Biology subjects

Sudmant, P. H.

Publications and source records attributed to Sudmant, P. H..

At least 19 recordsLinked to original sources

bioRxiv2026

CypA is a molecular barrier to HIV emergence from Eastern chimpanzees

Of the two lineages of lentivirus that endemically infect chimpanzees, only one has served as a source of infections in hu-mans. Using HIV-CRISPR screening, we identify factors that limit the replication of lentivirus from Eastern chimpanzees. We find that CypA restricts nonzoonotic Eastern chimpanzee lentivirus due to a unique feature encoded in capsid. The ability of CypA to restrict lentivirus replication is surprising given that CypA is a host factor exploited by HIV to promote its replica-tion. The selective ability of CypA to restrict this virus provides a molecular explanation as to why lentivirus from Eastern Chimpanzees has never been observed to infect humans. Our work has important implications for understanding the origins of HIV-1 and the potential for novel zoonosis of primate lentiviruses.

microbiology↗

bioRxiv2026

The evolution of structural variation across 500 million years of vertebrate evolution

Structural variants (SVs) contribute substantially to genetic variation and play vital roles in adaptation and disease1,2. Nonetheless, SVs are poorly captured by short reads and thus remain understudied, especially in non-model organisms3,4. Here, using haplotype-resolved genome assemblies from >600 vertebrate species, we comprehensively survey the landscape of SVs across >500 million years of evolution. We identify 35.3 million SVs and 3.12 billion single nucleotide variants (SNVs) segregating between two representative haplotypes across species, with SVs impacting [~]12-fold more base pairs. SV and SNV heterozygosity are correlated across species, with endangered and threatened species exhibiting reduced genetic diversity. However, the contribution of SVs relative to SNVs fundamentally differs across major vertebrate clades: given the same number of SNVs, fishes, amphibians, and reptiles have 4.3-to-9.1 times the number of SVs than birds, and 1.7-to-3.6 times more than mammals. This reduction in the relative contribution of SVs in mammals and birds is linked to fewer non-repeat-associated SVs as well as lower transposable element (TE) abundance and diversity. We identify features underlying genomic instability across vertebrates, finding that SVs frequently occur in repetitive and SNV-rich regions and are mediated by both homology and non-canonical DNA structures. Notably, G-quadruplex structures are enriched 11.5-fold around SV breakpoints in birds, while Z-DNA structures are enriched 2.2-fold in cartilaginous fishes. TEs uniquely contribute to SVs both directly through transposition and indirectly by mediating ectopic recombination, with the proportion of TE-mediated SVs influenced by both genomic TE density and diversity. We identify >10,000 instances of recent TE turnover including extinction of LINE-2 in therian mammals and slowing of CR1 activity in passerine birds. Finally, we show that SVs have an outsized role in functional genetic variation and are >70 times more likely to strongly impact protein-coding sequences than SNVs. While SVs are on average deleterious, we identify extensive recurrent structural variation across multiple taxa in genes involved in sensory, immune, and metabolic systems. Together, this study highlights extraordinary variation in the abundance, composition, mechanism, and functional impact of SVs across vertebrates.

evolutionary biology↗

bioRxiv2026

Two melanic pigment patterns are associated with a sex chromosome-linked oncogene in the mountain swordtail Xiphophorus nezahualcoyotl

Sex-linked traits are widespread, but their genetic architecture has been challenging to characterize, due in part to the repetitive and structurally complex nature of sex chromosomes. In swordtails and platyfish of the genus Xiphophorus, diverse melanic pigmentation patterns are thought to be controlled by a region on the sex chromosomes classically referred to as the "macromelanophore determining locus". Despite nearly a century of study, the identity of the causal gene remains controversial, partially due to previous inability to fully sequence the sex chromosomes. Here, we characterize and investigate two melanin-based pigmentation phenotypes in the species X. nezahualcoyotl: "spotted side" and "marmoratus". We generate a gapless near-telomere-to-telomere X. nezahualcoyotl assembly and perform GWAS to identify regions associated with pigmentation pattern variation and sex-determination. We find both patterns map near the sex-determining region and to a narrow interval near the oncogene xmrk. By generating additional long-read assemblies of sex chromosomes derived from individuals with distinct phenotypes, we find haplotypes containing xmrk can be both X- and Y-linked, and vary dramatically in gene content, structure, and accumulation of repetitive elements including a newly described composite satellite. This variability may impact the regions stability and affect recombination between haplotypes associated with each pattern. Our results shed light on a longstanding debate surrounding the genetic architecture of sex-linked phenotypes. More generally, we showcase how long-read sequencing can reveal phenotypic variation linked to complex and dynamic genomic regions, which may contribute to the evolution of diverse sex-linked traits.

evolutionary biology↗

bioRxiv2026

A Pan-pangenome illuminates complex structural variation and selection in humans, chimpanzees, and bonobos

Complete, haplotype-resolved genome assemblies have provided unprecedented insight into the evolution of structurally complex, rapidly evolving regions of human genomes1-6; however, population-scale pangenome resources of our closest relatives, chimpanzees and bonobos (genus, Pan), are necessary to ascertain the origins and evolutionary context of these loci. Here, we sequence and assemble 58 haplotypes from four distinct Pan clades to high contiguity (median contig NG50=54 Mb), including eight near-T2T genomes. These genomes reveal previously intractable genetic variation increasing estimates of genome-wide genetic diversity 6-37% across populations compared to short-read estimates7. We identify recurrent structural polymorphisms across species impacting genes associated with immune response and host-pathogen interaction and find that structural variants (SVs) are 170- to 260-fold more likely than single nucleotide variants (SNVs) to exhibit high-impact effects across species. Contrasting SV patterns across primates we find that transposable element mutation rates differ by as much as threefold between species. We show that human disease-associated short tandem repeat (TR) loci have uniquely expanded in humans sensitizing our species to these TR-expansion disorders. Physically phased haplotypes enable reconstruction of genome-wide genealogical histories, uncovering ancient, functional genetic variation maintained by balancing selection, as well as signatures of recent adaptation in chimpanzee subspecies. Several malaria-associated loci exhibit ancient structural polymorphism, including the African great ape-specific glycophorin (GYP) gene expansion. We characterize the sequence, structure, and composition of diverse glycophorin haplotypes in humans and chimpanzees. We identify independent malaria-protective GYPA-B fusion events in humans and novel chimpanzee glycophorin genes resulting from both ancient and recent fusion events demonstrating parallel adaptations to pathogen resistance across hominins. Together, our resource highlights the critical importance of nonhuman primate population-scale pangenomics for understanding the evolution of complex genome structures and the biodiversity of our endangered closest living relatives.

evolutionary biology↗

bioRxiv2026

Linking genotype to longevity under genealogical discordance in Sebastes rockfishes

AO_SCPLOWBSTRACTC_SCPLOWRockfishes (genus Sebastes) show extreme variation in longevity among closely related species, but the evolutionary history of this young radiation is highly complex. To unpack these relationships and to associate genotypes with phenotypes, we quantified genealogical discordance among 55 Sebastes species and implemented a phyloGWAS framework that incorporates discordant gene histories into genotype-longevity association tests. We found that genealogical discordance is extremely high: the inferred species tree topology differed among several ILS-aware methods, with most internal branches having low concordance factors regardless of which method was used. Nevertheless, some phylogenetic structure was shared by all inferred species trees. We used simulations to assess the statistical properties of phyloGWAS applied to complex traits using different genetic relatedness matrices (GRMs) and under varying levels of discordance. Adding an accurate GRM reduced false positives relative to a model without relatedness, but GRMs only modestly increased power to detect true positives. Using multiple approaches on the Sebastes data, phyloGWAS identified several variants associated with longevity. Our results indicate that extreme genealogical discordance is a core feature of Sebastes evolution and that phyloGWAS can help in connecting genotype to phenotype under these conditions.

evolutionary biology↗

bioRxiv2026

Population-scalable genotyping from low-coverage sequencing data using pangenome graphs

Pangenome-based genotyping of structurally complex loci remains challenging at low sequencing depths, particularly when samples are of low quality, such as in ancient DNA. We present COSIGT (COsine SImilarity-based GenoTyper), a method that infers structural genotypes by matching short-read coverage patterns to pangenome haplotypes using cosine similarity. COSIGT maintains robust accuracy at low coverage (1-2X), outperforming existing methods where depth-sensitive approaches degrade. We demonstrate scalability to thousands of modern and ancient genomes, enabling population-scale analyses of complex variation from low-coverage data.

bioinformatics↗

bioRxiv2026

Pangenome graphs reveal the extent and complexity of genetic variation in North America's most abundant mammal

Pangenome methods reduce reference bias and enable the characterization of previously inaccessible genomic variation within a species, and are thus especially useful for species with high levels of genetic diversity. Here, we constructed a pangenome for the deer mouse (Peromyscus maniculatus), a model for studying local adaptation and a potent reservoir for diverse zoonotic diseases, using long-read assemblies from 14 ecologically and biogeographically diverse populations and 2 outgroup species (totaling 19 haplotypes). The total length of the pangenome is 3.9 Gb, but only 1.4 Gb is shared across all haplotypes, suggesting vast structural diversity. From this pangenome we identified [~]108.3 million single nucleotide polymorphisms (SNPs), [~]23.9 million indels (variants < 50 bp), and [~]2.4 million structural variants (variants > 50 bp) as well as complex genetic variation driven by massive chromosomal rearrangements and an unprecedented diversity of centromeric satellite positions. Furthermore, we uncover widespread gene copy number variation (CNVs)-some genes vary in number by an order of magnitude across deer mouse haplotypes-in addition to several gene-rich loci that display high levels of structural diversity. Such genes are enriched for functions related to sensory perception, environmental interaction, and immune responses and many display signatures of positive selection at the molecular level, suggesting functional diversification. Our work provides important insight into the utility of pangenomes for genetically diverse species and illuminates underappreciated genomic plasticity within a mammalian species.

evolutionary biology↗

bioRxiv2026

Sequence models conditioned on splicing factor expression predict splicing in unseen tissues

Predicting how RNA splicing varies across tissues is important for understanding the impact of genetic variation and identifying splicing-based disease mechanisms. Although many sequence-based deep learning models have been developed to predict splicing, most predict splice sites rather than full splicing events, are restricted to tissues seen during training, or do not account for trans-regulatory variation such as differences in splicing factor expression. Here, we present Splice Ninja, a sequence-based deep learning model that predicts percent spliced-in (PSI) values for individual splicing events across tissues by conditioning on the expression levels of 301 splicing factors. Trained on PSI measurements from many different human tissues and cell types, Splice Ninja is evaluated on three entirely held-out tissues. Despite not seeing these tissues during training, it makes accurate PSI predictions and can identify a substantial fraction of splicing events with high tissue-specificity. Its performance is comparable to Pangolin [1], which is trained directly on the test tissues, but falls short of TrASPr [2], a substantially larger model also trained on the test tissues. Splice Ninja demonstrates that integrating trans-regulatory context into sequence-based splicing models enables generalization to new cellular environments. This framework offers a promising direction for building robust, context-aware predictors of alternative splicing. Our code is available at https://github.com/anikethjr/splice_ninja.

genomics↗

bioRxiv2026

Comparative genomics of Tandem Repeat variation in apes

Tandem repeats (TRs) are highly mutable DNA elements that influence gene regulation1, protein structure2, and disease3. Until recently, their repetitive nature has hindered accurate TR sequencing and genotyping, resulting in sparse comparative data across species. In addition, we lack population-aware approaches to analyze TR conservation, divergence, and mutational dynamics. Here, leveraging telomere-to-telomere primate genomes and long-read data from 46 humans and 23 chimpanzees, we constructed a catalog of homologous TR loci, and developed an analytical framework to jointly analyze TR variation within- and between-species. Across primates, TR diversity and conservation vary strongly with genomic context, with coding and 5 UTR TRs exhibiting reduced polymorphism and constraint across species, consistent with stabilizing selection. Yet, while TRs are depleted in coding sequence, they are enriched in 5 UTRs, suggesting functional roles that outweighs mutational risks. TR heterozygosity varies across motif lengths and is concordant with both evolutionary and trio-based mutation rate estimates4. Introducing an HKA-like approach to control for locus-specific mutation rates, we identified TRs with signatures of directional and balancing selection. These candidates are significantly enriched in genes involved in nervous system development and synaptic function, highlighting TRs as potential contributors to neural evolution. Further, TR divergence correlates with gene expression divergence, particularly for promoter-related TRs and expression in organoids related to neurodevelopment, implicating a subset of regulatory TRs as candidates for adaptive expression evolution. Finally, trait-associated TRs display longer alleles and higher diversity in humans compared to chimpanzees, consistent with lineage-specific runaway mutations and/or directional selection5. Together, our results establish a comparative framework for TR evolutionary analyses, revealing how mutational processes and selection jointly shape repeat variation, and supporting their role as both conserved functional elements and as drivers of evolutionary innovation.

evolutionary biology↗

bioRxiv2025

Machine learning-based prediction of human structural variation and characterization of associated sequence determinants

Structural variants (SVs) represent a major source of genetic diversity and play key roles in human disease and evolution. Yet, the extent to which local sequence context shapes the likelihood of structural variant formation remains poorly quantified. Here, we develop machine learning models to predict the occurrence of SVs across the human genome and characterize genomic determinants associated with their formation. We developed both a sequence only-based convolutional neural network (CNN) model as well as a random forest approach integrating diverse genomic annotations. Both models achieve high predictive performance individually (>90% AUROC) which can be further improved in an ensemble. The predictive ability of these models demonstrates that SV-prone regions can be accurately inferred from sequence context. Model interpretability techniques reveal key genomic contributors to SVs, including effects of sequence motifs such as microhomology and non-canonical DNA structures, as well as the presence of SV hotspots. We find that different classes of SVs exhibit distinct sequence determinants, with transposable elements and inversions displaying particularly unique signatures. Moreover, predicted SV probability correlates with allele frequency and gene functional constraint, indicating the potential utility of the model for variant effect prediction. These findings demonstrate that machine learning models trained on local sequence features can identify unstable genomic regions and provide a framework for quantifying SV susceptibility and SV variant effects in personalized genomics.

genetics↗

bioRxiv2025

Direct identification of de novo mobile element insertions from single molecule sequencing of human sperm

Mobile element insertions (MEIs) are a significant source of human genetic variation, yet the rates and properties of de novo MEIs are poorly characterized due to technical limitations in sequencing technology. Here, we directly sequenced individual gametes from sperm samples of 19 donors (aged 27-62) using highly accurate PacBio long-read sequencing to identify de novo retrotransposition events without familial inference. We developed a "self-alignment" strategy using personalized genome assemblies that enables high-precision, single-read detection of de novo MEIs. Using this method, we identified 43 de novo Alu insertions, revealing >9-fold variation in Alu retrotransposition rates between individuals (ranging from 0 to 0.148 insertions/gamete). We found a significant increase in Alu activity with paternal age, yielding a 4.67% increase in insertions per gamete per year of additional paternal age, representing a direct observation of age-associated increases in structural variant (SV) mutation rates. De novo Alu insertions predominantly represent evolutionarily young AluYa5 and AluYb8 subfamilies and bear characteristic molecular signatures of target-primed reverse transcription (TPRT). Our population-averaged rate of 4.52 insertions per 100 gametes aligns well with previous population genetic estimates, validating both direct observation and population approaches for estimating de novo MEI rates. These results establish direct gamete sequencing as a powerful method for characterizing germline mutation processes and reveal age as a significant determinant of de novo retrotransposition in the male germline.

genetics↗

bioRxiv2025

Phylogenetically diverse introgression drives subtle population structure in Pacific rockfishes

Genomic methods have shown that admixture and introgression is common across animal taxa. Pacific rockfishes, genus Sebastes, are group of commercially important species that primarily inhabit inshore, shelf, and slope habitats along the North American west coast. Among these, Copper and Quillback Rockfishes (abbreviated to Copper and Quillback) are closely related species known to hybridize, particularly within the Salish Sea in North Americas Pacific Northwest. Here, we investigate genetic population structure and introgression patterns in Copper and Quillback from Alaska to California. Using whole-genome resequencing (WGS) across a broad geographic range, we seek to (1) compare population structure between these species, and (2) assess how introgression affects population structure patterns. Our analyses reveal that Copper exhibit much higher levels of population differentiation compared to Quillback, especially separating Salish Sea samples from all other populations. In contrast, Quillback populations appear to be nearly panmictic, with lower overall differentiation. Surprisingly, we detected signatures of introgression from 13 other rockfish species in Copper and 16 species in Quillback. This introgression was highly regional suggesting hybridization depended on geographic context and congener ranges. Yelloweye Rockfish introgression drives the strongest signal of regional population structure in Quillback. These findings provide novel insights into the range-wide genetic structure of these species and highlight that hybridization in Sebastes is phylogenetically broader than previously appreciated.

evolutionary biology↗

bioRxiv2025

Rapid turnover and recurrent structural variation at the 17q21.31 locus in modern and ancient human genomes, and primates

The 17q21.31 locus in humans harbors several complex structural haplotypes including a [~]970kb inversion. Different inversion haplotypes have been associated with susceptibility to microdeletions causing Koolen-de Vries syndrome and variation in fecundity and recombination rates. Here, using 210 haplotype-resolved human genome assemblies and pangenome graph-based approaches we characterize 11 distinct structural haplotypes, several of which have not been previously described. Extending our analyses to a set of haplotype-resolved great-ape genomes, we characterize the structure of an independent inversion in chimpanzees which extends an additional 650kb, encompasses 5 additional genes, and is [~]2 million years younger than the human inversion. We further determine that gorillas exhibit an independent duplication of the KANSL1 gene which may predispose them to Koolen-de Vries syndrome causing microdeletions. Using short read sequencing data we characterize 17q21.31 haplotype diversity worldwide in [~]5174 individuals from 107 populations finding increased frequencies of KANSL1 duplication-containing haplotypes in both European and South Asian populations as well as 8 double recombination events between inverted and non-inverted haplotypes ranging in size from 20-180kb. Finally, using 626 ancient Eurasian human genomes we show the frequency of haplotypes containing KANSL1 duplications has increased [~]6-fold over the past 12 thousand years in Europe. Together, our results highlight the dynamics, complexity, and recurrent, independent evolution of a medically relevant locus across humans and great apes.

genomics↗

bioRxiv2025

Genomic and functional adaptations in guanylate-binding protein 5 (GBP5) highlight specificities of bat antiviral innate immunity

Bats are asymptomatic reservoirs of several zoonotic viruses. This may result from long-term coevolution between viruses and bats, that have led to host adaptations contributing to an effective balance between strong antiviral responses with innate immune tolerance. To better understand these virus-host interactions, we combined comparative transcriptomics, phylogenomics and functional assays to characterize the evolution of bat innate immune antiviral factors. First, we stimulated the type I interferon immune pathway in Myotis yumanensis primary cells and identified guanylate-binding protein 5 (GBP5) as the most differentially expressed interferon-stimulated gene (ISG). Phylogenomic analyses showed that bat GBP5 has been under strong episodic positive selection, with numerous rapidly evolving sites and species-specific gene duplications, suggesting past evolutionary arms races. Functional tests on GBP5 orthologs from ten bat species covering the >60 million years of Chiroptera evolution revealed species- and virus-specific restrictions against RNA viruses (retrovirus HIV, and rhabdoviruses European bat lyssavirus and VSV), which are typical signatures of adaptations to past viral epidemics. Interestingly, we also observed a lineage-specific loss of the GBP5 prenylation motif in the common ancestor of Pipistrellus and Eptesicus bats, associated with different GBP5 subcellular localization and loss of antiviral functions. Resurrection of the ancestral prenylation motif in Eptesicus fuscus GBP5 rescued its subcellular localization, but not the complete antiviral activities, suggesting that additional determinants are necessary for the antiviral restriction. Altogether, our results highlight adaptations that contribute to bat specific immunity and provide insights into the functional evolution of antiviral effector GBP5. Key FindingsO_LIGBP5 is the most differentially expressed gene upon type I interferon stimulation of Myotis yumanensis primary cells. C_LIO_LIBat GBP5 has evolved under strong episodic genomic and genetic diversification, including early stop codon leading to protein truncation and loss of prenylation motif. C_LIO_LIGBP5 diversification in bats impacts their subcellular localization and antiviral functions. C_LIO_LIBat GBP5s exhibit species- and virus-specificity in their ability to inhibit infectivity of viral particles, bearing glycoproteins from retroviral HIV, vesicular stomatitis virus and European bat lyssavirus-1. C_LIO_LIResurrection of the ancestral prenylation motif in a bat GBP5 rescues its subcellular localization but not its full antiviral activity C_LI

immunology↗

bioRxiv2025

Avid lysosomal acidification in fibroblasts of the Mediterranean mouse Mus spretus

Failures of the lysosome-autophagy system are a hallmark of aging and many disease states. As a consequence, interventions that enhance lysosome function are of keen interest in the context of drug development. Throughout the biomedical literature, evolutionary biologists have found cases in which challenges faced by humans in clinical settings have been resolved by non-model organisms adapting to wild environments. Here, we used a primary cell culture approach to survey lysosomal characteristics in species of the genus Mus. We found that fibroblasts from M. spretus, a wild Mediterranean mouse, exhibited elevated lysosomal mass and enzyme activity along with reduced activity of {beta}-galactosidase, a classical marker of cellular senescence, compared to those from M. musculus, a related species adapted to human-associated environments. We propose that classic laboratory models of lysosome function and senescence may reflect characters that diverge from the phenotypes of wild mice. The M. spretus phenotype may ultimately serve as a blueprint for interventions that ameliorate lysosomal dysfunction under conditions of stress and disease.

evolutionary biology↗

bioRxiv2024

Extensive longevity and DNA virus-driven adaptation in nearctic Myotis bats

Summary ParagraphThe genus Myotis is one of the largest clades of bats, and exhibits some of the most extreme variation in lifespans among mammals alongside unique adaptations to viral tolerance and immune defense1-3. To study the evolution of these phenotypes we generated cell lines and near-complete genome assemblies for eight closely related Myotis species. Using genome-wide screens of positive selection, analyses of structural variation, and functional experiments in primary cells, we identify patterns of adaptation contributing to longevity, cancer resistance, and viral interactions. We demonstrate distinct modes of adaptation to DNA and RNA viruses compared to all other mammals, with bats exhibiting genome-wide overrepresentation of positive selection for DNA virus-interacting proteins and elevated rates of copy number variation for RNA virus-interacting proteins. Characterization of Myotis-specific duplications of the key immune factor protein kinase R (PKR) reveals multiple ancient segregating trans-species copy number polymorphisms. We show that the recurrent evolution of longevity seen in Myotis is associated with positive selection in cancer pathways, and demonstrate a unique response to DNA damage in primary cells of the long-lived M. lucifugus. Together, our results suggest that bats remarkable longevity and immunity are linked through pleiotropic adaptations to viruses and aging-related disease.

genomics↗

bioRxiv2024

TRACKing Tandem Repeats: a customizable pipeline for identification and cross-species comparisons

SummaryTRACK is a user-friendly command-line pipeline designed to consolidate the discovery and comparison of tandem repeats (TRs) across species. TRACK facilitates the cataloging and filtering of TRs based on reference genomes or T2T transcripts, and applies reciprocal LiftOver and sequence alignment methods to identify putative homologous TRs between species. For further streamlined analyses, TRACK can be used to genotype TRs and subsequently estimate and plot basic population genetic statistics. By integrating existing tools into one integrated workflow, TRACK enhances TR analysis accessibility and reproducibility, while offering flexibility for the user. AvailabilityThe TRACK toolkit with step-by-step tutorial is freely available at https://github.com/caroladam/track.

genomics↗

bioRxiv2024

Insights into non-crossover recombination from long-read sperm sequencing

Meiotic recombination is a fundamental process that generates genetic diversity by creating new combinations of existing alleles. Although human crossovers have been studied at the pedigree, population and single-cell level, the more frequent non-crossover events that lead to gene conversion are harder to study, particularly at the individual level. Here we show that single high-fidelity long sequencing reads from sperm can capture both crossovers and non-crossovers, allowing effectively arbitrary sample sizes for analysis from one male. Using fifteen sperm samples from thirteen donors we demonstrate variation between and within donors for the rates of different types of recombination. Intriguingly, we observe a tendency for non-crossover gene conversions to occur upstream of nearby PRDM9 binding sites, whereas crossover locations have a slight downstream bias. We further provide evidence for two distinct non-crossover processes. One gives rise to the vast majority of non-crossovers with mean conversion tract length under 50bp, which we suggest is an outcome of standard PRDM9-induced meiotic recombination. In contrast [~]2% of non-crossovers have much longer mean tract length, and potentially originate from the same process as complex events with more than two haplotype switches, which is not associated with PRDM9 binding sites and is also seen in somatic cells.

genetics↗