Enhancer Domains Predict Gene Pathogenicity and Inform Gene Discovery in Complex Disease.
Am J Hum Genet
; 106(2): 215-233, 2020 02 06.
Article
en En
| MEDLINE
| ID: mdl-32032514
ABSTRACT
Non-coding transcriptional regulatory elements are critical for controlling the spatiotemporal expression of genes. Here, we demonstrate that the sizes and number of enhancers linked to a gene reflect its disease pathogenicity. Moreover, genes with redundant enhancer domains are depleted of cis-acting genetic variants that disrupt gene expression, and they are buffered against the effects of disruptive non-coding mutations. Our results demonstrate that dosage-sensitive genes have evolved a robustness to the disruptive effects of genetic variation by expanding their regulatory domains. This solves a puzzle about why genes associated with human disease are depleted of cis-eQTLs (cis-expression quantitative trait loci), suggesting that this relationship might complicate gene identification in causal genome-wide association studies (GWASs) using eQTL information, and establishes a framework for identifying non-coding regulatory variation with phenotypic consequences.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Discapacidades del Desarrollo
/
Elementos de Facilitación Genéticos
/
Herencia Multifactorial
/
Polimorfismo de Nucleótido Simple
/
Sitios de Carácter Cuantitativo
/
Estudio de Asociación del Genoma Completo
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Límite:
Humans
Idioma:
En
Año:
2020
Tipo del documento:
Article