Personal and population genomics of human regulatory variation

Abstract

The characteristics and evolutionary forces acting on regulatory variation in humans remains elusive because of the difficulty in defining functionally important noncoding DNA. Here, we combine genome-scale maps of regulatory DNA marked by DNase I hypersensitive sites (DHSs) from 138 cell and tissue types with whole-genome sequences of 53 geographically diverse individuals in order to better delimit the patterns of regulatory variation in humans. We estimate that individuals likely harbor many more functionally important variants in regulatory DNA compared with protein-coding regions, although they are likely to have, on average, smaller effect sizes. Moreover, we demonstrate that there is significant heterogeneity in the level of functional constraint in regulatory DNA among different cell types. We also find marked variability in functional constraint among transcription factor motifs in regulatory DNA, with sequence motifs for major developmental regulators, such as HOX proteins, exhibiting levels of constraint comparable to protein-coding regions. Finally, we perform a genome-wide scan of recent positive selection and identify hundreds of novel substrates of adaptive regulatory evolution that are enriched for biologically interesting pathways such as melanogenesis and adipocytokine signaling. These data and results provide new insights into patterns of regulatory variation in individuals and populations and demonstrate that a large proportion of functionally important variation lies beyond the exome.

Comprehensive identification and analysis of human accelerated regulatory DNA

“…DHSs active in fetal cell types showed the highest levels of conservation, consistent with the observation that gene regulation in developmental pathways is highly conserved (Lowe et al 2011). Conversely, DHSs in malignant cell types exhibited the fewest conserved DHSs, which may reflect ectopic activation of chromatin (Vernot et al 2012). These patterns are also observed in cell-type-specific DHSs (Supplemental Fig.…”

Nanoscale chromatin profiling of gastric adenocarcinoma reveals cancer-associated cryptic promoters and somatically acquired regulatory elements

“…These results demonstrate that Nano-ChIP-seq can identify functional regulatory somatic mutations in GC, particularly when coupled with sensitive variant detection algorithms such as MuTect 45 . Discussion Regulatory elements are estimated to occupy 1.5-10% of the human genome 56 , and strongly influence development and disease 57,58 . However, locating these elements, and defining biological states regulating their activity, remains an important challenge.…”

Le cœur des ARN non codants

“…L'importance des longs ARN non codants dérivés de séquences amplificatrices dans ce processus est formellement démontrée par des expériences d'inactivation, dans lesquelles ces ARN sont dégradés par l'utilisation d'oligonucléotides spécifiques, résultant par voie de conséquence en une extinction de l'expression des gènes cibles [22]. De façon extrêmement intéressante, la vaste majorité des polymorphismes mononucléotidiques identifiés dans des études d'associations pangénomiques et associés à des traits phénotypiques liés à des pathologies chez l'homme, se situent dans des séquences amplificatrices [23][24][25]. Il est dès lors probable qu'une grande partie de ces mutations ponctuelles modifient l'expression ou la fonction de transcrits non codants issus des séquences amplificatrices.…”