Determining population specific haplotype structure

[MedGen]

Firstly I will add a caveat that I am not entirely familiar with the exact mathematical models and algorithms involved in this (phylogenetics), so I might not be able to clear up any misunderstandings.

 

I'm trying to see if there are representative haplotypic structures inherent to particular populations beyond that which is initially apparent by local LD; lets call them extended haplotypes.

 

Now I want to see if there is any evidence for these extended haplotypic structures (background haplotypic structure) that may confound the association signals seen in GWAS due to either a) insufficient marker coverage on commercially available SNP chips, or b) whether fallacious assumptions about (supposedly) genetically isolated populations are representative of their purported ancestral population.

 

I hypothesise that by looking at the divergence of these specific population haplotypes using phylogenetic inferences (based on an ancestral haplotype) it will be possible to determine if association signals are genuine for their associated disease, or whether they are an as yet un-accounted for confounding issue. This is of particular note where (perhaps to be expected) certain genetic variants are only associated with specific populations.

 

So, to my question, are there specific parameters that need to be applied, or variables that need to be accounted for when deriving phylogenies of haplotypes?

 

Thanks in advance.

[jimmydasaint]

MedGen, they are intelligent questions. Do you mean that you are looking for less associations of haplotype and disease than these strong correlations in this reference which looks at Ashkenazi Jewish patients and that that these confounding factors can be taken into account? Just trying to clarify what you meant...

 

Of 26 Ashkenazi Jewish patients with pemphigus vulgaris, 24 (92.3%) carried the major histocompatibility complex (MHC) class II alleles HLA-DR4, DQw3, of which all were of the subtype DR4, DQw8. From studies of the patients and their families, haplotypes were defined. It was found that, of the patients who carried HLA-DR4, DQw8, 75% carried one or the other (and in one case, both) of two haplotypes [HLA-B38, SC21, DR4] or HLA-B35, SC31, DR4. The former is a known extended haplotype among normal Jews, with a frequency of 0.102, and the latter may also be an extended haplotype in this ethnic group, with a frequency of 0.017 among normal haplotypes from Jews. Of the remaining DR4-positive patients, all but one had a presumed D-region segment (defined as SC21, DR4, DQw8 or SC31, DR4, DQw8 with variable HLA-B) of these haplotypes. Only one patient had DR4, DQw8 without any other markers of the extended haplotypes. The number of homozygotes and heterozygotes for DR4, DQw8 was consistent with dominant but not recessive (P less than 0.01) inheritance of a class II or a class II-linked susceptibility gene for the disease. Since the disease is entirely attributable to the presence of an antibody to an intraepidermal intercellular cement substance, it is likely that the class II susceptibility gene (on [HLA-B38, SC21, DR4, DQw8], HLA-B35, SC31, DR4, DQw8, or their segments, in Jewish patients) controls the production of the antibody as a dominantly expressed immune response gene.

 

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=54807

[MedGen]

MedGen, they are intelligent questions. Do you mean that you are looking for less associations of haplotype and disease than these strong correlations in this reference which looks at Ashkenazi Jewish patients and that that these confounding factors can be taken into account? Just trying to clarify what you meant...

 

 

 

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=54807

 

Thanks Jimmy, but I am aware of the potential of certain haplotypes predisposing to disease within certain populations. I want to see if these extend beyond what is normally detectable by using standard measures of linkage disequilibrium. What I was looking for was more the technical aspects of phylogenetics. I wondered whether it was possible to infer intra-population phylogenies from the haplotypes present in a population.

 

The extensive LD across the MHC doesn't really lend itself to well to this idea unfortunately. I was thinking of testing the idea on a slightly less extensive LD rich area to start with.

Edited February 8, 2009 by MedGen