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Influence of Dominance and Drift on Lethal Mutations in Human Populations.

ABSTRACT: We consider disease-causing mutations that are lethal when homozygous. Lethality involves the very strongest form of negative selection, with the selection coefficient against the disease-carrying homozygote having its maximum value of unity. We determine results for the behavior of the frequency of a lethal allele in an effectively infinite population. This includes an estimate of the time it takes to achieve equilibrium, and a description of transient behavior associated with a sudden change in the fitness of the heterozygote. We determine analogous results for a finite population, showing that a lethal disease-causing allele needs to be described by a modified Wright-Fisher model, which deviates from the standard model, where selection coefficients are assumed small compared with 1. We show that a by-product of the dynamics, resulting from the absence of the disease-allele carrying homozygote in adults, is the general constraint that the frequency of the disease-causing allele cannot exceed 12 . The results presented in this work should prove useful to a number of areas including analysis of lethal/near lethal mutations in Mendelian disorders and, in particular, for exploring how mutation-selection-drift balance explains the current spectrum of mutation frequencies in humans. While the number of empirical examples of overdominance in lethal genetic disorders is not large, relatively high observed heterozygote frequencies may be a hint of transient heterozygous advantage in nature. For lethal disorders with anomalous frequencies, such as cystic fibrosis and Tay-Sachs, our analysis lends further support to the role that transitory episodes of weak overdominance may play in the evolution of lethal mutations.

SUBMITTER: Waxman D

PROVIDER: S-EPMC7142268 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Influence of Dominance and Drift on Lethal Mutations in Human Populations.

Waxman David D Overall Andrew D J ADJ

Frontiers in genetics 20200402

We consider disease-causing mutations that are lethal when homozygous. Lethality involves the very strongest form of negative selection, with the selection coefficient against the disease-carrying homozygote having its maximum value of unity. We determine results for the behavior of the frequency of a lethal allele in an effectively infinite population. This includes an estimate of the time it takes to achieve equilibrium, and a description of transient behavior associated with a sudden change i ...[more]

PMID: 32300356

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Project description:Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

Project description:Reproduction is inherently risky, in part because genomic replication can introduce new mutations that are usually deleterious toward fitness. This risk is especially severe for organisms whose genomes replicate "semi-conservatively," e.g. viruses and bacteria, where no master copy of the genome is preserved. Lethal mutagenesis refers to extinction of populations due to an unbearably high mutation rate (U), and is important both theoretically and clinically, where drugs can extinguish pathogens by increasing their mutation rate. Previous theoretical models of lethal mutagenesis assume infinite population size (N). However, in addition to high U, small N can accelerate extinction by strengthening genetic drift and relaxing selection. Here, we examine how the time until extinction depends jointly on N and U. We first analytically compute the mean time until extinction (τ) in a simplistic model where all mutations are either lethal or neutral. The solution motivates the definition of two distinct regimes: a survival phase and an extinction phase, which differ dramatically in both how τ scales with N and in the coefficient of variation in time until extinction. Next, we perform stochastic population-genetics simulations on a realistic fitness landscape that both (i) features an epistatic distribution of fitness effects that agrees with experimental data on viruses and (ii) is based on the biophysics of protein folding. More specifically, we assume that mutations inflict fitness penalties proportional to the extent that they unfold proteins. We find that decreasing N can cause phase transition-like behavior from survival to extinction, which motivates the concept of "lethal isolation." Furthermore, we find that lethal mutagenesis and lethal isolation interact synergistically, which may have clinical implications for treating infections. Broadly, we conclude that stably folded proteins are only possible in ecological settings that support sufficiently large populations.

Dataset Information

Influence of Dominance and Drift on Lethal Mutations in Human Populations.

Publications

Influence of Dominance and Drift on Lethal Mutations in Human Populations.

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