes are associated or not

Question 7

How do we calculate LOD score?

Answer 7

log10 Pr of θ if the loci are linked/ Pr of θ if the loci are not linked

Question 8

What is Z max?

Answer 8

The maximum likelihood estimate for θ and this value tells us the most likelihood estimate of distance between 2 loci

Question 9

LOD score of 2 loci that never recombine

Answer 9

θ= 0

Question 10

Z> 3

Answer 10

significant evidence of linkage

Question 11

2<Z< 3

Answer 11

suggestive of LOD score

Question 12

-2 < Z < 2

Answer 12

non informative

Question 13

Z < -2

Answer 13

significant evidence against linkage: independent segregation

Question 14

LOD score Z

Answer 14

log10 (1-θ)^nr θ^r/ 0.5^tot

Question 15

What is the LOD score used for in a phase known pedigree?

Answer 15

To determine the power of association

Question 16

What is the LOD score used for in an unknown phase pedigree?

Answer 16

Estimate the recombination frequency and the power of statistical significance for that recombination frequency

Question 17

What are the parameters of the LOD score?

Answer 17

Mode of inheritance
Recombination fraction
Marker allele frequency
Disease allele frequency
Penetrance

Question 18

What type of markers are used and why?

Answer 18

microsatellites instead of SNP because they are highly polymorphic so there are many alleles in the population and is more likely to have informative meiosis

Question 19

Limitations of LOD score method

Answer 19

• a single locus inheritance so it is a genetic analysis which applies to Mendelian diseases
• requires specification of disease gene frequency and penetrance
• reduced power when disease mode is misspecified

Question 20

Fine mapping

Answer 20

Finding the most precise region so as to find the marker that co-segregated with the mutation: more markers are added to narrow down the breakpoint

Question 21

What can be done with LOD scores for single different families?

Answer 21

They can be summed up to calculate the total LOD score for that specific marker

Question 22

The case in consanguineous pedigrees

Answer 22

Genetic analysis is much easier: they same mutation is inherited by the father and the mother–> the allele of the marker that are associated with the mutation will be the same one

Question 23

When is homozygosity mapping used?

Answer 23

In consanguineous pedigrees