Characterization of Greater Middle Eastern genetic variation for enhanced disease gene discovery

Abstract

The Greater Middle East (GME) has been a central hub of human migration and population admixture. The tradition of consanguinity, variably practiced in the Gulf region, North Africa, and Central Asia ^{1– 3} , has resulted in an elevated burden of recessive disease ⁴ . Here we generated a whole exome GME variome from 1,111 unrelated subjects. We detected substantial diversity from sub-geographies, continental and subregional admixture, several ancient founder populations with little evidence of bottlenecks. Measured consanguinity was an order-of-magnitude above that of other sampled populations, and included an increased burden of runs of homozygosity (ROH), but no evidence for reduced burden of deleterious variation due to classically theorized ‘genetic purging’. Applying this database to unsolved GME recessive conditions reduced the number of potential disease-causing variants by 4–7-fold. These results reveal the variegated GME genetic architecture and support future human genetic discoveries in Mendelian and population genetics.