Analysis of Genetic Variation Indicates DNA Shape Involvement in Purifying Selection

Molecular Biology and Evolution
Xiaofei WangRemo Rohs

Abstract

Noncoding DNA sequences, which play various roles in gene expression and regulation, are under evolutionary pressure. Gene regulation requires specific protein-DNA binding events, and our previous studies showed that both DNA sequence and shape readout are employed by transcription factors (TFs) to achieve DNA binding specificity. By investigating the shape-disrupting properties of single nucleotide polymorphisms (SNPs) in human regulatory regions, we established a link between disruptive local DNA shape changes and loss of specific TF binding. Furthermore, we described cases where disease-associated SNPs may alter TF binding through DNA shape changes. This link led us to hypothesize that local DNA shape within and around TF binding sites is under selection pressure. To verify this hypothesis, we analyzed SNP data derived from 216 natural strains of Drosophila melanogaster. Comparing SNPs located in functional and nonfunctional regions within experimentally validated cis-regulatory modules (CRMs) from D. melanogaster that are active in the blastoderm stage of development, we found that SNPs within functional regions tended to cause smaller DNA shape variations. Furthermore, SNPs with higher minor allele frequency were more like...Continue Reading

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Citations

Sep 16, 2018·Genome Biology·Chaorui DuanWenfeng Qian
Oct 22, 2020·Nucleic Acids Research·Hannah C AinsworthCarl D Langefeld
May 1, 2021·International Journal of Molecular Sciences·Chia-Chun TsengShun-Jen Chang

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Datasets Mentioned

BETA
PRJNA36679
PRJNA74721

Methods Mentioned

BETA
ChIP-seq

Software Mentioned

DNAshape
REDfly
phastCons
UCSC Genome Browser

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