The Clark phaseable sample size problem: long-range phasing and loss of heterozygosity in GWAS

A phase transition is taking place today. The amount of data generated by genome resequencing technologies is so large that in some cases it is now less expensive to repeat the experiment than to store the information generated by the experiment. In the next few years, it is quite possible that millions of Americans will have been genotyped. The question then arises of how to make the best use of this information and jointly estimate the haplotypes of all these individuals. The premise of this article is that long shared genomic regions (or tracts) are unlikely unless the haplotypes are identical by descent. These tracts can be used as input for a Clark-like phasing method to obtain a phasing solution of the sample. We show on simulated data that the algorithm will get an almost perfect solution if the number of individuals being genotyped is large enough and the correctness of the algorithm grows with the number of individuals being genotyped. We also study a related problem that connects copy number variation with phasing algorithm success. A loss of heterozygosity (LOH) event is when, by the laws of Mendelian inheritance, an individual should be heterozygote but, due to a deletion polymorphism, is not. Such polymorphisms are difficult to detect using existing algorithms, but play an important role in the genetics of disease and will confuse haplotype phasing algorithms if not accounted for. We will present an algorithm for detecting LOH regions across the genomes of thousands of individuals. The design of the long-range phasing algorithm and the loss of heterozygosity inference algorithms was inspired by our analysis of the Multiple Sclerosis (MS) GWAS dataset of the International Multiple Sclerosis Genetics Consortium. We present similar results to those obtained from the MS data.