Extreme purifying selection against point mutations in the human genome

Dukler, Noah, Mughal, Mehreen, Ramani, Ritika, Huang, Yi-Fei, Siepel, Adam (September 2021) Extreme purifying selection against point mutations in the human genome. BioRxiv. (Unpublished)

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DOI: 10.1101/2021.08.23.457339


Genome sequencing of tens of thousands of humans has enabled the measurement of large selective effects for mutations to protein-coding genes. Here we describe a new method, called ExtRaINSIGHT, for measuring similar selective effects in noncoding as well as in coding regions of the human genome. ExtRaINSIGHT estimates the prevalance of strong purifying selection, or “ultraselection” (λs), as the fractional depletion of rare single-nucleotide variants in target genomic sites relative to matched sites that are putatively free from selection, after controlling for local variation and neighbor-dependence in mutation rate. We show using simulations that λs is closely related to the average site-specific selection coefficient against heterozygous point mutations, as predicted at mutation-selection balance. Applying ExtRaINSIGHT to 71,702 whole genome sequences from gnomAD v3, we find strong evidence of ultraselection in evolutionarily ancient miRNAs and neuronal protein-coding genes, as well as at splice sites. By contrast, we find weak evidence in other noncoding RNAs and transcription factor binding sites, and only modest evidence in ultraconserved elements and human accelerated regions. We estimate that ~0.3–0.5% of the human genome is ultraselected, implying ~0.3–0.4 lethal or nearly lethal de novo mutations per potential human zygote. Overall, our study sheds new light on the genome-wide distribution of fitness effects for new point mutations by combining deep new sequencing data sets and classical theory from population genetics.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > de novo mutation
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > genomes
organism description > animal > mammal > primates > hominids > human
CSHL Authors:
Communities: CSHL labs > Siepel lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 4 September 2021
Date Deposited: 26 May 2022 15:03
Last Modified: 26 May 2022 15:03
URI: https://repository.cshl.edu/id/eprint/40634

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