A mutation rate model at the basepair resolution identifies the mutagenic effect of polymerase III transcription

Seplyarskiy, Vladimir; Koch, Evan M.; Lee, Daniel J.; Lichtman, Joshua S.; Luan, Harding H.; Sunyaev, Shamil R.

doi:10.1038/s41588-023-01562-0

Cited by 9 publications

(8 citation statements)

References 46 publications

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“…If β/n ≪ 1, the ancestral process of tracing back to these mutations will be complete before the population has changed much in size and the results of Section 3.4 will hold. But this is clearly not the case for the gnomAD data in Wakeley et al (2023) and Seplyarskiy et al (2023). The distribution of n 1 in the non-Finnish European sample with n = 114K is well fit by β/n = 3.…”

Section: Discussionmentioning

confidence: 85%

“…See for example Fig. 3 in Seplyarskiy et al (2023). Sample sizes would need to be orders of magnitude greater for the results in Section 3.4 to hold in this case.…”

Section: Discussionmentioning

confidence: 99%

“…Wakeley et al (2023) also contains an application to the frequencies of single-nucleotide sites with counts n 1 ∈ {1, 2, …, 40} of synonymous mutations in a subsample of 57K non-Finnish European individuals ( n = 114K) from the gnomAD database (Karczewski et al, 2020). Dramatic differences in sample frequency distributions of rare alleles with different mutation rates, categorized by the ‘Roulette’ method of Seplyarskiy et al (2023), were well explained by an empirical demographic model with recurrent mutation but no selection. Seplyarskiy et al (2023, Fig.…”

Section: Introductionmentioning

confidence: 94%

“…Dramatic differences in sample frequency distributions of rare alleles with different mutation rates, categorized by the ‘Roulette’ method of Seplyarskiy et al (2023), were well explained by an empirical demographic model with recurrent mutation but no selection. Seplyarskiy et al (2023, Fig. 3a) showed using simulations that a neutral, parametric demographic model fitted to these data also explained the frequencies of mutation in counts n 1 ≤ 10 4 .…”

Section: Introductionmentioning

confidence: 94%

“…For single nucleotide sites, these population-scaled mutation rates have been estimated for many species, using average pairwise sequence differences and assuming constant population size, and are typically about 0.01 with a range of about 0.0001 to 0.1 (Leffler et al, 2012). Values for humans are smaller but they vary almost as widely among sites in the genome, with a mean of about 0.0008 and a range of about 0.0001 to 0.02 (Seplyarskiy et al, 2021(Seplyarskiy et al, , 2023Wakeley et al, 2023). In contrast, there is no reason to suppose that the selection parameter |α| is small (Eyre-Walker and Keightley, 2007;Chen et al, 2020;Agarwal et al, 2023).…”

Section: Introductionmentioning

confidence: 99%

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Latent mutations in the ancestries of alleles under selection

Fan¹,

Wakeley

2023

Preprint

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We consider a single genetic locus with two alleles A_1 and A_2 in a large haploid population. The locus is subject to selection and two-way, or recurrent, mutation. Assuming the allele frequencies follow a Wright-Fisher diffusion and have reached stationarity, we describe the asymptotic behaviors of the conditional gene genealogy and the latent mutations of a sample with known allele counts, when the count n_1 of allele A_1 is fixed, and when either or both the sample size n and the selection strength |β| tend to infinity. Our study extends previous work under neutrality to the case of non-neutral rare alleles, asserting that when selection is not too strong relative to the sample size, even if it is strongly positive or strongly negative in the usual sense (β → -∞ or β → +∞), the number of latent mutations of the n_1 copies of allele A_1 follows the same distribution as the number of alleles in the Ewens sampling formula. On the other hand, very strong positive selection relative to the sample size leads to neutral gene genealogies with a single ancient latent mutation. We also demonstrate robustness of our asymptotic results against changing population sizes, when one of |β| or n is large.

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Section: Discussionmentioning

confidence: 85%

“…See for example Fig. 3 in Seplyarskiy et al (2023). Sample sizes would need to be orders of magnitude greater for the results in Section 3.4 to hold in this case.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Latent mutations in the ancestries of alleles under selection

Fan¹,

Wakeley

2023

Preprint

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Latent mutations in the ancestries of alleles under selection

Fan,

Wakeley

2024

Theoretical Population Biology

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A deep catalogue of protein-coding variation in 983,578 individuals

Sun,

Bai,

Chen

et al. 2024

Nature

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Rare coding variants that substantially affect function provide insights into the biology of a gene 1 – 3 . However, ascertaining the frequency of such variants requires large sample sizes 4 – 8 . Here we present a catalogue of human protein-coding variation, derived from exome sequencing of 983,578 individuals across diverse populations. In total, 23% of the Regeneron Genetics Center Million Exome (RGC-ME) data come from individuals of African, East Asian, Indigenous American, Middle Eastern and South Asian ancestry. The catalogue includes more than 10.4 million missense and 1.1 million predicted loss-of-function (pLOF) variants. We identify individuals with rare biallelic pLOF variants in 4,848 genes, 1,751 of which have not been previously reported. From precise quantitative estimates of selection against heterozygous loss of function (LOF), we identify 3,988 LOF-intolerant genes, including 86 that were previously assessed as tolerant and 1,153 that lack established disease annotation. We also define regions of missense depletion at high resolution. Notably, 1,482 genes have regions that are depleted of missense variants despite being tolerant of pLOF variants. Finally, we estimate that 3% of individuals have a clinically actionable genetic variant, and that 11,773 variants reported in ClinVar with unknown significance are likely to be deleterious cryptic splice sites. To facilitate variant interpretation and genetics-informed precision medicine, we make this resource of coding variation from the RGC-ME dataset publicly accessible through a variant allele frequency browser.

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A mutation rate model at the basepair resolution identifies the mutagenic effect of polymerase III transcription

Cited by 9 publications

References 46 publications

Latent mutations in the ancestries of alleles under selection

Latent mutations in the ancestries of alleles under selection

Latent mutations in the ancestries of alleles under selection

A deep catalogue of protein-coding variation in 983,578 individuals

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