Author:
Coban-Akdemir Zeynep,Song Xiaofei,Pehlivan Davut,Karaca Ender,Bayram Yavuz,Gambin Tomasz,Jhangiani Shalini N.,Muzny Donna M.,Lewis Richard A.,Liu Pengfei,Boerwinkle Eric,Hamosh Ada,Gibbs Richard A.,Sutton V. Reid,Sobreira Nara,Carvalho Claudia M. B.,Posey Jennifer E.,Shaw Chad A.,Valle David,Lupski James R.,
Abstract
SummaryWe investigated the influences of admixture and consanguinity on the genetic architecture of disease by generating a database of variants derived from exome sequencing (ES) of 853 unrelated Turkish (TK) individuals with different disease phenotypes. We observed that TK genomes are more similar to Europeans with 69.3% of the unique variants (N = 356,613) not present in the Greater Middle Eastern variome. We found higher inbreeding coefficient values in the TK cohort correlating with a larger median span of long-sized (>1.606 Mb) runs of homozygosity (ROH). We show that long-sized ROHs arose from recently configured haplotypes and are enriched for rare homozygous deleterious variants. Such haplotypes, and the combinatorial effect of their embedded ultra-rare variants, provide the most explanatory molecular diagnoses for the TK individuals’ observed disease traits. Such haplotype evolution results in homozygosity of disease associated haplotypes due to identity-by-descent in a family or extended clan.
Publisher
Cold Spring Harbor Laboratory