Biology subjects

Beichman, A. C.

Publications and source records attributed to Beichman, A. C..

4 recordsLinked to original sources

bioRxiv2023

Reproductive life history may modulate selection on the germline mutation rate

Mutation rates vary across the tree of life by many orders of magnitude, with lower mutation rates in species that reproduce quickly and maintain large effective population sizes. A compelling explanation for this trend is that large effective population sizes facilitate selection against weakly deleterious "mutator alleles" such as variants that interfere with the molecular efficacy of DNA repair. However, in multicellular organisms, the relationship of the mutation rate to DNA repair efficacy is complicated by variation in reproductive age. Long generation times leave more time for mutations to accrue each generation, and late reproduction likely amplifies the fitness consequences of any DNA repair defect that creates extra mutations in the sperm or eggs. Here, we present theoretical and empirical evidence that a long generation time amplifies the strength of selection for low mutation rates in the spermatocytes and oocytes. This leads to the counterintuitive prediction that the species with the highest germline mutation rates per generation are also the species with most effective mechanisms for DNA proofreading and repair in their germ cells. In contrast, species with different generation times accumulate similar mutation loads during embryonic development. Our results parallel recent findings that the longest-lived species have the lowest mutation rates in adult somatic tissues, potentially due to selection to keep the lifetime mutation load below a harmful threshold. Significance StatementAll cells accumulate mutations due to DNA damage and replication errors. When mutations occur in germ tissues including sperm, eggs, and the early embryo, they create changes in the gene pool that can be passed down to future generations. Here, we examine how rates of germline mutations vary within and between mammalian species, and we find that species which reproduce at older ages tend to accumulate fewer mutations per year in their sperm and eggs. This finding suggests that the evolution of humans long reproductive lifespan created evolutionary pressure to improve the fidelity of DNA maintenance in germ tissues, paralleling the pressure to avoid accumulating too many mutations in the body over a long lifespan.

evolutionary biology↗

bioRxiv2023

Evolution of the mutation spectrum across a mammalian phylogeny

Little is known about how the spectrum and etiology of germline mutagenesis might vary among mammalian species. To shed light on this mystery, we quantify variation in mutational sequence context biases using polymorphism data from thirteen species of mice, apes, bears, wolves, and cetaceans. After normalizing the mutation spectrum for reference genome accessibility and k-mer content, we use the Mantel test to deduce that mutation spectrum divergence is highly correlated with genetic divergence between species, whereas life history traits like reproductive age are weaker predictors of mutation spectrum divergence. Potential bioinformatic confounders are only weakly related to a small set of mutation spectrum features. We find that clocklike mutational signatures previously inferred from human cancers cannot explain the phylogenetic signal exhibited by the mammalian mutation spectrum, despite the ability of these clocklike signatures to fit each species 3-mer spectrum with high cosine similarity. In contrast, parental aging signatures inferred from human de novo mutation data appear to explain much of the mutation spectrums phylogenetic signal when fit to non-context-dependent mutation spectrum data in combination with a novel mutational signature. We posit that future models purporting to explain the etiology of mammalian mutagenesis need to capture the fact that more closely related species have more similar mutation spectra; a model that fits each marginal spectrum with high cosine similarity is not guaranteed to capture this hierarchy of mutation spectrum variation among species.

evolutionary biology↗

bioRxiv2022

Evolution of the SARS-CoV-2 mutational spectrum

SARS-CoV-2 evolves rapidly in part because of its high mutation rate. Here we examine whether this mutational process itself has changed during viral evolution. To do this, we quantify the relative rates of different types of single nucleotide mutations at four-fold degenerate sites in the viral genome across millions of human SARS-CoV-2 sequences. We find clear shifts in the relative rates of several types of mutations during SARS-CoV-2 evolution. The most striking trend is a roughly two-fold decrease in the relative rate of G[->]T mutations in Omicron versus early clades, as was recently noted by Ruis et al (2022). There is also a decrease in the relative rate of C[->]T mutations in Delta, and other subtle changes in the mutation spectrum along the phylogeny. We speculate that these changes in the mutation spectrum could arise from viral mutations that affect genome replication, packaging, and antagonization of host innate-immune factors--although environmental factors could also play a role. Interestingly, the mutation spectrum of Omicron is more similar than that of earlier SARS-CoV-2 clades to the spectrum that shaped the long-term evolution of sarbecoviruses. Overall, our work shows that the mutation process is itself a dynamic variable during SARS-CoV-2 evolution, and suggests that human SARS-CoV-2 may be trending towards a mutation spectrum more similar to that of other animal sarbecoviruses.

evolutionary biology↗

bioRxiv2022

Genomic underpinnings of population persistence in Isle Royale moose

Island ecosystems provide models to assess the impacts of isolation on population persistence. However, most studies of persistence have focused on a single species, without comparisons to other organisms they interact with in the ecosystem. The simple predator-prey system of moose and gray wolves on Isle Royale provides allows a direct contrast of genetic variation in a prey species with their natural predator. Wolves on Isle Royale exhibited signs of severe inbreeding depression, which nearly drove the population to extinction in 2019. In the relative absence of wolves, the moose population has thrived and exhibits no obvious signs of inbreeding depression despite being isolated for [~]120 years and having low genetic diversity. Here, we examine the genomic underpinnings of population persistence in the Isle Royale moose population. We document high levels of inbreeding in the population, roughly as high as the wolf population at the time of its decline. However, inbreeding in the moose population manifests in the form of intermediate-length runs of homozygosity indicative of gradual inbreeding, contrasting with the severe recent inbreeding observed in the wolf population. Using simulations, we demonstrate that this more gradual inbreeding in the moose population has resulted in an estimated 50% purging of the inbreeding load, helping to explain the continued persistence of the population. However, we also document notable increases in genetic load, which could eventually threaten population viability over the long term. Finally, we document low diversity in mainland North American moose populations due to a severe founder event occurring near the end of the Holocene. Overall, our results demonstrate a complex relationship between inbreeding, genetic diversity, and population viability that highlights the importance of maintaining isolated populations at moderate size to avert extinction from genetic factors. Significance statementIsolated wildlife populations face a high risk of extinction due in part to the deleterious consequences of inbreeding. Whether purifying natural selection can overcome these negative impacts by "purging" harmful recessive mutations is a topic of active debate. We characterized the extent of purging in an isolated moose population. Our results demonstrate signatures of gradual inbreeding in the population, ideal circumstances to facilitate purging. Using simulations, we demonstrate substantial potential for purging in the population, though we also show that fitness is reduced by small population size and inbreeding. Our findings provide insight into the mechanisms enabling persistence in isolated populations, with implications for conserving the growing number of isolated populations worldwide.

evolutionary biology↗