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Variation in DNA repair genes can increase cancer risk by elevating the rate of oncogenic mutation. Defects in one such gene, MUTYH, are known to elevate the incidence of colorectal cancer in a recessive Mendelian manner. Recent evidence has also linked MUTYH to a mutator phenotype affecting normal somatic cells as well as the female germline. Here, we use whole genome sequencing to measure germline de novo mutation rates in a large extended family containing both mothers and fathers who are affected by pathogenic MUTYH variation. By developing novel methodology that uses siblings as "surrogate parents" to identify de novo mutations, we were able to include mutation data from several children whose parents were unavailable for sequencing. In the children of mothers affected by the pathogenic MUTYH genotype p.Y179C/V234M, we identify an elevation of the C>A mutation rate that is weaker than mutator effects previously reported to be caused by other pathogenic MUTYH genotypes, suggesting that mutation rates in normal tissues may be useful for classifying cancer-associated variation along a continuum of severity. Surprisingly, we detect no significant elevation of the C>A mutation rate in children born to a father with the same MUTYH genotype, and we similarly find that the mutator effect of the mouse homolog Mutyh appears to be localized to embryonic development, not the spermatocytes. Our results suggest that maternal MUTYH variants can cause germline mutations by attenuating the repair of oxidative DNA damage in the early embryo., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Genetics Society of America.)

Variation in DNA repair genes can increase cancer risk by elevating the rate of oncogenic mutation. Defects in one such gene, MUTYH , are known to elevate the incidence of colorectal cancer in a recessive Mendelian manner. Recent evidence has also linked MUTYH to a mutator phenotype affecting normal somatic cells as well as the female germline. Here, we use whole genome sequencing to measure germline de novo mutation rates in a large extended family containing both mothers and fathers who are affected by pathogenic MUTYH variation. By developing novel methodology that uses siblings as "surrogate parents" to identify de novo mutations, we were able to include mutation data from several children whose parents were unavailable for sequencing. In the children of mothers affected by the pathogenic MUTYH genotype p.Y179C/V234M, we identify an elevation of the C>A mutation rate that is weaker than mutator effects previously reported to be caused by other pathogenic MUTYH genotypes, suggesting that mutation rates in normal tissues may be useful for classifying cancer-associated variation along a continuum of severity. Surprisingly, we detect no significant elevation of the C>A mutation rate in children born to a father with the same MUTYH genotype, and we similarly find that the mutator effect of the mouse homolog Mutyh appears to be localized to embryonic development, not the spermatocytes. Our results suggest that maternal MUTYH variants can cause germline mutations by attenuating the repair of oxidative DNA damage in the early embryo., Competing Interests: Competing interest statement B.S. consults for the company Constantiam Biosciences. J.O.K serves as a scientific advisor to the company MyOme. The authors declare no other competing interests.

Novel sequencing technologies are making it increasingly possible to measure the mutation rates of somatic cell lineages. Accurate germline mutation rate measurement technologies have also been available for a decade, making it possible to assess how this fundamental evolutionary parameter varies across the tree of life. Here, we review some classical theories about germline and somatic mutation rate evolution that were formulated using principles of population genetics and the biology of aging and cancer. We find that somatic mutation rate measurements, while still limited in phylogenetic diversity, seem consistent with the theory that selection to preserve the soma is proportional to life span. However, germline and somatic theories make conflicting predictions regarding which species should have the most accurate DNA repair. Resolving this conflict will require carefully measuring how mutation rates scale with time and cell division and achieving a better understanding of mutation rate pleiotropy among cell types.

Although evolutionary biologists have long theorized that variation in DNA repair efficacy might explain some of the diversity of lifespan and cancer incidence across species, we have little data on the variability of normal germline mutagenesis outside of humans. Here, we shed light on the spectrum and etiology of mutagenesis across mammals by quantifying 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 clock-like mutational signatures previously inferred from human cancers cannot explain the phylogenetic signal exhibited by the mammalian mutation spectrum, despite the ability of these 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 1-mer spectrum's phylogenetic signal 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., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Twentieth century industrial whaling pushed several species to the brink of extinction, with fin whales being the most impacted. However, a small, resident population in the Gulf of California was not targeted by whaling. Here, we analyzed 50 whole-genomes from the Eastern North Pacific (ENP) and Gulf of California (GOC) fin whale populations to investigate their demographic history and the genomic effects of natural and human-induced bottlenecks. We show that the two populations diverged ~16,000 years ago, after which the ENP population expanded and then suffered a 99% reduction in effective size during the whaling period. In contrast, the GOC population remained small and isolated, receiving less than one migrant per generation. However, this low level of migration has been crucial for maintaining its viability. Our study exposes the severity of whaling, emphasizes the importance of migration, and demonstrates the use of genome-based analyses and simulations to inform conservation strategies., (© 2023. Springer Nature Limited.)

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 4-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 2-fold decrease in the relative rate of G→T mutations in Omicron versus early clades, as was recently noted by Ruis et al. (2022. Mutational spectra distinguish SARS-CoV-2 replication niches. bioRxiv, doi:10.1101/2022.09.27.509649). 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 toward a mutation spectrum more similar to that of other animal sarbecoviruses., Competing Interests: Conflict of interest statement. J.D.B. is on the scientific advisory boards of Apriori Bio, Aerium Therapeutics, and Oncorus. J.D.B. receives royalty payments as an inventor on Fred Hutch’s licensed patents related to viral deep mutational scanning., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Island ecosystems provide natural laboratories 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 case study of moose and gray wolves on Isle Royale allows for a direct contrast of genetic variation in isolated populations that have experienced dramatically differing population trajectories over the past decade. Whereas the Isle Royale wolf population recently declined nearly to extinction due to severe inbreeding depression, the moose population has thrived and continues to persist, despite having low genetic diversity and being isolated for ∼120 years. Here, we examine the patterns of genomic variation underlying the continued persistence of 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 suggestive of historical inbreeding and purging, contrasting with the long runs of homozygosity observed in the smaller wolf population. Using simulations, we confirm that substantial purging has likely occurred in the moose population. However, we also document notable increases in genetic load, which could eventually threaten population viability over the long term. Overall, our results demonstrate a complex relationship between inbreeding, genetic diversity, and population viability that highlights the use of genomic datasets and computational simulation tools for understanding the factors enabling persistence in isolated populations., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

The genetic consequences of species-wide declines are rarely quantified because the timing and extent of the decline varies across the species' range. The sea otter (Enhydra lutris) is a unique model in this regard. Their dramatic decline from thousands to fewer than 100 individuals per population occurred range-wide and nearly simultaneously due to the 18th-19th century fur trade. Consequently, each sea otter population represents an independent natural experiment of recovery after extreme population decline. We designed sequence capture probes for 50 Mb of sea otter exonic and neutral genomic regions. We sequenced 107 sea otters from five populations that span the species range to high coverage (18-76×) and three historical Californian samples from ~1500 and ~200 years ago to low coverage (1.5-3.5×). We observe distinct population structure and find that sea otters in California are the last survivors of a divergent lineage isolated for thousands of years and therefore warrant special conservation concern. We detect signals of extreme population decline in every surviving sea otter population and use this demographic history to design forward-in-time simulations of coding sequence. Our simulations indicate that this decline could lower the fitness of recovering populations for generations. However, the simulations also demonstrate how historically low effective population sizes prior to the fur trade may have mitigated the effects of population decline on genetic health. Our comprehensive approach shows how demographic inference from genomic data, coupled with simulations, allows assessment of extinction risk and different models of recovery., (© 2021 John Wiley & Sons Ltd.)

In cases of severe wildlife population decline, a key question is whether recovery efforts will be impeded by genetic factors, such as inbreeding depression. Decades of excess mortality from gillnet fishing have driven Mexico's vaquita porpoise ( Phocoena sinus ) to ~10 remaining individuals. We analyzed whole-genome sequences from 20 vaquitas and integrated genomic and demographic information into stochastic, individual-based simulations to quantify the species' recovery potential. Our analysis suggests that the vaquita's historical rarity has resulted in a low burden of segregating deleterious variation, reducing the risk of inbreeding depression. Similarly, genome-informed simulations suggest that the vaquita can recover if bycatch mortality is immediately halted. This study provides hope for vaquitas and other naturally rare endangered species and highlights the utility of genomics in predicting extinction risk.

Although germline mutation rates and spectra can vary within and between species, common genetic modifiers of the mutation rate have not been identified in nature 1 . Here we searched for loci that influence germline mutagenesis using a uniquely powerful resource: a panel of recombinant inbred mouse lines known as the BXD, descended from the laboratory strains C57BL/6J (B haplotype) and DBA/2J (D haplotype). Each BXD lineage has been maintained by brother-sister mating in the near absence of natural selection, accumulating de novo mutations for up to 50 years on a known genetic background that is a unique linear mosaic of B and D haplotypes 2 . We show that mice inheriting D haplotypes at a quantitative trait locus on chromosome 4 accumulate C>A germline mutations at a 50% higher rate than those inheriting B haplotypes, primarily owing to the activity of a C>A-dominated mutational signature known as SBS18. The B and D quantitative trait locus haplotypes encode different alleles of Mutyh, a DNA repair gene that underlies the heritable cancer predisposition syndrome that causes colorectal tumors with a high SBS18 mutation load 3,4 . Both B and D Mutyh alleles are present in wild populations of Mus musculus domesticus, providing evidence that common genetic variation modulates germline mutagenesis in a model mammalian species., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Habitat loss and alteration has driven many species into decline, often to the point of requiring protection and intervention to avert extinction. Genomic data provide the opportunity to inform conservation and recovery efforts with details about vital evolutionary processes with a resolution far beyond that of traditional genetic approaches. The tricolored blackbird ( Agelaius tricolor ) has suffered severe losses during the previous century largely due to anthropogenic impacts on their habitat. Using a dataset composed of a whole genome paired with reduced representation libraries (RAD-Seq) from samples collected across the species' range, we find evidence for panmixia using multiple methods, including PCA (no geographic clustering), admixture analyses (ADMIXTURE and TESS conclude K = 1), and comparisons of genetic differentiation (average FST = 0.029). Demographic modeling approaches recovered an ancient decline that had a strong impact on genetic diversity but did not detect any effect from the known recent decline. We also did not detect any evidence for selection, and hence adaptive variation, at any site, either geographic or genomic. These results indicate that species continues to have high vagility across its range despite population decline and habitat loss and should be managed as a single unit., Competing Interests: None declared., (© 2020 The Authors. Evolutionary Applications published by John Wiley & Sons Ltd.)

Despite its recent invasion into the marine realm, the sea otter (Enhydra lutris) has evolved a suite of adaptations for life in cold coastal waters, including limb modifications and dense insulating fur. This uniquely dense coat led to the near-extinction of sea otters during the 18th-20th century fur trade and an extreme population bottleneck. We used the de novo genome of the southern sea otter (E. l. nereis) to reconstruct its evolutionary history, identify genes influencing aquatic adaptation, and detect signals of population bottlenecks. We compared the genome of the southern sea otter with the tropical freshwater-living giant otter (Pteronura brasiliensis) to assess common and divergent genomic trends between otter species, and with the closely related northern sea otter (E. l. kenyoni) to uncover population-level trends. We found signals of positive selection in genes related to aquatic adaptations, particularly limb development and polygenic selection on genes related to hair follicle development. We found extensive pseudogenization of olfactory receptor genes in both the sea otter and giant otter lineages, consistent with patterns of sensory gene loss in other aquatic mammals. At the population level, the southern sea otter and the northern sea otter showed extremely low genomic diversity, signals of recent inbreeding, and demographic histories marked by population declines. These declines may predate the fur trade and appear to have resulted in an increase in putatively deleterious variants that could impact the future recovery of the sea otter., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Inference of demographic history from genetic data is a primary goal of population genetics of model and nonmodel organisms. Whole genome-based approaches such as the pairwise/multiple sequentially Markovian coalescent methods use genomic data from one to four individuals to infer the demographic history of an entire population, while site frequency spectrum (SFS)-based methods use the distribution of allele frequencies in a sample to reconstruct the same historical events. Although both methods are extensively used in empirical studies and perform well on data simulated under simple models, there have been only limited comparisons of them in more complex and realistic settings. Here we use published demographic models based on data from three human populations (Yoruba, descendants of northwest-Europeans, and Han Chinese) as an empirical test case to study the behavior of both inference procedures. We find that several of the demographic histories inferred by the whole genome-based methods do not predict the genome-wide distribution of heterozygosity, nor do they predict the empirical SFS. However, using simulated data, we also find that the whole genome methods can reconstruct the complex demographic models inferred by SFS-based methods, suggesting that the discordant patterns of genetic variation are not attributable to a lack of statistical power, but may reflect unmodeled complexities in the underlying demography. More generally, our findings indicate that demographic inference from a small number of genomes, routine in genomic studies of nonmodel organisms, should be interpreted cautiously, as these models cannot recapitulate other summaries of the data., (Copyright © 2017 Beichman et al.)

Mammals host gut microbiomes of immense physiological consequence, but the determinants of diversity in these communities remain poorly understood. Diet appears to be the dominant factor, but host phylogeny also seems to be an important, if unpredictable, correlate. Here we show that baleen whales, which prey on animals (fish and crustaceans), harbor unique gut microbiomes with surprising parallels in functional capacity and higher level taxonomy to those of terrestrial herbivores. These similarities likely reflect a shared role for fermentative metabolisms despite a shift in primary carbon sources from plant-derived to animal-derived polysaccharides, such as chitin. In contrast, protein catabolism and essential amino acid synthesis pathways in baleen whale microbiomes more closely resemble those of terrestrial carnivores. Our results demonstrate that functional attributes of the microbiome can vary independently even given an animal-derived diet, illustrating how diet and evolutionary history combine to shape microbial diversity in the mammalian gut.