Biology subjects

Munch, K.

Publications and source records attributed to Munch, K..

13 recordsLinked to original sources

bioRxiv2026

A Curated Genome-Scale Nucleotide Diversity Panel of Non-Human Primates

BackgroundPrimates constitute one of the most phylogenetically and ecologically diverse Eutherian mammalian orders, with a central role in advancing our knowledge of human evolution, speciation processes and conservation biology. While thousands of whole-genome sequences have been generated across a multitude of primate taxa, discrepancies in data processing - particularly the lack of ploidy-aware variant calling in sex-linked regions - have limited the utility of existing datasets for large-scale comparative analyses. ResultsHere, we utilized publicly available short-read sequencing data of non-human primates, recently published primate genome assemblies and a ploidy-aware variant calling procedure to generate a genome-scale nucleotide diversity panel comprising 3,240 individuals from 269 species and 71 genera. To further facilitate cross-species comparisons, we generated a multiple-genome alignment of primate assemblies used for variant calling. ConclusionThis curated resource of non-human primate diversity provides a foundation for future research in primate evolutionary biology, speciation, and sex chromosome evolution (https://pure.au.dk/portal/en/datasets/primate-diversity-panel/).

genomics↗

bioRxiv2025

Treatment of STEC infection via CRISPR-Cas targeted cleavage of the Shiga toxin gene in animal models

Escherichia coli is a ubiquitous gut commensal but also an opportunistic pathogen responsible for severe intestinal and extra-intestinal infections. Shiga toxin-producing E. coli (STEC) pose a significant public health threat, particularly in children, where infections can lead to bloody diarrhea and progress to hemolytic uremic syndrome (HUS), a life-threatening condition with long-term complications. Antibiotics are contraindicated in STEC infections due to their potential to induce prophages carrying Shiga toxin (stx) genes, triggering toxin production. Here, we present a CRISPR-based antimicrobial strategy that selectively targets and eliminates O157 STEC clinical isolates while preventing toxin release. We designed a Cas12 nuclease to cleave >99% of all stx variants found in O157 strains, leading to bacterial killing and suppression of toxin production. To enable targeted delivery, we engineered a bacteriophage-derived capsid to specifically transfer a non-replicative DNA payload to E. coli O157, preventing its dissemination. In a mouse STEC colonization model, our therapeutic candidate, EB003, reduced bacterial burden by a factor of 3x103. In an infant rabbit disease model, EB003 mitigated clinical symptoms, abrogated stx-mediated toxicity, and accelerated epithelial repair at therapeutically relevant doses. These findings demonstrate the potential of CRISPR-based antimicrobials for treating STEC infections and support further clinical development of EB003 as a precision therapeutic against antibiotic-refractory bacterial pathogens.

synthetic biology↗

bioRxiv2024

Negative selection on baboon admixture is strongest on chromosome X

The six admixing baboon species offer a natural experiment to study negative selection on admixture and potentially genetic incompatibility in species with divergence resembling that between anatomically modern and extinct human subspecies such as Neanderthals. We analyze 156 high-coverage genomes sampled from seven olive and four yellow baboon populations shaped by admixture in two different reticulation events. In Tanzania, olive and yellow baboons admix despite 1.3 million years of divergence. In Ethiopia, olive baboons have invaded and displaced an ancient Hamadryas-like population separated by 0.6 million years, thus mirroring the displacement of Neanderthals by modern humans. Analyzing local ancestry across whole genome, we find evidence of negative selection on minor parent ancestry in Tanzanian yellow and olive baboon populations reaching far behind the hybrid zone and in Ethiopian olive baboons. We find that evidence of selection against admixture is up to seven times stronger on the X chromosome. The proportion of minor parent ancestry is substantially higher on the X chromosome in Ethiopian olive and yellow baboon populations, which displaced the populations now representing their minor parent ancestry. This additional MPA is concentrated in a few genomic regions with high frequency. This indicates that this original ancestry was retained by negative selection on the invading ancestry, suggesting that these loci play a role in emerging reproductive barriers in the Papio as well as the Homo genus.

genetics↗

bioRxiv2023

Genome-wide coancestry reveals details of ancient and recent male-driven reticulation in baboons

Baboons (genus Papio) are a morphologically and behaviorally diverse clade of catarrhine monkeys that have experienced hybridization between phenotypically and genetically distinct phylogenetic species. We used high coverage whole genome sequences from 225 wild baboons representing 19 geographic localities to investigate population genomics and inter-species gene flow. Our analyses provide an expanded picture of evolutionary reticulation among species and reveal novel patterns of population structure within and among species, including differential admixture among conspecific populations. We describe the first example of a baboon population with a genetic composition that is derived from three distinct lineages. The results reveal processes, both ancient and recent, that produced the observed mismatch between phylogenetic relationships based on matrilineal, patrilineal, and biparental inheritance. We also identified several candidate genes that may contribute to species-specific phenotypes. One-Sentence SummaryGenomic data for 225 baboons reveal novel sites of inter-species gene flow and local effects due to differences in admixture.

evolutionary biology↗

bioRxiv2022

Versatile detection of diverse selective sweeps with Flex-sweep

Understanding the impacts of selection pressures influencing modern-day genomic diversity is a major goal of evolutionary genomics. In particular, the contribution of selective sweeps to adaptation remains an open question, with persistent statistical limitations on the power and specificity of sweep detection methods. Sweeps with subtle genomic signals have been particularly challenging to detect. While many existing methods powerfully detect specific types of sweeps and/or those with strong signals, their power comes at the expense of versatility. We present Flex-sweep, a machine learning-based tool designed to detect sweeps with a variety of subtle signals, including those thousands of generations old. It is especially valuable for non-model organisms, for which we have neither expectations about the overall characteristics of sweeps nor outgroups with population-level sequencing to otherwise facilitate detecting very old sweeps. We show that Flex-sweep has the power to detect sweeps with subtle signals, even in the face of demographic model misspecification, recombination rate heterogeneity, and background selection. Flex-sweep detects sweeps up to 0.125 * 4Ne generations old, including those that are weak, soft, and/or incomplete; it can also detect strong, complete sweeps up to 0.25 * 4Ne generations old. We apply Flex-sweep to the 1000 Genomes Yoruba data set and, in addition to recovering previously identified sweeps, show that sweeps disproportionately occur within genic regions and close to regulatory regions. In addition, we show that virus-interacting proteins (VIPs) are strongly enriched for selective sweeps, recapitulating previous results that demonstrate the importance of viruses as a driver of adaptive evolution in humans.

bioinformatics↗

bioRxiv2022

Extraordinary selection on the human X chromosome associated with archaic admixture

The X chromosome in non-African human populations shows less diversity and less Neanderthal introgression than expected under the standard neutral model. We analyzed 162 X chromosomes from human males worldwide and discovered 14 chromosomal regions where haplotypes of several hundred kilobases rapidly rose to high frequencies in non-Africans. These observations cannot be explained by neutral genetic drift in realistic demographic scenarios and are only consistent with partial selective sweeps produced by strong selection. Using an approach for inferring individual Neanderthal-derived haplotypes, which do not rely on an archaic reference genome, we further discover that the swept haplotypes are devoid of the archaic ancestry otherwise typical of the affected chromosomal regions. The ancient Ust-Ishim male carries its expected proportion of these haplotypes, implying that the sweeps must have occurred between 45,000 and 55,000 years ago. Finally, we find that the chromosomal positions of sweeps overlap previously reported hotspots of selection in great ape evolution. We propose that this puzzling combination of observations points to a general mechanism of positive selection unique to the X chromosome.

evolutionary biology↗

bioRxiv2022

Graph-based algorithms for phase-type distributions

Phase-type distributions model the time until absorption in continuous or discrete-time Markov chains on a finite state space. The multivariate phase-type distributions have diverse and important applications by modeling rewards accumulated at visited states. However, even moderately sized state spaces make the traditional matrix-based equations computationally infeasible. State spaces of phase-type distributions are often large but sparse, with only a few transitions from a state. This sparseness makes a graph-based representation of the phase-type distribution more natural and efficient than the traditional matrix-based representation. In this paper, we develop graph-based algorithms for analyzing phase-type distributions. In addition to algorithms for state space construction, reward transformation, and moments calculation, we give algorithms for the marginal distribution functions of multivariate phase-type distributions and for the state probability vector of the underlying Markov chains of both time-homogeneous and time-inhomogeneous phase-type distributions. The algorithms are available as a numerically stable and memory-efficient open source software package written in C named ptdalgorithms. This library exposes all methods in the programming languages C and R. We compare the running time of ptdalgorithms to the fastest tools using a traditional matrix-based formulation. This comparison includes the computation of the probability distribution, which is usually computed by exponentiation of the sub-intensity or sub-transition matrix. We also compare time spent calculating the moments of (multivariate) phase-type distributions usually defined by inversion of the same matrices. The numerical results of our graph-based and traditional matrix-based methods are identical, and our graph-based algorithms are often orders of magnitudes faster. Finally, we demonstrate with a classic problem from population genetics how ptdalgorithms serves as a much faster, simpler, and completely general modeling alternative.

bioinformatics↗

bioRxiv2019

Comparison of the full distribution of fitness effects of new amino acid mutations across great apes

The distribution of fitness effects (DFE) is central to many questions in evolutionary biology. However, little is known about the differences in DFEs between closely related species. We use more than 9,000 coding genes orthologous one-to-one across great apes, gibbons, and macaques to assess the stability of the DFE across great apes. We use the unfolded site frequency spectrum of polymorphic mutations (n = 8 haploid chromosomes per population) to estimate the DFE. We find that the shape of the deleterious DFE is strikingly similar across great apes. We confirm that effective population size (Ne) is a strong predictor of the strength of negative selection, consistent with the Nearly Neutral Theory. However, we also find that the strength of negative selection varies more than expected given the differences in Ne between species. Across species, mean fitness effects of new deleterious mutations co-varies with Ne, consistent with positive epistasis among deleterious mutations. We find that the strength of negative selection for the smallest populations: bonobos and western chimpanzees, is higher than expected given their Ne. This may result from a more efficient purging of strongly deleterious recessive variants in these populations. Forward simulations confirm that these findings are not artifacts of the way we are inferring Ne and DFE parameters. All findings are replicated using only GC-conservative mutations, thereby confirming that GC-biased gene conversion is not affecting our conclusions.

evolutionary biology↗

bioRxiv2019

Viruses rule over adaptation in conserved human proteins

Adaptive evolution often involves fast-evolving proteins, and the fastest-evolving proteins in primates include antiviral proteins engaged in an arms race with viruses 1-3. Even though fast-evolving antiviral proteins are the most studied cases of primate host adaptation against viruses, viruses predominantly interact with host proteins that are broadly conserved between distant species in order to complete their replication cycle 4. Broadly conserved proteins are generally viewed as playing a negligible role in adaptive evolution. Here, we used a dataset of ~4,500 human proteins known to physically interact with viruses (VIPs for Virus-Interacting Proteins), to test the involvement of broadly conserved proteins in adaptive evolution against viruses. We found that VIPs conserved between animals and fungi have experienced not only high rates of adaption, but also strong adaptive events. Broadly conserved proteins that do not interact with viruses experienced very little adaptation. As a result, the arms race with viruses explains more than 75% of adaptation in the most phylogenetically conserved subset of the human proteome. Our results imply that broadly conserved proteins have played a significant role in adaptation, and that viruses were likely one of very few selective pressures that were able to force the conserved, central pillars of host cellular functions to adapt during evolution.

evolutionary biology↗

bioRxiv2018

Strong selective sweeps before 45,000BP displaced archaic admixture across the human X chromosome

The X chromosome in non-African populations has less diversity and less Neanderthal introgression than expected. We analyzed X chromosome diversity across the globe and discovered seventeen chromosomal regions, where haplotypes of several hundred kilobases have recently reached high frequencies in non-African populations only. The selective sweeps must have occurred more than 45,000 years ago because the ancient Ust-Ishim male also carries its expected proportion of these haplotypes. Surprisingly, the swept haplotypes are entirely devoid of Neanderthal introgression, which implies that a population without Neanderthal admixture contributed the swept haplotypes. It also implies that the sweeps must have happened after the main interbreeding event with Neanderthals about 55,000 BP. These swept haplotypes may thus be the only genetic remnants of an earlier out-of-Africa event.\n\nOne Sentence SummaryAfter humans expanded out of Africa, the X chromosome experienced a burst of extreme natural selection that removed Neanderthal admixture.

genomics↗

bioRxiv2018

Impact of mutation rate and selection at linked sites on fine-scale DNA variation across the homininae genome

DNA diversity varies across the genome of many species. Variation in diversity across a genome might arise for one of three reasons; regional variation in the mutation rate, selection and biased gene conversion. We show that both non-coding and non-synonymous diversity are correlated to a measure of the mutation rate, the recombination rate and the density of conserved sequences in 50KB windows across the genomes of humans and non-human homininae. We show these patterns persist even when we restrict our analysis to GC-conservative mutations, demonstrating that the patterns are not driven by biased gene conversion. The positive correlation between diversity and our measure of the mutation rate seems to be largely a direct consequence of regions with higher mutation rates having more diversity. However, the positive correlation with recombination rate and the negative correlation with the density of conserved sequences suggests that selection at linked sites affect levels of diversity. This is supported by the observation that the ratio of the number of non-synonymous to non-coding polymorphisms is negatively correlated to a measure of the effective population size across the genome. Furthermore, we find evidence that these genomic variables are better predictors of non-coding diversity in large homininae populations than in small populations, after accounting for statistical power. This is consistent with genetic drift decreasing the impact of selection at linked sites in small populations. In conclusion, our comparative analyses describe for the first time how recombination rate, gene density, mutation rate and genetic drift interact to produce the patterns of DNA diversity that we observe along and between homininae genomes.

evolutionary biology↗

bioRxiv2017

Dynamic copy number evolution of X- and Y-linked ampliconic genes in human populations

Ampliconic genes are good candidates for speciation genes: they are testis-expressed, multicopy and localized on sex chromosomes. Moreover, copy number variation in a specific ampliconic gene pair (Slx and Sly) is involved in hybrid incompatibilities between M. musculus and M. domesticus. However, we know little about the distribution of the ampliconic genes copy number and their turnover in human populations. Here we explore the evolution of human X- and Y-linked ampliconic genes by investigating copy number variation (CNV) and coding variation between populations using the Simons Genome Diversity Project. We develop a method to assess CNVs using the read-depth on modified X and Y chromosome targets containing only one repetition of each ampliconic gene. Our results reveal extensive standing variation in copy number both within and between human populations for several ampliconic genes. For the Y chromosome, we can infer multiple independent amplifications and losses of these gene copies even within closely related Y haplogroups, that diversified less than 50,000 years ago. For the X chromosome, we also find high copy number and coding diversity within populations. While we cannot rule out that neutral processes are at the origin of this high diversity, this study gives insights on the distribution of copy number within human populations, and demonstrates an extremely fast turnover in copy number of these regions.

evolutionary biology↗

bioRxiv2017

Positively selected effector genes and their contribution to virulence in the smut fungus Sporisorium reilianum

Plants and fungi display a broad range of interactions in natural and agricultural ecosystems ranging from symbiosis to parasitism. These ecological interactions result in coevolution between genes belonging to different partners. A well-understood example are secreted fungal effector proteins and their host targets, which play an important role in pathogenic interactions. Biotrophic smut fungi (Basidiomycota) are well-suited to investigate the evolution of plant pathogens, because several reference genomes and genetic tools are available for these species. Here, we used the genomes of Sporisorium reilianum f. sp. zeae and S. reilianum f. sp. reilianum, two closely related formae speciales infecting maize and sorghum, respectively, together with the genomes of Ustilago hordei, Ustilago maydis and Sporisorium scitamineum to identify and characterize genes displaying signatures of positive selection. We identified 154 gene families having undergone positive selection during species divergence in at least one lineage, among which 77% were identified in the two investigated formae speciales of S. reilianum. Remarkably, only 29% of positively selected genes encode predicted secreted proteins. We assessed the contribution to virulence of nine of these candidate effector genes in S. reilianum f. sp. zeae by deleting individual genes, including a homologue of the effector gene pit2 previously characterized in U. maydis. Only the pit2 deletion mutant was found to be strongly reduced in virulence. Additional experiments are required to understand the molecular mechanisms underlying the selection forces acting on the other candidate effector genes, as well as the large fraction of positively selected genes encoding predicted cytoplasmic proteins.

evolutionary biology↗