Biology subjects

Harris, K.

Publications and source records attributed to Harris, K..

At least 19 recordsLinked to original sources

bioRxiv2026

PlumageParts: A fine-grained avian plumage segmentation dataset and benchmark for ecological image analysis

Fine-grained localisation of plumage regions is a prerequisite for computational analyses of avian colouration, patterning and visual traits in ecological and evolutionary research. Progress is limited by the scarcity of image resources with annotations aligned to biologically meaningful anatomical units: existing avian benchmarks provide either landmark points or coarse part categories that do not capture ornithologically defined plumage regions. We present a curated dataset of 4,705 bird images annotated for nine plumage regions: head, throat, breast, belly, vent, back, coverts, remiges and tail. Spanning 39 avian orders and 222 families, the dataset provides a taxonomically broad resource for fine-grained avian image analysis. The dataset was built through an iterative model-assisted annotation workflow, in which model predictions were reviewed and corrected rather than drawn from scratch, improving the efficiency of region-level annotation. We benchmark classical segmentation architectures, SAM-based models and self-supervised foundation-model encoders on this task. A frozen DINOv3 encoder with a lightweight decoder achieved the highest performance on the held-out test set, reaching 84.01% mean Intersection over Union while requiring substantially less memory than end-to-end fine-tuning. The model generalised to external avian benchmarks, including the bird subset of PartImageNet and CUB-200-2011, and achieved competitive performance on the full PartImageNet part-segmentation benchmark, which includes diverse animal taxa. We provide a modular detect-track-segment pipeline as a proof-of-concept extension to video data. Together, these results show that anatomically grounded avian annotations can serve both as a resource for plumage phenotyping and as a benchmark for efficient, transferable biological part segmentation. Author SummaryBirds vary enormously in colour and pattern, but studying this variation at large scales requires more than identifying the bird in a photograph. Researchers often need to know where each colour or pattern occurs on the body, such as on the head, throat, breast, wing or tail. We created PlumageParts to make this kind of region-level analysis easier. The dataset contains 4,705 bird images annotated into nine biologically meaningful plumage regions, covering a wide range of bird families and orders. To build the dataset efficiently, we used a model-assisted workflow in which computer-generated masks were checked and corrected by researchers rather than drawn entirely by hand. We then tested several image-segmentation approaches and found that a frozen self-supervised vision model, combined with a lightweight decoder, provided accurate plumage-region predictions while requiring relatively modest computing resources. The same approach also performed well on a broader animal part-segmentation benchmark, suggesting that it may be useful beyond birds when suitable annotations are available. By releasing the annotations, code and trained model, we aim to support future studies of bird plumage and biologically meaningful image segmentation.

ecology↗

bioRxiv2026

Dual stimulation of CD40 and 41BB pathways during ex-vivo TIL expansion enhances CD8+ T cell expansion

BackgroundTumor-infiltrating lymphocyte (TIL) therapy has demonstrated clinical efficacy in malignant melanoma; however, inefficient ex vivo expansion remains a major limitation. We previously showed that stimulation of tumor-infiltrating B cells via CD40-CD40L axis improves TIL expansion, and that direct activation of the 41BB-41BBL pathway on T cells enhances CD8 T cell outgrowth. We hypothesized that adding simultaneous targeting of both pathways would augment the growth and activity of CD8+ cytotoxic T cells. We conducted a study with the objective of determining the feasibility of dual stimulation with human tumors as justification for a Phase I trial. MethodsCD40L variants were generated by yeast display selection and evaluated for B cell binding and activation. The effects of CD40L variants on TIL expansion were evaluated using tumors derived from standard of care resections using fragment method. Based on these findings, a bi-specific molecule was designed and generated fusing a CD40L variant and 41BB to the N- and C-termini of a trimeric leucine zipper. The effects of the bi-specific molecule (termed CD40LEPC6-41BBL) on TIL expansion were evaluated in TIL cultures derived from lung tumor and melanoma fragments. TIL phenotypes were assessed by flow cytometry, including high-dimensional FlowSOM analysis, and tumor reactivity by autologous tumor co-culture assays. ResultsEach of our engineered CD40L variants bound B cells and induced CD80/CD86 expression at levels comparable to wild-type CD40L. Supplementation of TIL cultures with CD40L variants increased the success rate of TIL expansion compared to control. We then developed a bi-specific CD40LEPC6-41BBL molecule capable of binding to both B and T cells. Addition of CD40LEPC6-41BBL significantly increased total TIL yield and improved expansion success rates in both lung tumor and melanoma cultures. In particular, CD40LEPC6-41BBL promoted preferential expansion of CD8 T cells. High-dimensional analysis revealed enrichment of CD8 T cell clusters expressing CD39, CD69, TIM3, and CD56 in cultures supplemented with CD40LEPC6-41BBL. Furthermore, treated cultures displayed increased frequencies of CD27 CD4 T cells. Functional assessment suggested a trend toward enhanced tumor reactivity in melanoma-derived TIL products expanded with CD40LEPC6-41BBL. ConclusionsSimultaneous stimulation of CD40 and 41BB pathways using a novel bi-specific molecule resulted in qualitative and quantitative enhancement of TIL products. These findings support dual targeting of tumor-infiltrating B cells and T cells as a promising strategy to optimize TIL manufacturing for adoptive cell therapy in Phase I trials.

immunology↗

bioRxiv2026

The avian colourscape is disproportionately threatened by species extinctions

The impact of projected extinctions on global animal colour diversity remains unknown. Combining citizen science with self-supervised deep learning, we built novel representations of bird plumage colour patterning based on >125,000 museum specimen images covering 9,143 species. We demonstrate that losing currently threatened bird species will drive a disproportionate reduction in avian plumage diversity, with the most severe losses occurring in tropical and subtropical regions. Furthermore, while humans generally find non-typical plumage phenotypes more aesthetically attractive, threatened species are unexpectedly deemed less visually appealing despite their comparatively unusual plumages. Overall, our results highlight severe, imminent threats to the existing avian colourscape and raise critical questions about the future of animal colour diversity in a changing world.

ecology↗

bioRxiv2025

The discovery and patterns of the underlying long-standing mild-effect mutator alleles in S. cerevisiae populations

Most mutations are neutral or deleterious, and mutator alleles that substantially increase the mutation rate of an organism are believed to be short-lived in natural populations. Theory suggests that mutator alleles of modest effect have the potential to segregate nearly neutrally, but this prediction has been difficult to test experimentally. Here, we report strong genomic signatures consistent with the transmission and long-term maintenance of at least one natural mutator allele in Saccharomyces cerevisiae isolates. Specifically, such signatures are consistent with segregation of mutator alleles that disproportionately increase A>C mutations in the African Beer strains of S. cerevisiae. Remarkably, the mutation spectra of African Beer strains deviate from that of other S. cerevisiae natural isolates more than some Saccharomyces species differ from each other. Furthermore, computational analysis suggests mutator allele introgression from the African Beer population into a subset of French Dairy yeast, motivating us to experimentally measure the de novo mutation rates and spectra of these strains. We observed a consistent but weak enrichment of A>C and A>G de novo mutations in the African Beer population, with the A>C enrichment also evident in the French Dairy subset. Unexpectedly, other de novo mutation types varied more substantially among strains, including one outlier African Beer strain (AFL) with an excess of C>A mutations. Overall, our measurements reveal that de novo mutation spectra show greater variability among populations compared to the mutation spectra of rare polymorphisms, which in turn show greater variability than the spectra of all polymorphisms. Together, while additional mutator alleles may segregate in natural populations, mild enrichment of A>C and A>G types in African Beer strains reflects mutator alleles with weak effects that can persist and accumulate mutations through evolution.

evolutionary biology↗

bioRxiv2025

A telomere-to-telomere map of somatic mutation burden and functional impact in cancer

Oncogenesis involves widespread genetic and epigenetic alterations, yet the full spectrum of somatic variation genome-wide remains unresolved. We generated a near-telomere-to-telomere (T2T) diploid assembly of a donor paired with deep short- and long-read sequencing of their melanoma. This revealed that 16% of somatic variants occur in sequences absent from GRCh38, with satellite repeats acting as hotspots for UV-induced damage due to sequence-intrinsic mutability and inefficient repair. Centromere kinetochore domains emerged as focal sites of structural, genetic, and epigenetic variation, leading to remodeling of centromere kinetochore binding domains during tumor evolution. Single-molecule telomere reconstructions uncovered cycles of attrition, deletion, and telomerase-mediated extension that shape cancer telomeres. Finally, diploid chromatin maps exposed that copy number alterations and epimutations, rather than point mutations, predominate in rewiring cancer regulatory programs. These findings define the full landscape of a cancers somatic variation and their functional impact, establishing a blueprint for T2T studies of mosaicism.

genomics↗

bioRxiv2025

The selective dynamics of interruptions at short tandem repeats

Short tandem repeats (STRs) are hotspots of genomic instability that mutate at rates orders of magnitude greater than non-repetitive loci due to frequent replication slippage. Expansions at some STR loci cause Mendelian diseases, while variation at other noncoding loci may affect complex traits, possibly by altering transcription factor occupancy of nearby binding sites. Accordingly, some STRs are inferred to be under purifying selection, regardless of their instability. One or more "interruptions", or bases that disrupt the locuss canonical repeat, significantly decrease an STRs mutability. For example, the onset of Huntingtons Disease, a neurodegenerative disorder associated with somatic expansions of a trinucleotide coding STR, is delayed in individuals whose inherited alleles contain interruptions. Thus, interruptions that decrease mutation rate at some coding loci may broadly protect against deleterious phenotypes associated with locus instability. However, interruptions may themselves be deleterious at constrained loci, particularly at noncoding loci in gene regulatory elements, possibly disrupting the formation of secondary structures key to their function. We therefore hypothesized that the frequency of interruptions could depend on a locuss functional importance-at constrained loci, the fitness effects of expansions but also interruptions could be more deleterious than at neutral loci. To test this hypothesis, we examined the distribution of interruptions at [~]650,000 autosomal STRs. In the [~]2,500 3- or 6bp-motif coding STRs, we find that synonymous interruption density increases with purifying selection on the gene, while the opposite is true for missense-causing interruptions. In contrast, noncoding STRs in gene regulatory elements harbor fewer interruptions than those unassociated with function and putatively evolving neutrally. Our findings indicate that the abundance of interruptions may be partially explained at coding STRs by the benefit of lower instability. In contrast, maintaining a minimum core stretch of uninterrupted repeat may be key to the function of noncoding STRs that fall within regulatory elements, outweighing the benefits of stability.

evolutionary biology↗

bioRxiv2025

A signature-agnostic test for differences between tumor mutation spectra reveals carcinogen and ancestry effects

Despite dozens of tools to identify mutational signatures in cancer samples, there is not an established metric for quantifying whether signature exposures differ significantly between two heterogeneous groups of samples. We demonstrate that a signature-agnostic metric - the aggregate mutation spectrum distance permutation method (AMSD) - can rigorously determine whether mutational exposures differ between groups, a hypothesis that is not directly addressed by signature analysis. First, we reanalyze a study of carcinogen exposure in mice, determining that eleven of twenty tested carcinogens produce significant mutation spectrum shifts. Only three of these carcinogens were previously reported to induce distinct mutational signatures, suggesting that many carcinogens perturb mutagenesis by altering the composition of endogenous signatures. Next, we interrogate whether patient ancestry has a measurable impact on human tumor mutation spectra, finding significant ancestry-associated differences across ten cancer types. Some have been previously reported, such as elevated SBS4 in African lung adenocarcinomas, while some have not to our knowledge been reported, such as elevated SBS17a/b in European esophageal carcinomas. These examples suggest that AMSD is a robust tool for detecting differences among groups of tumors or other mutated samples, complementing descriptive signature deconvolution and enabling the discovery of environmental and genetic influences on mutagenesis.

cancer biology↗

bioRxiv2025

Spatial and Temporal Patterns of Wolf Occurrences on the Summer Range of the Eastern Migratory Cape Churchill Caribou Population in the Hudson Bay Lowlands of Manitoba

Wolves (Canis lupus) function as a top predator across diverse ecosystems including the sub-arctic, and they have been managed in often controversial ways. Communities and scientists are increasingly supporting minimally invasive research and monitoring, including using trail cameras. We employed a network of 15 Reconyx trail cameras at three monitoring areas aimed at detecting the spatial and temporal aspects of wolf occurrences within the summer range of Eastern Migratory Cape Churchill caribou in Wapusk National Park in the Hudson Bay Lowlands of Manitoba, Canada from 2013-2021. In this first peer-reviewed quantitative study of wolves in the region, we found that wolves detection events were generally consistent across years. Wolf distribution was consistently positively skewed toward the southern part of the caribou summer range in all years. Wolves experienced extreme environmental conditions, with a 60{degrees}C range in temperature, from a low of -32{degrees}C in winter to a high of +28{degrees}C in summer and an annual change in day length of >11 hours between summer and winter. Wolves occurred most commonly in spring and summer and occurred at equal frequency during night and day overall but selected for nighttime in September, October, and November as day length shortened dramatically.

ecology↗

bioRxiv2025

Capsule-Based Single-Cell Genome Sequencing

Single-cell genomics methods have unveiled the heterogeneity present in seemingly homogenous populations of cells, however, these techniques require meticulous optimization. How exactly does one handle and manipulate the biological contents from a single cell? Here, we introduce and characterize a novel semi-permeable capsule (SPC), capable of isolating single cells and their contents while facilitating biomolecular exchange based on size-selectivity. These capsules maintain stability under diverse physical and chemical conditions and allow selective diffusion of biomolecules, effectively retaining larger biomolecules including genomic DNA, and cellular complexes, while permitting the exchange of smaller molecules, including primers and enzymes. We demonstrate the utility of SPCs for single cell assays by performing the simultaneous culture of over 500,000 cellular colonies, demonstrating efficient and unbiased nucleic acid amplification, and performing combinatorial indexing-based single-cell whole genome sequencing (sc-WGS). Notably, SPC-based sc-WGS facilitates uniform genome coverage and minimal cross-contamination allowing for the detection of genomic variants with high sensitivity and specificity. Leveraging these properties, we conducted a proof-of-concept lineage tracing experiment using cells harboring the hypermutator polymerase {varepsilon} allele (POLE P286R). Sequencing of 1000 single cell genomes at low depth facilitated the capture of lineage marks deposited throughout the genome during each cell division and the subsequent reconstruction of cellular genealogies. Capsule-based sc-WGS expands the single-cell genomics toolkit and will facilitate the investigation of somatic variants, resolved to single cells at scale.

genomics↗

bioRxiv2024

Direct measurement of the mutation rate and its evolutionary consequences in a critically endangered mollusk

The rate at which mutations arise is a fundamental parameter of biology. Despite recent progress in measuring germline mutation rates across diverse taxa, such estimates are missing for much of Earths biodiversity. We present the first estimate of a germline mutation rate from the phylum Mollusca, which is diverged by more than 1200 Ma years from the closest relative for which a mutation rate estimate exists. We sequenced three pedigreed families of the white abalone Haliotis sorenseni, a long-lived, large-bodied, and critically endangered mollusk, and estimated a de novo mutation rate of 8.60e-09 single nucleotide mutations per site per generation. This mutation rate is similar to rates measured in vertebrates with similar generation times and longevity to abalone, and higher than mutation rates measured in faster-reproducing invertebrates. We use our estimated rate to infer baseline effective population sizes (Ne) across multiple Pacific abalone and find that abalone persisted over most of their evolutionary history as large and stable populations, in contrast to extreme fluctuations over recent history and small census sizes in the present day. We then use our mutation rate to infer the timing and pattern of evolution of the abalone genus Haliotis, which was previously unknown due to few fossil calibrations. Our results are an important step toward understanding mutation rate evolution and establish a key parameter for conservation and evolutionary genomics research in mollusks.

evolutionary biology↗

bioRxiv2024

URA6 mutations provide an alternative mechanism for 5-FOA resistance in Saccharomyces cerevisiae

The URA3 gene is frequently used in the budding yeast community as the mutation target for 5-fluoroorotic acid (5-FOA) resistance. We identified a class of ura6 mutants that can grow in the presence of 5-FOA. Unlike ura3 mutants, ura6 mutants remain prototrophic and are able to grow in the absence of uracil. In addition to 5-FOA resistance, we found that ura6 mutants are also resistant to 5-fluorocytosine (5-FC) and 5-fluorouracil (5-FU). In total, we identified 50 unique missense mutations across 32 unique amino acid positions of Ura6 which confer resistance to 5-FOA. We found that 28 out of the 32 affected positions are located in regions conserved between Saccharomyces cerevisiae and three clinically relevant pathogenic fungi. Metabolic analysis revealed a build-up of uridine monophosphate (UMP) and 5-fluorouridine monophosphate (5-FUMP) in ura6 mutants, indicating a reduction in Ura6 activity. Despite the accumulation of UMP in ura6 mutants, uridine diphosphate and triphosphate (UDP, UTP) levels were similar across mutants and wild type. These findings suggest that missense mutations to URA6, can result in reduction of uridylate kinase activity and lead to cross resistance to fluorinated prodrugs that incorporate into both the de novo pyrimidine synthesis and the pyrimidine salvage pathway.

genetics↗

bioRxiv2024

Superoxide enters neurons via LRRC8A-containing volume-regulated anion channels

Superoxide (O2-) is both an intercellular signaling molecule and a cause of neuronal oxidative stress. Superoxide entry into neurons is thought to be indirect, requiring its dismutation to nonpolar hydrogen peroxide. Here we show instead that superoxide enters neurons directly, via LRRC8A-containing volume-sensitive organic anion channels. In primary cultures, neuronal oxidative stress induced either by NMDA receptor stimulation or exposure to authentic superoxide was blocked by the anion channel blockers DIDS and DCPIB and by LRRC8A gene disruption. In mouse cortex, neuronal oxidative stress induced by either NMDA injection or transient ischemia was likewise blocked by both DCPIB and LRRC8A gene disruption. These findings identify a role for LRRC8A-containing volume-sensitive organic anion channels in neuronal oxidative signaling, stress, and glutamate excitotoxicity.

neuroscience↗

bioRxiv2023

Effects of parental age and polymer composition on short tandem repeat de novo mutation rates

Short tandem repeats (STRs) are hotspots of genomic variability in the human germline because of their high mutation rates, which have long been attributed largely to polymerase slippage during DNA replication. This model suggests that STR mutation rates should scale linearly with a fathers age, as progenitor cells continually divide after puberty. In contrast, it suggests that STR mutation rates should not scale with a mothers age at her childs conception, since oocytes spend a mothers reproductive years arrested in meiosis II and undergo a fixed number of cell divisions that are independent of the age at ovulation. Yet, mirroring recent findings, we find that STR mutation rates covary with paternal and maternal age, implying that some STR mutations are caused by DNA damage in quiescent cells rather than the classical mechanism of polymerase slippage in replicating progenitor cells. These results also echo the recent finding that DNA damage in quiescent oocytes is a significant source of de novo SNVs and corroborate evidence of STR expansion in postmitotic cells. However, we find that the maternal age effect is not confined to previously discovered hotspots of oocyte mutagenesis, nor are post-zygotic mutations likely to contribute significantly. STR nucleotide composition demonstrates divergent effects on DNM rates between sexes. Unlike the paternal lineage, maternally derived DNMs at A/T STRs display a significantly greater association with maternal age than DNMs at GC-containing STRs. These observations may suggest the mechanism and developmental timing of certain STR mutations and are especially surprising considering the prior belief in replication slippage as the dominant mechanism of STR mutagenesis. Author SummaryWe have long known that tandem repeats are hypermutable and attributed that hypermutability to slippage during DNA replication. Contradicting this long-held theory, we show that tandem repeats accumulate mutations in maternal germ cells during periods when these cells do not replicate. This bolsters a new consensus that DNA replication is not the only driver of mutagenesis, even at loci where replicative slippage is possible. Patterns shared by certain loci enriched for mutations from older mothers may hint at mechanisms.

evolutionary biology↗

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

Rapid and high yield isolation of extracellular vesicles with purity by application of size exclusion fast performance liquid chromatography.

Extracellular Vesicles (EVs) have emerged as potential biomarkers for diagnosing a range of diseases without invasive procedures. Extracellular vesicles also offer an advantage compared to synthetic vesicles, for delivery of various drugs. However, limitations in segregating EVs from soluble proteins have led to inconsistent EV retrieval rates with low levels of purity. Here, we report a new high-yield (>95%) and rapid (<20 min) EV isolation method called Size Exclusion - Fast Performance Liquid Chromatography (SE-FPLC). We show SE-FPLC can effectively isolate EVs from multiple sources including EVs derived from human and mouse cells and serum. The results indicate that SE-FPLC can successfully remove highly abundant protein contaminants such as albumin and lipoprotein complexes, which can represent a major hurdle in large scale isolation of EVs for clinical translation. Additionally, the high-yield nature of SE- FPLC allows for easy industrial upscaling of extracellular vesicles production for various clinical utilities. Moreover, SE-FPLC enables analysis of very small volumes of blood for use in point-of-care diagnostics in the clinic. Collectively, SE-FPLC offers many advantages over current EV isolation methods and offers rapid clinical utility potential.

bioengineering↗

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↗

bioRxiv2023

Epistasis between mutator alleles contributes to germline mutation rate variability in laboratory mice

Maintaining germline genome integrity is essential and enormously complex. Although many proteins are involved in DNA replication, proofreading, and repair [1], mutator alleles have largely eluded detection in mammals. DNA replication and repair proteins often recognize sequence motifs or excise lesions at specific nucleotides. Thus, we might expect that the spectrum of de novo mutations -- the frequencies of C>T, A>G, etc. -- will differ between genomes that harbor either a mutator or wild-type allele. Previously, we used quantitative trait locus mapping to discover candidate mutator alleles in the DNA repair gene Mutyh that increased the C>A germline mutation rate in a family of inbred mice known as the BXDs [2,3]. In this study we developed a new method to detect alleles associated with mutation spectrum variation and applied it to mutation data from the BXDs. We discovered an additional C>A mutator locus on chromosome 6 that overlaps Ogg1, a DNA glycosylase involved in the same base-excision repair network as Mutyh [4]. Its effect depended on the presence of a mutator allele near Mutyh, and BXDs with mutator alleles at both loci had greater numbers of C>A mutations than those with mutator alleles at either locus alone. Our new methods for analyzing mutation spectra reveal evidence of epistasis between germline mutator alleles and may be applicable to mutation data from humans and other model organisms.

genetics↗

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↗