RESUMEN
Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes1. Here we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence predicted loss-of-function variants in this cohort after filtering for artefacts caused by sequencing and annotation errors. Using an improved model of human mutation rates, we classify human protein-coding genes along a spectrum that represents tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve the power of gene discovery for both common and rare diseases.
Asunto(s)
Exoma/genética , Genes Esenciales/genética , Variación Genética/genética , Genoma Humano/genética , Adulto , Encéfalo/metabolismo , Enfermedades Cardiovasculares/genética , Estudios de Cohortes , Bases de Datos Genéticas , Femenino , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Humanos , Mutación con Pérdida de Función/genética , Masculino , Tasa de Mutación , Proproteína Convertasa 9/genética , ARN Mensajero/genética , Reproducibilidad de los Resultados , Secuenciación del Exoma , Secuenciación Completa del GenomaRESUMEN
Allozymic variation in proteins encoded by 25 loci was analyzed electrophoretically in 1982 and 1983 in 356 individual plants from a dense population of wild barley, Hordeum spontaneum, the progenitor of cultivated barley. The test involved six microniches organized in a mosaic pattern in the open Tabor oak forest at Neve Ya'ar, Israel. The microniches were i) sun-soil, ii) sun-rock, iii) shade-soil, iv) shade-rock, and the contact zones: v) soil periphery of the sun-rock microniche, and vi) soil periphery of the shade-rock microniche. Discriminant analysis indicated significant multilocus allozymic differentiation between the microniches. Our results suggest that allozyme polymorphisms in wild barley are at least partly adaptive and differentiate predominately by microniche ecological selection, rather than by stochastic processes and/or neutrality of allozymic variants.