Low-coverage sequencing cost-effectively detects known and novel variation in underrepresented populations
Martin AR., Atkinson EG., Chapman SB., Stevenson A., Stroud RE., Abebe T., Akena D., Alemayehu M., Ashaba FK., Atwoli L., Bowers T., Chibnik LB., Daly MJ., DeSmet T., Dodge S., Fekadu A., Ferriera S., Gelaye B., Gichuru S., Injera WE., James R., Kariuki SM., Kigen G., Koenen KC., Kwobah E., Kyebuzibwa J., Majara L., Musinguzi H., Mwema RM., Neale BM., Newman CP., Newton CRJC., Pickrell JK., Ramesar R., Shiferaw W., Stein DJ., Teferra S., van der Merwe C., Zingela Z.
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Genetic studies of biomedical phenotypes in underrepresented populations identify disproportionate numbers of novel associations. However, current genomics infrastructure--including most genotyping arrays and sequenced reference panels--best serves populations of European descent. A critical step for facilitating genetic studies in underrepresented populations is to ensure that genetic technologies accurately capture variation in all populations. Here, we quantify the accuracy of low-coverage sequencing in diverse African populations.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>We sequenced the whole genomes of 91 individuals to high-coverage (≥20X) from the Neuropsychiatric Genetics of African Population-Psychosis (NeuroGAP-Psychosis) study, in which participants were recruited from Ethiopia, Kenya, South Africa, and Uganda. We empirically tested two data generation strategies, GWAS arrays versus low-coverage sequencing, by calculating the concordance of imputed variants from these technologies with those from deep whole genome sequencing data. We show that low-coverage sequencing at a depth of ≥4X captures variants of all frequencies more accurately than all commonly used GWAS arrays investigated and at a comparable cost. Lower depths of sequencing (0.5-1X) performed comparable to commonly used low-density GWAS arrays. Low-coverage sequencing is also sensitive to novel variation, with 4X sequencing detecting 45% of singletons and 95% of common variants identified in high-coverage African whole genomes.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>These results indicate that low-coverage sequencing approaches surmount the problems induced by the ascertainment of common genotyping arrays, including those that capture variation most common in Europeans and Africans. Low-coverage sequencing effectively identifies novel variation (particularly in underrepresented populations), and presents opportunities to enhance variant discovery at a similar cost to traditional approaches.</jats:p></jats:sec>