Purifying selection on noncoding deletions of human regulatory loci detected using their cellular pleiotropy

Abstract

Genomic deletions provide a powerful loss-of-function model in noncoding regions to assess the role of purifying selection on genetic variation. Regulatory element function is characterized by nonuniform tissue and cell type activity, necessarily linking the study of fitness consequences from regulatory variants to their corresponding cellular activity. We generated a callset of deletions from genomes in the Alzheimer's Disease Neuroimaging Initiative (ADNI) and used deletions from The 1000 Genomes Project Consortium (1000GP) in order to examine whether purifying selection preserves noncoding sites of chromatin accessibility marked by DNase I hypersensitivity (DHS), histone modification (enhancer, transcribed, Polycomb-repressed, heterochromatin), and chromatin loop anchors. To examine this in a cellular activity-aware manner, we developed a statistical method, pleiotropy ratio score (PlyRS), which calculates a correlation-adjusted count of “cellular pleiotropy” for each noncoding base pair by analyzing shared regulatory annotations across tissues and cell types. By comparing real deletion PlyRS values to simulations in a length-matched framework and by using genomic covariates in analyses, we found that purifying selection acts to preserve both DHS and enhancer noncoding sites. However, we did not find evidence of purifying selection for noncoding transcribed, Polycomb-repressed, or heterochromatin sites beyond that of the noncoding background. Additionally, we found evidence that purifying selection is acting on chromatin loop integrity by preserving colocalized CTCF binding sites. At regions of DHS, enhancer, and CTCF within chromatin loop anchors, we found evidence that both sites of activity specific to a particular tissue or cell type and sites of cellularly pleiotropic activity are preserved by selection.

Both Binding Strength and Evolutionary Accessibility Affect the Population Frequency of Transcription Factor Binding Sequences in Arabidopsis thaliana

“…To this end, we first identified 8,333 genomic loci that are bound by 1 of 19 analyzed transcription factors in vivo. Consistent with previous reports in A. thaliana and other species, we found low genetic diversity at bound loci, suggesting that they are subject to purifying selection ( Heyndrickx et al 2014 ; Wang et al 2018 ; Radke et al 2021 ). We then studied two factors that may contribute to the high population frequency of transcription factor binding sequences, namely a sequence’s binding affinity and its evolutionary accessibility.…”

Pleiotropic enhancers are ubiquitous regulatory elements in the human genome

“…Altogether, the analysis of ENCODE and FANTOM5 enhancers suggests that pleiotropic enhancers are ubiquitous regulatory elements in the human genome. The notion that such a high proportion of human enhancers can be pleiotropic suggests that small regions of regulatory DNA may contain abundant regulatory information and that these regions evolve under important evolutionary constraints, as was previously observed for some mammalian (Fish et al 2017;Hiller et al 2012) and human (Radke et al 2021) pleiotropic enhancers.…”