Extreme purifying selection against point mutations in the human genome

Dukler, Noah, Mughal, Mehreen R, Ramani, Ritika, Huang, Yi-Fei, Siepel, Adam (July 2022) Extreme purifying selection against point mutations in the human genome. Nature Communications, 13 (1). p. 4312. ISSN 2041-1723

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Abstract

Large-scale genome sequencing has enabled the measurement of strong purifying selection in protein-coding genes. Here we describe a new method, called ExtRaINSIGHT, for measuring such selection in noncoding as well as coding regions of the human genome. ExtRaINSIGHT estimates the prevalence of "ultraselection" by the fractional depletion of rare single-nucleotide variants, after controlling for variation in mutation rates. Applying ExtRaINSIGHT to 71,702 whole genome sequences from gnomAD v3, we find abundant ultraselection in evolutionarily ancient miRNAs and neuronal protein-coding genes, as well as at splice sites. By contrast, we find much less ultraselection in other noncoding RNAs and transcription factor binding sites, and only modest levels in ultraconserved elements. We estimate that ~0.4-0.7% of the human genome is ultraselected, implying ~ 0.26-0.51 strongly deleterious mutations per generation. Overall, our study sheds new light on the genome-wide distribution of fitness effects by combining deep sequencing data and classical theory from population genetics.

Item Type:	Paper
Subjects:	bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics evolution bioinformatics > genomics and proteomics > genetics & nucleic acid processing > genomes bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mutations bioinformatics > genomics and proteomics > genetics & nucleic acid processing > population genetics
CSHL Authors:	Dukler, Noah Mughal, Mehreen Ramani, Ritika Siepel, Adam
Communities:	CSHL labs > Siepel lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	25 July 2022
Date Deposited:	22 Aug 2022 01:49
Last Modified:	11 Jan 2024 19:42
PMCID:	PMC9314448
URI:	https://repository.cshl.edu/id/eprint/40694

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