Singleton Variants Dominate the Genetic Architecture of Human Gene Expression

Abstract

The vast majority of human mutations have minor allele frequencies (MAF) under 1%, with the plurality observed only once (i.e., “singletons”). While Mendelian diseases are predominantly caused by rare alleles, their cumulative contribution to complex phenotypes remains largely unknown. We develop and rigorously validate an approach to jointly estimate the contribution of all alleles, including singletons, to phenotypic variation. We apply our approach to transcriptional regulation, an intermediate between genetic variation and complex disease. Using whole genome DNA and RNA sequencing data from 360 European individuals, we find that singletons contribute ~23% of cis-heritability across genes (dwarfing the contributions of other frequencies), with the vast majority (67-90%) of singleton heritability deriving from ultra rare variants absent from thousands of additional samples. Strikingly, over half of all cis-heritability is contributed by globally rare variants (MAF<0.1%), demonstrating that rampant purifying selection shapes the regulatory architecture of most human genes.