RT Journal Article
SR Electronic
T1 Singleton Variants Dominate the Genetic Architecture of Human Gene Expression
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 219238
DO 10.1101/219238
A1 Ryan D. Hernandez
A1 Lawrence H. Uricchio
A1 Kevin Hartman
A1 Chun Ye
A1 Andrew Dahl
A1 Noah Zaitlen
YR 2017
UL http://biorxiv.org/content/early/2017/11/14/219238.abstract
AB 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 role in complex phenotypes remains largely unknown. We develop and rigorously validate an approach to jointly estimate the contribution of alleles with different frequencies, 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 alone contribute ~23% of all cis-heritability across genes (dwarfing the contributions of other frequencies). We then integrate external estimates of global MAF from worldwide samples to improve our inference, and find that average cis-heritability is 15.3%. Strikingly, 50.9% of cis-heritability is contributed by globally rare variants (MAF<0.1%), implicating purifying selection as a pervasive force shaping the regulatory architecture of most human genes.One Sentence Summary The vast majority of variants so far discovered in humans are rare, and together they have a substantial impact on gene regulation.