Linkage analysis Flashcards
What does linkage analysis do?
estimates the recombination frequency hence the genetic distance
linkage
Alleles of loci close on the same chromosome are co-segregating more often than expected from random segregation
Which pedigrees are suitable for linkage analysis?
- Multigenerational pedigrees, at least 3
- critical meiosis must be informative
- phase must be known
What is needed if there is a high recombination fraction between 2 loci?
The more meioses are needed to obtain evidence that they are linked
Why do we use the likelihood based method?
Because in most pedigrees it is not possible to conclusively count the recombinants
What is the likelihood based method used for?
To estimate if the genes are associated or not
How do we calculate LOD score?
log10 Pr of θ if the loci are linked/ Pr of θ if the loci are not linked
What is Z max?
The maximum likelihood estimate for θ and this value tells us the most likelihood estimate of distance between 2 loci
LOD score of 2 loci that never recombine
θ= 0
Z> 3
significant evidence of linkage
2<Z< 3
suggestive of LOD score
-2 < Z < 2
non informative
Z < -2
significant evidence against linkage: independent segregation
LOD score Z
log10 (1-θ)^nr θ^r/ 0.5^tot
What is the LOD score used for in a phase known pedigree?
To determine the power of association
What is the LOD score used for in an unknown phase pedigree?
Estimate the recombination frequency and the power of statistical significance for that recombination frequency
What are the parameters of the LOD score?
Mode of inheritance
Recombination fraction
Marker allele frequency
Disease allele frequency
Penetrance
What type of markers are used and why?
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
Limitations of LOD score method
- 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
Fine mapping
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
What can be done with LOD scores for single different families?
They can be summed up to calculate the total LOD score for that specific marker
The case in consanguineous pedigrees
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
When is homozygosity mapping used?
In consanguineous pedigrees
