Abstract
The theory of population genetics leads to the expectation that in very large populations the frequencies of recessive lethal mutations are close to the square root of the mutation rate, corresponding to mutation-selection balance. There are numerous examples where the frequencies of such alleles are orders of magnitude larger than this result. In this work we theoretically investigate the role of temporal fluctuations in the heterozygous effect (h) for lethal mutations in very large populations. For fluctuations of h, around a mean value of \(\bar{h}\), we find a biased outcome that is described by an effective dominance coefficient, heff, that is generally less than the mean dominance coefficient, i.e., \({h}_{{\rm{eff}}}\, < \, \bar{h}\). In the case where the mean dominance coefficient is zero, the effective dominance coefficient is negative: heff < 0, corresponding to the lethal allele behaving as though overdominant and having an elevated mean frequency. This case plausibly explains mean allele frequencies that are an order of magnitude larger than the equilibrium frequency of a recessive allele with a constant dominance coefficient. Our analysis may be relevant to explaining lethal disorders with anomalously high frequencies, such as cystic fibrosis and Tay-Sachs, and may open the door to further investigations into the statistics of fluctuations of the heterozygous effect.
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Notes
Temporal homogeneity means the correlation of h (t1) and h (t2) only depends on t1 and t2 in the combination t1 − t2.
The approach we adopt, that the correlation time is non-zero but we treat as being negligible, plays an important role in the way the noise is treated (see Part D of the “Supplementary Material”).
If h(t) is correlated over relatively long times, then it ceases to behave like random fluctuations and is more plausibly represented as a known function of time.
The form of heff in Eq. (15) has a wider applicability than just fluctuating h. For the alternative selection scheme waa = 0, waA = 1 − ζ and wAA = 1 + η, where ∣ζ∣ and ∣η∣ are small, an approximation for the force is F(x) ≃ u − (η + ζ)x − x2 (see Eq. (B2) of Part B of the “Supplementary Material”). When there are fluctuations in the fitnesses of the non-lethal genotypes, i.e., in ζ and η, all results will be equivalent to just h fluctuating providing η(t) + ζ(t) has the same statistical properties as those we have adopted for h(t).
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We thank Professor Akihiro Fujimoto and two anonymous reviewers for comments which have helped us to significantly improve this manuscript.
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Overall, A.D.J., Waxman, D. Lethal mutations with fluctuating heterozygous effect: the lethal force of effective dominance. J Hum Genet 65, 1105–1113 (2020). https://doi.org/10.1038/s10038-020-0801-3
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DOI: https://doi.org/10.1038/s10038-020-0801-3