oa Severe loss-of-function mutations affect critical genes and pathways in the Qatari population

Exome sequencing was used to study genetic variation in the Qatari population. We sequenced 100 healthy Qataris (50X average depth, with >80% of sites at >10x depth) representing the 3 major Qatari genetic subpopulations (Q1 - Bedouin, Q2 - Persian/South Asian, Q3 - African). A total of ~174,000 high quality variants were identified, of which 1306 were predicted to cause loss of function (frameshift/stop-gain/splice/start-loss) in 1102 unique genes. Of these, 471 (36%) were novel Qatari variants (absent from public databases) of which 43 were observed in 2 or more individuals, suggesting a population allele frequency =1%. 54 of 471 loss of function mutations affected genes in the OMIM database with a confirmed disease-causing status. Of these, 30 occurred in genes known to cause severe autosomal recessive disease. Of interest, some of these mutation had allele frequencies of up to 8% in Qataris. We further focused on the subset that were nonsense mutations (n=671/1306). These occurred in 616 of 1102 unique genes and resulted in a median truncated protein length of 54.3%. 237 of 671 nonsense mutations were novel to Qataris, suggesting that a significant number of variants from this population are yet to be sampled and covered in public databases. When nonsense alleles were considered in the 3 separate Qatari subpopulations, the Q3 population displayed the highest number of nonsense alleles per individual (mean: 40.7, range: 28-55), consistent with the highest genome diversity due to African ancestry. Surprisingly, despite having the lowest number of heterozygous nonsense mutations (mean: 22.8, range: 16-31), the Q1 subpopulation had at least 20% more homozygous nonsense mutations (range: 2-15, mean: 6.7) per individual than either Q2 or Q3, consistent with the high levels of consanguinity in this population. Specifically, the Q1 had significantly higher allele frequencies than the rest of the world for 2 autosomal recessive disease genes, including 1 individual homozygous for a nonsense mutation in POMT1 which causes muscular dystrophy, and 4 individuals heterozygous for a mutation that truncates the Holoprocencephaly-causing TGIF1 gene to 7.5% full length. Additionally, the population as a whole had higher allele frequencies for 6 other autosomal-recessive-disease-causing mutations, bearing significant health implications for the Qatari population in particular, and for this highly consanguineous region of the world in general.