Exposing the evolutionary weak spots of the humangenome CSHL NatureComms
. Interestingly, despite their extreme levels of cross-species conservation, UCNEs show only modest levels of ultraselection, with= 0.09. This observation suggests that what is unusual about these elements is not the strength of selection acting on them , but instead the uniformity of selection acting at each nucleotide . Notably, HARs display only slightly lower levels of ultraselection than UCNEs and levels comparable to those of conserved sequences in introns.
Our assumption is that any point mutation at these ultraselected sites will be strongly deleterious, and simulations indicate that the detected sites are indeed subject to extreme purifying selection . Thus, if we multiply the expected numbers of sites by twice the estimated per-generation, per-nucleotide mutation rate , we obtain expected numbers of de novo strongly deleterious mutations per potential zygote . By this method, we estimate 0.258 ± 0.
. The expected number of strongly deleterious mutations per potential zygote increases to 0.505 ± 0.003, of which 0.12 fall in CDSs. Taking these calculations together, we estimate a range of 0.26–0.51 strongly deleterious mutations per potential zygote, implying a high genetic burden but one that appears to be roughly compatible with other lines of evidence .
We performed a parallel analysis using INSIGHT, to estimate the numbers and distribution of more weakly deleterious mutations . In this case, we estimate that 3.2% of sites are under selection and the expected number ofdeleterious mutations per fertilization is 2.21. The fraction of deleterious mutations from CDS is 22%, with most of the remainder coming from introns and intergenic regions. lncRNAs andUTRs also make significant contributions.
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