Biology subjects

Rogers, J.

Publications and source records attributed to Rogers, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Historic and contemporary museum specimens implicate Northern Red-backed Vole (Clethrionomys rutilus) as borealpox host as early as 1990s

Borealpox virus (BRPV; formerly Alaskapox) is an orthopoxvirus that has caused seven reported human infections in Alaska since 2015, including a fatal case in 2023. The natural reservoir of BRPV is unknown, although previous investigations have raised the possibility of wild small mammals transmitting the virus to humans, either through direct contact or via domestic cats and dogs. To understand which species may be involved in the maintenance and/or spillover of BRPV in Alaska, we trapped and sampled wild small mammals (including voles, shrews, and squirrels) in 2021 and 2024 near reported human case locations in Fairbanks and the Kenai Peninsula, respectively. We found evidence of previous exposure to orthopoxviruses in five species (including the House Mouse, Mus musculus) and detected BRPV DNA as well as viable virus in Northern Red-backed Voles (Clethrionomys rutilus). Further, screening of tissues from historical museum specimens revealed BRPV DNA in C. rutilus specimens collected in Denali National Park and Preserve in 1998 and 1999, 17 years before the first reported human case of BRPV. Phylogenomic analysis of all human and animal BRPV isolates strongly supports the hypothesis of local human infections through multiple spillover events. These findings suggest C. rutilus as a possible reservoir species for BRPV and indicate that BRPV has been present in Alaskan wild small-mammal populations for at least 25 years. Our study highlights the potential of museum collections to elucidate the temporal, spatial, and host ranges of emerging pathogens. Further museum- and field-based sampling will clarify the true geographic range of BRPV, which is closely related to Old World orthopoxviruses and may be circulating beyond North America.

ecology↗

bioRxiv2026

Creating bacterial genomic diversity through large-scale reconfigurations reveals phenotype robustness to organizational genome change

The ability to generate genomic diversity expands opportunities for understanding and engineering biology. Here, we demonstrate on-demand generation of diversity in bacterial genome configurations and its application to probing physiology under altered genome organization. We engineered the fast-growing bacterium Vibrio natriegens to enable large-scale stochastic duplications, translocations, inversions, and deletions, producing populations with a wide range of genome arrangements. We investigated phenotypic robustness to genome reconfigurations and found that distinct genome organizations can support stable physiology, indicating that bacteria may tolerate chromosomal alterations more readily than previously appreciated. Our work provides a framework for advancing the understanding and engineering of bacterial genomes and suggests that genome reconfigurations may contribute to phenogenetic drift, allowing for evolutionary exploration while preserving phenotype.

synthetic biology↗

bioRxiv2025

MosaicSim: A Novel Mosaic Variant Simulator Reveals Diminishing Returns of Ultra-High Coverage for Mosaic Variant Detection

Genetic mutations within select cells of a tissue, termed mosaic variants (MV), are being increasingly recognized for their role in human disease. This growing interest underscores the need for specialized tools to detect and analyze MVs. However, such detection methods still lack thorough evaluation, largely due to missing benchmarking datasets that are large, reliable, and reflective of the complexity of biological samples. To address this gap, we developed MosaicSim, a tool for simulating variants in realistic sequencing data. The TweakVar workflow is at the tools core and represents a unique simulation pipeline that layers simulated MVs onto empirical whole genome sequencing data, generating a large, realistic ground truth dataset that combines the strengths of both simulation and biological data. To demonstrate the functionality of the workflow, we simulated 1,000 mosaic single nucleotide polymorphisms using TweakVar within whole genome sequencing files of different coverages. MVs were called with Illuminas DRAGEN and compared to the ground truth. Our results show 150x-445x coverage performed comparably, with a true-positive rate between 50.4% (300x) and 54.9% (150x) and no false-positives detected. Across all samples, increasing variant allele frequency had a significant positive effect on call success. Additionally, we observed that call rates for variants in lower complexity regions improved with increasing read depth. We did not find significant effects attributable to specific mutation patterns or mean read map quality. MosaicSim fills a critical unmet need by providing representative, customizable ground truth datasets for MV benchmarking, enabling systematic evaluation and optimization of variant calling methods.

genomics↗

bioRxiv2025

Chimeric Antigen Receptors Transmit Piconewton Forces that are Coupled with T Cell Function

Chimeric antigen receptor (CAR) T cells are engineered to display a receptor that binds antigens expressed on the surface of cancerous cells, which leads to cancer cytotoxicity. Recently, the T cell field has come to recognize the role of small, piconewton level forces in establishing specificity and cytotoxicity in naive T cells with the {beta} TCR, raising the possibility that these forces could be present in CAR T cells. Using DNA-based tension probes, we reveal 8-19 pN mechanical forces with [~]1 sec timescales transmitted by CAR T cells to their target antigens. CAR-antigen force magnitude is independent of CAR expression level and shows heterogeneity across different T cell donors, suggesting utility as a biomarker of T cell fitness. Using an established exhaustion model, we show strong correlation between CAR exhaustion, cytotoxic capacity, and CAR-antigen force, suggesting that CAR mechanics provide a biomarker of CAR potency complementary to functional assays. Pharmacological inhibition studies demonstrate that CAR forces are driven by actin, Zap70 and Src family proximal kinases. Titration of dasatinib, a clinically used tyrosine kinase inhibitor also dampens both CAR-antigen tension and CAR function in a dose-dependent manner. Structural engineering of the CAR confirms that force levels are modulated by the scFv receptor and co-stimulatory domains, but force transmission requires CD3{zeta} ITAMs. Taken together, this work shows that CAR T cells transmit pN force to their cognate antigens which holds potential significance in the design and screening of CAR therapeutic candidates and for predicting treatment outcomes in a personalized fashion.

biophysics↗

bioRxiv2025

Drift and isolation drive genomic erosion and island speciation in a lineage of macaques

Allopatric speciation, especially on large islands and archipelagos, is a significant driver of evolutionary diversification, as geographic isolation fosters the independent evolution of populations1,2. In these isolated populations, lineage sorting and genetic drift dominate, accelerating allele fixation and reducing shared genetic variation3,4. Here, we investigated how sea-level transgression during the Early Holocene triggered rapid speciation in large vertebrates by studying macaques isolated on Dangan Island (DGD), located just 30 km from present-day Hong Kong. Whole-genome sequencing revealed that [~]10,000 years of isolation drove the macaques evolution into a distinct species, as indicated by pronounced genomic divergence (mean Fst > = 0.462 vs. mainland), 1.94 million lineage-specific variants, and complete ancestral differentiation with no evidence of post-isolation gene flow. A severe demographic collapse (effective population size, Ne {approx} 40) led to substantial genomic erosion (65.8% loss of genetic diversity). Paradoxically, this also enhanced resilience through drift-mediated genetic triage. Increased homozygosity exposed and purged lethal recessive alleles in lipid metabolism pathways (68% reduction in genetic load), while simultaneously fixing mildly deleterious variants--such as a splice-site mutation in SKAP2--thereby generating a form of genomic "burden" alongside rapid immune adaptation via 251 fixed missense mutations. These findings demonstrate that island isolation can drive vertebrate speciation within a few thousand years, with genetic drift playing a dominant role in shaping genomic architecture. Accordingly, conservation strategies should prioritize monitoring loss-of-function (LoF) variants in essential pathways and prescreening for deleterious allele combinations between donors and recipients prior to implementing genetic rescue in small, drift-sensitive populations.

genomics↗

bioRxiv2025

A phylogenetic protein-coding genome-phenome map of complex traits across 224 primate species.

Complex traits arise from networks of coding and regulatory loci, making it difficult to resolve their genetic basis. Macroevolutionary studies leverage tens of millions of years of divergence across species to uncover fixed genomic changes invisible to within-species approaches, such as GWAS, offering a complementary framework for generating hypotheses in biomedical research. Here, we present the first phylogenetic protein-coding primate-wide genome-phenome map (P3GMap), spanning 200 curated traits across 224 primate species, which we release through the Primate Genome-Phenome Archive (PGA, https://pgarchive.github.io). Using two complementary approaches, convergent amino acid substitutions and relative evolutionary rates, we linked protein-coding variation to complex phenotypes and identified thousands of candidate gene-trait associations, including lineage-specific signals related to diet, immunity, and lifespan. One sentence summaryCross-species genome-phenome mapping in primates reveals thousands of protein-coding variants linked to the evolution of complex traits.

evolutionary biology↗

bioRxiv2025

Shared genetic basis for brain structure, insulin resistance and inflammation in schizophrenia: a colocalization study

Schizophrenia (SZ) is accompanied by structural brain alterations and elevated cardiometabolic risk, potentially linked through shared immune-metabolic mechanisms. To test for shared genetic underpinnings, we performed multi-trait colocalization across SZ, structural MRI measures (bilateral cortical thickness, grey matter volume), insulin resistance markers (TG:HDL-C ratio, fasting insulin adjusted for BMI), and IL-6 signalling traits (IL-6, IL-6R, IL-6ST) at 185 genome-wide significant loci. Colocalization was detected at 53 loci, including a robust cluster at the SLC39A8 missense variant rs13107325 linking SZ with cortical structure, peripheral IL-6ST, and TG:HDL-C (PPcoloc = 0.73-0.99). A secondary, lower-confidence colocalization signal at FGF21 (PPcoloc = 0.6) further implicated metabolic- behavioural coupling as a convergent pathway. Downstream analyses of rs13107325 pQTLs indicated enrichment in synaptic development and cardiometabolic pathways. Together, these findings identify rs13107325 as a shared causal variant bridging neurodevelopment, immunity, and metabolism, and highlight metal-ion transport and FGF21 signalling as potential therapeutic entry points to address the intertwined psychiatric and metabolic burden of SZ.

neuroscience↗

bioRxiv2025

Data-Driven Discovery of Mechanistic Ecosystem Models with LLMs

Ecosystem models are essential for ecosystem management, but their development traditionally requires significant time and expertise, creating bottlenecks in addressing urgent environmental challenges. We present LEMMA (LLM Enabled Mechanistic Modelling for ecosystem Assessment), a framework that programmatically generates and iteratively refines mechanistic ecosystem models by combining large language models (LLMs) for equation synthesis and parameter search, evolutionary algorithms for structural optimization, and Template Model Builder (TMB) for efficient parameter estimation. We critically review LEMMAs ability to recover known ecological relationships through two complementary marine case studies: (1) a nutrient-phytoplankton-zooplankton model, and (2) a Crown-of-Thorns starfish (COTS) model. In the first case, our best models displayed almost perfect recovery of known ecological dynamics while maintaining strong predictive performance across multivariate time-series. In the second case, best LEMMA generated models approached human expert models in terms of their ability to successfully capture COTS outbreak dynamics and demonstrated strong out-of-sample predictive power. LEMMA produces interpretable models with meaningful parameters that capture real biological processes, facilitating scientific insight and potentially accelerating management applications. By dramatically accelerating model development while offering ecological interpretability, LEMMA offers a powerful new tool for addressing urgent ecological challenges in a changing world.

ecology↗

bioRxiv2025

The genomic landscape of spider monkeys and northern muriquis from a conservation perspective

BackgroundMost populations of spider monkeys (Ateles) and muriquis (Brachyteles), two Neotropical primate genera, are under severe anthropogenic threats. Yet, taxon-wide population-level studies leveraging their degree of endangerment linked to their genetic diversity patterns and demographic history are lacking. To properly address this, there is a need to expand from morphological and genetic marker-based studies. ResultsWe generated high-coverage genome sequencing for 58 individuals sampled across 8 Atelidae species, in the first population-wide study of all extant spider monkey species, in the wild and captivity, alongside northern muriquis (Brachyteles hypoxanthus). Additionally, we present a high-contiguity reference genome for Ateles hybridus. Here, we observe the overall levels of genetic diversity and genetic load of the analyzed populations do not align to their IUCN endangerment category. Moreover, we show that in the wild, genetic load is overall higher compared to the captive populations analyzed. Then, we depict two main trans and cis-Andean sister clades in Ateles, and further structure and dynamics outlined by the Madeira River in the latter clade. Lastly, we find that genes in highly divergent regions between Ateles and B. hypoxanthus are involved in central nervous system development and photorreception. ConclusionsOur study shows i) the lack of concordance between the genetic diversity levels and extinction risk of these populations, suggestive of recent and strong external drivers; ii) increased genetic load in the wild in contrast to effective captive management, indicating mostly past demographic events; iii) structure and dynamics in spider monkeys that agrees with common biogeographical patterns and iv) genetic divergence between Ateles and Brachyteles potentially linked to distinct environmental light levels.

genomics↗

bioRxiv2024

Unprecedented female mutation bias in aye-ayes

Every mammal studied to date has been found to have a male mutation bias: male parents transmit more de novo mutations to offspring than female parents, contributing increasingly more mutations with age. Although male-biased mutation has been studied for more than 75 years, its causes are still debated. One obstacle to understanding this pattern is its near universality--without variation in mutation bias, it is difficult to find an underlying cause. Here, we present new data on multiple pedigrees from two primate species: aye-ayes (Daubentonia madagascarensis), a member of the strepsirrhine primates, and olive baboons (Papio anubis). In stark contrast to the pattern found across mammals, we find a much larger effect of maternal age than paternal age on mutation rates in the aye-aye. In addition, older aye-aye mothers transmit substantially more mutations than older fathers. We carry out both computational and experimental validation of our results, contrasting them with results from baboons and other primates using the same methodologies. Further, we analyze a set of DNA repair and replication genes to identify candidate mutations that may be responsible for the change in mutation bias observed in aye-ayes. Our results demonstrate that mutation bias is not an immutable trait, but rather one that can evolve between closely related species. Further work on aye-ayes (and possibly other lemuriform primates) should help to explain the molecular basis for sex-biased mutation.

evolutionary biology↗

bioRxiv2024

Genomic signatures of island colonization in highly diverse primates

Understanding how small populations cope with loss of genetic diversity and deleterious variation is crucial to address the current biodiversity crisis. Insular populations are particularly interesting as they have often persisted at low population sizes and higher inbreeding than their mainland counterparts. While the genome-wide consequences of inbreeding in threatened insular species have received some attention, comparative genomics between insular and mainland populations of wide-spread and genetically diverse species have rarely been performed. Yet, they are particularly well suited to inform about the consequences of drastic population declines from initially large populations - a phenomenon that is becoming increasingly common. The spot-nosed monkey (Cercopithecus petaurista), the Campbells monkey (Cercopithecus campbelli) and the green monkey (Chlorocebus sabaeus) are common and genetically diverse West African primates. Insular populations can be found at the Bijagos Archipelago, Guinea-Bissau. Here, we assessed the genome-wide diversity, inbreeding, genetic load and adaptive variation using whole genome sequencing data from insular and mainland populations. In the three species, island populations showed lower genome-wide diversity and higher inbreeding. Genetic drift has likely promoted the conversion of masked genetic load into realized load without increased purging of deleterious variation. Additionally, we found no evidence for accumulation of deleterious variation, suggesting that these populations are not yet at risk of extinction by genetic factors and may act as reservoirs of mainland genetic diversity. We highlight, however, that other anthropogenic factors are threatening these insular primates and therefore conservation management should target their immediate threats and safeguard against additional loss of diversity.

genomics↗

bioRxiv2024

Low mutation rate but high male-bias in the germline of a short-lived opossum

Age and sex have been found to be important determinants of the mutation rate per generation in mammals, but the mechanisms underlying these factors are still unclear. One approach to distinguishing between alternative mechanisms is to study species that reproduce at very young ages, as competing hypotheses make different predictions about patterns of mutation in these organisms. Here, we study the germline mutation rate in the gray short-tailed opossum, Monodelphis domestica, a laboratory model species that becomes reproductively mature at less than six months of age. Whole-genome sequencing of 22 trios reveals the lowest mutation rate per generation found in mammals thus far (0.26 x 10-8 per base pair per generation at an average parental age of 313 days), which is expected given their early reproduction. We also examine the mutation spectrum and find fewer mutations at CpG sites in opossums than in humans, consistent with the lower CpG content in the opossum genome. We observe that two-thirds of mutations are inherited from the male parent in opossums, slightly lower than the degree of male bias observed in organisms that reproduce at much older ages. Nevertheless, the very young age at reproduction in opossums suggests that ongoing spermatogonial divisions in males after puberty are not the primary driver of the observed male mutation bias. These findings contribute to a growing body of evidence that the differences between male and female germline mutation may arise from mechanisms other than cell division post-puberty. Article SummaryThis study investigates the germline mutation rate in the gray short-tailed opossum, a marsupial with early reproductive maturity. By sequencing 22 families, we report the lowest mutation rate recorded in mammals but a typical male mutation bias. These findings add to growing evidence that challenges the traditional view that continuing cell division is the primary driver of male-biased mutations. Instead, the study suggests that alternative mechanisms, such as differences in DNA repair, may influence sex-specific mutation rates.

evolutionary biology↗

bioRxiv2024

Multi-Channel Funnel Adapted Sensing Tube (MFAST) for the Simple and Duplex Detection of Parasites

Leishmaniasis poses a significant global health threat, infecting millions of people annually, particularly in tropical and subtropical regions. Timely and accurate detection of Leishmania species is crucial for effective treatment and control of this debilitating disease. This study introduces the Multi-channel Funnel Adapted Sensing Tube (MFAST) chip, an innovative diagnostic tool designed for the rapid detection of Leishmania panamensis. MFAST is fabricated through 3D printing and sacrificial molding of acrylonitrile butadiene styrene (ABS) and the reagents are transported between the reservoirs by gravity. We combine experiments and finite element analysis to reduce the leaking issues and facilitate smoother fluid flow, improving the overall performance of the device. Highly sensitive and specific RPA-CRISPR/Cas12a assay is utilized in the chip, achieving a detection limit as low as 1,000 parasites/mL (detecting as few as 5 parasites per reaction). The multi-channel design enables duplex detection, allowing for simultaneous identification of both L. braziliensis and L. panamensis through distinct channels. Furthermore, stability tests indicate that lyophilized reagents retain functionality for up to 15 days when stored at 4 {degrees}C, underscoring the potential of this chip for practical diagnostic applications in low-resource settings.

bioengineering↗

bioRxiv2023

Complete genomic assembly of Mauritian cynomolgus macaque killer immunoglobulin-like receptor and natural killer group 2 haplotypes

Mauritian-origin cynomolgus macaques (MCM) serve as a powerful nonhuman primate model in biomedical research due to their unique genetic homogeneity, which simplifies experimental designs. Despite their extensive use, a comprehensive understanding of crucial immune-regulating gene families, particularly killer immunoglobulin-like receptors (KIR) and natural killer group 2 (NKG2), has been hindered by the lack of detailed genomic reference assemblies. In this study, we employ advanced long-read sequencing techniques to completely assemble eight KIR and seven NKG2 genomic haplotypes, providing an extensive insight into the structural and allelic diversity of these immunoregulatory gene clusters. Leveraging these genomic resources, we prototype a strategy for genotyping KIR and NKG2 using short-read, whole exome capture data, illustrating the potential for cost-effective multi-locus genotyping at colony scale. These results mark a significant enhancement for biomedical research in MCMs and underscores the feasibility of broad-scale genetic investigations.

genomics↗

bioRxiv2023

Anaerobic fungi in the tortoise alimentary tract illuminate early stages of host-fungal symbiosis and Neocallimastigomycota evolution

The anaerobic gut fungi (AGF, Neocallimastigomycota) reside in the alimentary tract of herbivores. While their presence in mammals is well documented, evidence for their occurrence in non-mammalian hosts is currently sparse. Here we report on AGF communities in tortoises (family Testudinidae). Culture-independent surveys of tortoise fecal samples identified a unique AGF community, with three novel deep-branching genera representing >90% of sequences in most samples. Representatives of all genera were successfully isolated under strict anaerobic conditions at 30{degrees}C or 39{degrees}C. Transcriptomics-enabled phylogenomic and molecular dating analysis indicated an ancient, deep-branching position in the AGF tree for these genera, with an evolutionary divergence time estimate of 104-112 million years ago (Mya). Such estimates push the establishment of animal- Neocallimastigomycota symbiosis from the early Paleogene (67 Mya) to the early Cretaceous (112 Mya). Further, compared to their mammalian counterparts, tortoise-associated isolates exhibited a more limited capacity for plant polysaccharides metabolism and lacked genes encoding several carbohydrate active enzyme (CAZyme) families mediating their degradation. Finally, we demonstrate that the observed curtailed degradation capacities and reduced CAZyme repretoire in tortoise-associated AGF is driven by the paucity of horizontal gene transfer (HGT) in tortoise-associated AGF genomes, compared to the massive HGT occurrence in mammalian AGF taxa. The reduced CAZyome and overall secretory machinery observed is also reflected in an altered cellulosomal production capacity in tortoise-associated AGF. Our findings provide novel insights into the scope of phylogenetic diversity, ecological distribution, evolutionary history, evolution of fungal-host nutritional symbiosis, and dynamics of genes and traits acquisition in Neocallimastigomycota. SignificanceAnaerobic gut fungi (AGF) are encountered in the rumen and hindgut of mammalian herbivores. However, their occurrence outside their canonical mammalian hosts is currently unclear. We report the identification, isolation, and characterization of novel, deep-branching AGF genera from tortoises. Such discovery expands the phylogenetic diversity and host range of the AGF and revises estimates of the phylums evolutionary time to the early Cretaceous (112 Mya). We also demonstrate that tortoise-sourced AGF lack multiple metabolic features compared to their mammalian counterparts, and identify the relative paucity of HGT events in tortoise-associated genera as a major factor underpinning such differences. Our results alter our understanding of the scope of phylogenetic diversity, ecological distribution, and evolutionary history of the AGF.

microbiology↗

bioRxiv2023

Strong immunogenicity & protection in mice with PlaCCine: A COVID-19 DNA vaccine formulated with a functional polymer

DNA- based vaccines have demonstrated the potential as a safe and effective modality. PlaCCine, a DNA-based vaccine approach described subsequently relies on a synthetic DNA delivery system and is independent of virus or device. The synthetic functionalized polymer combined with DNA demonstrated stability over 12 months at 4C and for one month at 25C. Transfection efficiency compared to naked DNA increased by 5-15-fold in murine skeletal muscle. Studies of DNA vaccines expressing spike proteins from variants D614G (pVAC15), Delta (pVAC16), or a D614G + Delta combination (pVAC17) were conducted. Mice immunized intramuscular injection (IM) with pVAC15, pVAC16 or pVAC17 formulated with functionalized polymer and adjuvant resulted in induction of spike-specific humoral and cellular responses. Antibody responses were observed after one immunization. And endpoint IgG titers increased to greater than 1x 105 two weeks after the second injection. Neutralizing antibodies as determined by a pseudovirus competition assay were observed following vaccination with pVAC15, pVAC16 or pVAC17. Spike specific T cell immune responses were also observed following vaccination and flow cytometry analysis demonstrated the cellular immune responses included both CD4 and CD8 spike specific T cells. The immune responses in vaccinated mice were maintained for up to 14 months after vaccination. In an immunization and challenge study of K18 hACE2 transgenic mice pVAC15, pVAC16 and pVAC17 induced immune responses lead to decreased lung viral loads by greater than 90% along with improved clinical score. These findings suggest that PlaCCine DNA vaccines are effective and stable and further development against emerging SARS-CoV-2 variants is warranted.

immunology↗

bioRxiv2023

Whole genome approach to the structure and dynamics of Cacajao wild populations

Despite showing the greatest primate diversity on the planet, genomic studies on Amazonian primates show very little representation in the literature. With 48 geolocalized high coverage whole genomes from wild uakari monkeys, we present the first population-level study on platyrrhines using whole genome data. In a very restricted range of the Amazon rainforest, eight uakari species (Cacajao genus) have been described and categorized into bald and black uakaris, based on phenotypic and ecological differences. Despite a slight habitat overlap, we show that posterior to their split 0.92 Mya, bald and black uakaris have remained independent, without gene flow. Nowadays, these two groups present distinct genetic diversity and group-specific variation linked to pathogens. We propose differing hydrology patterns and effectiveness of geographic barriers have modulated the intra-group connectivity and structure of uakari populations. Beyond increasing their representation, with this work we explored the effects of the Amazon rainforests dynamism on platyrrhine species.

evolutionary biology↗

bioRxiv2023

Robust inference of historical human generation times

Ragsdale and Thornton (2023) raise concerns about our recent estimates of historical human generation times, concluding that our results were "predominantly driven by nonbiological artifacts." While we believe these authors have pointed out several important sources of uncertainty, we show here that their main concerns are either not relevant to our study or support our conclusions as much as they cast doubt on them. In particular, the demographic simulations carried out by Ragsdale and Thornton assume all individuals with recent African ancestry are from West Africa, which is not appropriate for our sample. In contrast to the lack of visual concordance between predictions and data cited by these authors as evidence for a lack of fit, we demonstrate that our model provides a good statistical fit to data on the overall historical mutation spectrum, though one particular mutation type is an outlier. Furthermore, we show that the historical generation times inferred when using alternative methods for estimating the ages of individual alleles are largely in agreement with our results, particularly so when using results from Relate. Importantly, these analyses, as well as recent work from an independent group, confirm the idea that a model built on de novo mutations and applied to polymorphism data provides useful and reliable estimates of generation times in widely distant mammals.

evolutionary biology↗