Ultrarare variants drive substantial cis heritability of human gene expression.

摘要: The vast majority of human mutations have minor allele frequencies under 1%, with the plurality observed only once (that is, 'singletons'). While Mendelian diseases are predominantly caused by rare alleles, their cumulative contribution to complex phenotypes is largely unknown. We develop and rigorously validate an approach jointly estimate all including singletons, phenotypic variation. apply our transcriptional regulation, intermediate between genetic variation disease. Using whole-genome DNA lymphoblastoid cell line RNA sequencing data from 360 European individuals, we conservatively that singletons contribute approximately 25% cis heritability across genes (dwarfing contributions other frequencies). (approximately 76%) singleton derives ultrarare variants absent thousands additional samples. inference procedure demonstrate results consistent pervasive purifying selection shaping regulatory architecture most genes.