Ultrarare variants drive substantial cis heritability of human gene expression.
Nat Genet
; 51(9): 1349-1355, 2019 09.
Article
em En
| MEDLINE
| ID: mdl-31477931
ABSTRACT
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 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 lymphoblastoid cell line RNA sequencing data from 360 European individuals, we conservatively estimate that singletons contribute approximately 25% of cis heritability across genes (dwarfing the contributions of other frequencies). The majority (approximately 76%) of singleton heritability derives from ultrarare variants absent from thousands of additional samples. We develop an inference procedure to demonstrate that our results are consistent with pervasive purifying selection shaping the regulatory architecture of most human genes.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Genoma Humano
/
Regulação da Expressão Gênica
/
Herança Multifatorial
/
Polimorfismo de Nucleotídeo Único
/
Estudo de Associação Genômica Ampla
/
Transcriptoma
Limite:
Humans
País/Região como assunto:
Europa
Idioma:
En
Revista:
Nat Genet
Assunto da revista:
GENETICA MEDICA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Estados Unidos