Recurrent mutation in the ancestry of a rare variant

Abstract Recurrent mutation produces multiple copies of the same allele which may be co-segregating in a population. Yet, most analyses of allele-frequency or site-frequency spectra assume that all observed copies of an allele trace back to a single mutation. We develop a sampling theory for the num...

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Bibliographic Details
Published in:Genetics (Austin) 2023-07, Vol.224 (3)
Main Authors: Wakeley, John, Fan, Wai-Tong (Louis), Koch, Evan, Sunyaev, Shamil
Format: Article
Language:English
Subjects:
Alleles
Frequency spectrum
Gene Frequency
Genetics
Genetics, Population
Genomes
Humans
Investigation
Models, Genetic
Mutation
Mutation Rate
Mutation rates
Population genetics
Populations
Sampling
Single-nucleotide polymorphism
Spectra
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Summary:Abstract Recurrent mutation produces multiple copies of the same allele which may be co-segregating in a population. Yet, most analyses of allele-frequency or site-frequency spectra assume that all observed copies of an allele trace back to a single mutation. We develop a sampling theory for the number of latent mutations in the ancestry of a rare variant, specifically a variant observed in relatively small count in a large sample. Our results follow from the statistical independence of low-count mutations, which we show to hold for the standard neutral coalescent or diffusion model of population genetics as well as for more general coalescent trees. For populations of constant size, these counts are distributed like the number of alleles in the Ewens sampling formula. We develop a Poisson sampling model for populations of varying size and illustrate it using new results for site-frequency spectra in an exponentially growing population. We apply our model to a large data set of human SNPs and use it to explain dramatic differences in site-frequency spectra across the range of mutation rates in the human genome.
ISSN:1943-2631
0016-6731
1943-2631
DOI:10.1093/genetics/iyad049