Extreme purifying selection against point mutations in the human genome

Dukler, Noah; Mughal, Mehreen R.; Ramani, Ritika; Huang, Yi; Siepel, Adam

doi:10.1038/s41467-022-31872-6

Cited by 26 publications

(20 citation statements)

References 63 publications

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“…We show a strong bias for GC4 content at constrained sites, which may help 'flag' transcripts as native 22 , and that single-exon genes and first exons of multi-exon genes have higher GC4 content across mammals, a pattern previously shown in humans 26 . We also show strong evidence for high constraint at 4d sites that occur at exon-intron boundaries, essential for ensuring the production of accurate transcripts 26,[46][47][48] . Whilst constraint on 4d sites at exon boundaries is generally high, it explains <3% of the overall 4d constraint we observe.…”

Section: Discussionmentioning

confidence: 64%

Interpreting mammalian evolutionary constraint at synonymous sites in light of the unwanted transcript hypothesis

Christmas,

Dong,

Meadows

et al. 2024

Preprint

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The unwanted transcript hypothesis presents a potential explanation for cryptic evolutionary constraint at synonymous sites in species with low effective population sizes, such as humans and other mammals. Selection for higher GC content and against mutations that alter splicing in native transcripts is predicted to shape synonymous site content and protect against unwanted transcripts. Here, we interpret mammalian synonymous site constraint in this context. Utilising the largest alignment of 240 placental mammal genomes and single-base resolution constraint scores, we show that 20.8% of four-fold degenerate sites are under significant constraint across mammals. There is a strong bias for guanine (G) and cytosine (C) at constrained sites, marked constraint near splice sites, and variation in human populations shows a bias against mutations that reduce synonymous site GC content. We find evidence for higher constraint on four-fold degenerate sites in species with small historic effective population sizes and high young transposable element genome content. Genes enriched for synonymous site constraint, including those forming CpG sites, are tightly regulated and integral to organismal viability through their involvement in embryo development and transcriptional regulation.

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Section: Discussionmentioning

confidence: 64%

Interpreting mammalian evolutionary constraint at synonymous sites in light of the unwanted transcript hypothesis

Christmas,

Dong,

Meadows

et al. 2024

Preprint

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“…However, we note that a major limitation of our study is that we are unable to finely estimate selection and dominance parameters for strongly deleterious mutations, which as defined here encompass a wide range of |s| from 0.01 to 1. This limitation is due to SFS-based methods being underpowered for estimating the strongly deleterious tail of the DFE [44], due to the fact that such mutations tend not to be segregating in genetic variation datasets [48][49][50]. Thus, an important area for future work is to further refine selection and dominance parameters for strongly deleterious mutations and determine whether dominance parameters may differ between strongly deleterious mutations (|s| on the order of ~0.01) and lethal mutations (|s|=1).…”

Section: Discussionmentioning

confidence: 99%

Constraining models of dominance for nonsynonymous mutations in the human genome

Kyriazis,

Lohmueller

2024

Preprint

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Dominance is a fundamental parameter in genetics, determining the dynamics of natural selection on deleterious and beneficial mutations, the patterns of genetic variation in natural populations, and the severity of inbreeding depression in a population. Despite this importance, dominance parameters remain poorly known, particularly in humans or other non-model organisms. A key reason for this lack of information about dominance is that it is extremely challenging to disentangle the selection coefficient (s) of a mutation from its dominance coefficient (h). Here, we explore dominance and selection parameters in humans by fitting models to the site frequency spectrum (SFS) for nonsynonymous mutations. When assuming a single dominance coefficient for all nonsynonymous mutations, we find that numeroushvalues can fit the data, so long ashis greater than ∼0.15. Moreover, we also observe that theoretically-predicted models with a negative relationship betweenhandscan also fit the data well, including models withh=0.05 for strongly deleterious mutations. Finally, we use our estimated dominance and selection parameters to inform simulations revisiting the question of whether the out-of-Africa bottleneck has led to differences in genetic load between African and non-African human populations. These simulations suggest that the relative burden of genetic load in non-African populations depends on the dominance model assumed, with slight increases for more weakly recessive models and slight decreases shown for more strongly recessive models. Moreover, these results also demonstrate that models of partially recessive nonsynonymous mutations can explain the observed severity of inbreeding depression in humans, bridging the gap between molecular population genetics and direct measures of fitness in humans. Our work represents a comprehensive assessment of dominance and deleterious variation in humans, with implications for parameterizing models of deleterious variation in humans and other mammalian species.Author SummaryThe dominance coefficient (h) of a mutation determines its impact on organismal fitness when heterozygous. For instance, fully recessive mutations (h=0) have no effects on fitness when heterozygous whereas additive mutations (h=0.5) have an effect that is intermediate to the two heterozygous mutations. The extent to which deleterious mutations may be recessive, additive, or dominant is a key area of study in evolutionary genetics. However, dominance parameters remain poorly known in humans and most other organisms due to a variety of technical challenges. In this study, we aim to constrain the possible set of dominance and selection parameters for amino acid changing mutations in humans. We find that a wide range of models are possible, including models with a theoretically-predicted relationship betweenhands. We then use a range of plausible selection and dominance models to explore how deleterious variation may have been shaped by the out-of-Africa bottleneck in humans. Our results highlight the subtle influence of dominance on patterns of genetic load in humans and demonstrate that models of partially recessive mutations at amino-acid-changing sites can explain the observed effects of inbreeding on mortality in humans.

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“…This apparently strong purifying selection has been proven difficult to reconcile with recent findings demonstrating remarkable resilience of UCNEs to variation (Snetkova, Ypsilanti, et al, 2021). Moreover, it has been suggested that weaker but uniform levels of purifying selection across hundreds of bases and different species could bring together these otherwise contradictory observations and explain why rare variants are not significantly depleted within UCNEs (Dukler et al, 2022). Our primary search space for variants with potential functional effects comprised 178 ultrarare variants located within 84 putatively active UCNEs associated with 29 genes.…”

Section: Discussionmentioning

confidence: 99%

Multi-omics analysis in human retina uncovers ultraconservedcis-regulatory elements at rare eye disease loci

Soriano

Rey

Mukherjee

et al. 2023

Preprint

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Cross-species genome comparisons have revealed a substantial number of ultraconserved non-coding elements (UCNEs). Several of these elements have proved to be essential tissue- and cell type-specificcis-regulators of developmental gene expression. Here, we characterized a set of UCNEs, as candidate CREs (cCREs) during retinal development and evaluate the contribution of their genomic variation to rare eye diseases, for which pathogenic non-coding variants are emerging. Integration of bulk and single-cell retinal multi-omics data revealed 594 genes under potentialcis-regulatory control of UCNEs, of which 45 are implicated in rare eye disease. Mining of candidatecis-regulatory UCNEs in WGS data derived from the rare eye disease cohort of Genomics England revealed 178 ultrarare variants within 84 UCNEs associated with 29 disease genes. Overall, we provide a comprehensive annotation of ultraconserved non-coding regions acting as cCREs during retinal development which can be targets of non-coding variation underlying rare eye diseases.

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Extreme purifying selection against point mutations in the human genome

Cited by 26 publications

References 63 publications

Interpreting mammalian evolutionary constraint at synonymous sites in light of the unwanted transcript hypothesis

Interpreting mammalian evolutionary constraint at synonymous sites in light of the unwanted transcript hypothesis

Constraining models of dominance for nonsynonymous mutations in the human genome

Multi-omics analysis in human retina uncovers ultraconservedcis-regulatory elements at rare eye disease loci

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