“Extreme Purifying Selection against Point Mutations in the Human Genome”, 2021-09-04 (; similar):
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 prevalence 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.
…What are the implications of our estimate of ~0.3–0.4 for the number of nearly lethal mutations per potential fertilization? This estimate implies a fairly high genetic burden for severely deleterious mutations (not to mention the additional burden imposed by weakly deleterious mutations), but one that appears to be in the plausible range (eg.23, 28). One rough point of comparison is the rate of spontaneous abortion, which has been estimated to be as high as 50% for mothers of prime reproductive age.49, 50 This quantity, of course, is not the same as the rate of nearly lethal mutations, for a variety of reasons—spontaneous abortion typically describes death prior to birth conditional on a detectable pregnancy, whereas our measure includes mutations that are lethal near the time of fertilization or even prior to fertilization, and also includes mutations that cause death after birth, that do not cause death but prevent an organism from reproducing, or that severely reduce fitness over several generations. In addition, many of the mutations that cause spontaneous abortion in the fetus are not point mutations, but instead major structural variants that often alter karyotype.49 At the same time, spontaneous abortion is only partly a consequence of the genetics of the embryo, also depending strongly on the environment and the genetics of the mother. Nevertheless, it is notable that these quite different estimates are in rough agreement with one another, suggesting an overlap in what they are measuring, perhaps with other factors approximately cancelling.