In:
Nature Communications, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2020-10-01)
Kurzfassung:
High-altitude adaptation of Tibetans represents a remarkable case of natural selection during recent human evolution. Previous genome-wide scans found many non-coding variants under selection, suggesting a pressing need to understand the functional role of non-coding regulatory elements (REs). Here, we generate time courses of paired ATAC-seq and RNA-seq data on cultured HUVECs under hypoxic and normoxic conditions. We further develop a variant interpretation methodology (vPECA) to identify active selected REs (ASREs) and associated regulatory network. We discover three causal SNPs of EPAS1 , the key adaptive gene for Tibetans. These SNPs decrease the accessibility of ASREs with weakened binding strength of relevant TFs, and cooperatively down-regulate EPAS1 expression. We further construct the downstream network of EPAS1 , elucidating its roles in hypoxic response and angiogenesis. Collectively, we provide a systematic approach to interpret phenotype-associated noncoding variants in proper cell types and relevant dynamic conditions, to model their impact on gene regulation.
Materialart:
Online-Ressource
ISSN:
2041-1723
DOI:
10.1038/s41467-020-18638-8
Sprache:
Englisch
Verlag:
Springer Science and Business Media LLC
Publikationsdatum:
2020
ZDB Id:
2553671-0