PT - JOURNAL ARTICLE AU - Noah Dukler AU - Mehreen R. Mughal AU - Ritika Ramani AU - Yi-Fei Huang AU - Adam Siepel TI - Extreme purifying selection against point mutations in the human genome AID - 10.1101/2021.08.23.457339 DP - 2021 Jan 01 TA - bioRxiv PG - 2021.08.23.457339 4099 - http://biorxiv.org/content/early/2021/08/23/2021.08.23.457339.short 4100 - http://biorxiv.org/content/early/2021/08/23/2021.08.23.457339.full AB - Genome sequencing of tens of thousands of human individuals has recently 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 at individual sites 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 (minor allele frequency < 0.1%) in a target set of genomic sites relative to matched sites that are putatively neutrally evolving, in a manner that controls for local variation and neighbor-dependence in mutation rate. We show using simulations that, above an appropriate threshold, 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 particularly strong evidence of ultraselection in evolutionarily ancient miRNAs and neuronal protein-coding genes, as well as at splice sites. Moreover, our estimated selection coefficient against heterozygous amino-acid replacements across the genome (at 1.4%) is substantially larger than previous estimates based on smaller sample sizes. By contrast, we find weak evidence of ultraselection 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, with one third to one half of ultraselected sites falling in coding regions. These estimates suggest ∼0.3–0.4 lethal or nearly lethal de novo mutations per potential human zygote, together with ∼2 de novo mutations that are more weakly deleterious. 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.Competing Interest StatementThe authors have declared no competing interest.