Biology subjects

Schierup, M. H.

Publications and source records attributed to Schierup, M. H..

At least 19 recordsLinked to original sources

bioRxiv2026

Intra-specific evidence to support the drift-barrier hypothesis of mutation rate evolution

Rates of de novo mutations ({micro}) are highly variable among different taxa but less is known about their variability at the intraspecific level. Using a large data set (n=364 trios) from eight nine-spined stickleback (Pungitius pungitius) populations differing in their effective population sizes (Ne), we tested the prediction of the drift-barrier hypothesis (DBH) that {micro} scales negatively with increasing Ne. Indeed, {micro} was a negative function of Ne, also after correcting for phylogenetic non-independence of populations. While the range of variation in mutation rates across populations spanned more than a 4-fold range ({micro} = 1.60 - 6.99 x 10-9), we discovered one highly mutable family with a five-times higher mutation rate than the population average. Evidence was also found (i) for reduced efficiency of selection in small freshwater populations subject to strong genetic drift, (ii) that maternal age associates positively with {micro}, and shorter generation time elevates per-year mutation rates, (iii) that both replication errors and DNA repair efficiency contributed to {micro}, and that (iv) mutation rate variation has a polygenic basis. In general, the results provide support for the DBH identifying elevated mutation rates in populations subject to strong genetic drift.

genomics↗

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

Convergent Evolution of Sociality Causes Reduction of Mutation Rates in Spiders

Germline mutation rates influence the pace of molecular evolution, yet the roles of selection and life history in shaping their evolution remain to be determined. Comparative systems with replicated evolutionary transitions provide a unique opportunity to determine how changes in life history influence germline mutation rates. In the spider genus Stegodyphus, permanent sociality evolved independently three times within the past million years and is associated with obligate inbreeding, female-biased sex ratios, reduced fecundity, and sharply reduced effective population sizes. We sequenced 202 parent-offspring trios from 34 full-sibling families across three social and four closely related subsocial species and analysed quality-filtered trios in a phylogenetic comparative framework. Each independent transition to sociality was associated with an approximately 2-fold reduction in the de novo mutation rate in the germline. Phylogenetic analyses of synonymous branch lengths suggest that the mutation rates declined in parallel with the transitions to sociality. These rapid reductions in mutation rates in social lineages with small effective population sizes run counter to the drift-barrier hypothesis, which predicts that reduced selection efficacy would lead to higher mutation rates. We find no evidence that reduced mutation rates in the social species was favoured by selection for improving DNA repair efficiency, since there is no upregulation of DNA repair pathway genes in the ovaries of the social species. On the contrary, the mutation rate is reduced across mutational classes and in somatic tissue in social species compared with their subsocial counterparts. These patterns suggest that the reduction in mutation rate in social spiders is a consequence of convergent life history changes, including reduced body size and production of fewer, larger eggs. Our results highlight that the evolution of sociality, which entails major life history changes, can rapidly reshape fundamental evolutionary parameters, such as the germline mutation rate.

evolutionary biology↗

bioRxiv2024

Rate of de novo mutations in the three-spined stickleback

Being a fundamentally important genetic parameter and evolutionary force, estimates of germline mutation rates have many uses in evolutionary biology. However, accurate estimates of de novo mutation (DNM) rates are still relatively scarce even for extensively studied evolutionary biology models. We estimated DNM rates for the three-spined stickleback (Gasterosteus aculeatus), the supermodel of ecology and evolutionary biology. Using a large number of family trios sequenced to depth of 45x coverage, we identified 115 unique mutations genome wide and estimated the DNM rate at {micro} = 5.05 x 10-9/bp/gen without any detectable sex bias. The localised DNM rate was found to be positively correlated with recombination rate supporting the notion that recombination is a mutagenic process. Comparison of {micro} and genomic characteristics to those of the related nine-spined stickleback (Pungitius pungitius) revealed a high degree of similarity suggesting that despite 17.5 million years of independent evolution, the mutational processes in the two species appear to have been conserved.

evolutionary biology↗

bioRxiv2024

Trade-offs beget trade-offs: Causal analysis of mammalian population dynamics

Survival and reproduction strategies in mammals are determined by trade-offs between life history traits. In turn, the unique configuration of traits that characterize mammalian species give rise to species-specific population dynamics. The dependence of population dynamics on life history has been primarily studied as the relationship between population density and size-related traits. With the recent accumulation of genomic data, the effective population size (Ne) over million-year timescales has become quantifiable for a large proportion of mammal species. Using phylogenetic path analysis, we compared the dependence of population density and Ne on eleven traits that characterize mammalian allometry, diet and reproduction. We found variable impacts of traits on the two metrics of population dynamics across different classifications of mammalian species. For example, we found a negative association between brain size and both population density and Ne overall, but brain size was positively associated with Ne in carnivorans. Dietary specialization had a negative effect on population density, especially in ungulates. Ne of ungulates and primates was strongly affected by time to maturity and weaning age, respectively, highlighting the difference in reproductive strategy between these orders. The relationship between Ne and adult mass showed a gradient in association strength from cold to warm biomes. Together, our findings demonstrate that trade-offs not only characterize life-history evolution, but also extend across different metrics of population dynamics and vary among species groups. This challenges the static nature of the "energetic equivalence" rule and has major implications for selecting appropriate metrics for species conservation and restoration strategies.

evolutionary biology↗

bioRxiv2024

Estimating gene conversion tract length and rate from PacBio HiFi data

Gene conversions are broadly defined as the transfer of genetic material from a donor to an acceptor sequence and can happen both in meiosis and mitosis. They are a subset of non-crossover events and, like crossover events, gene conversion can generate new combinations of alleles and counteract mutation load by reverting germline mutations through GC-biased gene conversion. Estimating gene conversion rate and the distribution of gene conversion tract lengths remains challenging. We present a new method for estimating tract length, rate and detection probability of non-crossover events directly in HiFi PacBio long read data. The method can be used to make inference from sequencing of gametes from a single individual. The method is unbiased even under low single nucleotide variant (SNV) densities and does not necessitate any demographic or evolutionary assumptions. We test the accuracy and robustness of our method using simulated datasets where we vary length of tracts, number of tracts, the genomic SNV density and levels of correlation between SNV density and NCO event position. Our simulations show that under low SNV densities, like those found in humans, only a minute fraction ([~]2%) of NCO events are expected to become visible as gene conversions by moving at least one SNV. We finally illustrate our method by applying it to PacBio sequencing data from human sperm.

genomics↗

bioRxiv2024

Insights into gene conversion and crossing-over processes from long-read sequencing of human, chimpanzee and gorilla testes and sperm

Homologous recombination rearranges genetic information during meiosis to generate new combinations of variants. Recombination also causes new mutations, affects the GC content of the genome and reduces selective interference. Here, we use HiFi long-read sequencing to directly detect crossover and gene conversion events from switches between the two haplotypes along single HiFi-reads from testis tissue of humans, chimpanzees and gorillas as well as human sperm samples. Furthermore, based on DNA methylation calls, we classify the cellular origin of reads to either somatic or germline cells in the testis tissue. We identify 1692 crossovers and 1032 gene conversions in nine samples and investigate their chromosomal distribution. Crossovers are more telomeric and correlate better with recombination maps than gene conversions. We show a strong concordance between a human double-strand break map and the human samples, but not for the other species, supporting different PRDM9-programmed double-strand break loci. We estimate the average gene conversion tract lengths to be similar and very short in all three species (means 40-100 bp, fitted well by a geometric distribution) and that 95-98% of non-crossover events do not involve tracts intersecting with polymorphism and are therefore not detectable. Finally, we detect a GC bias in the gene conversion of both single and multiple SNVs and show that the GC-biased gene conversion affects SNVs flanking crossover events. This implies that gene conversion events associated with crossover events are much longer (estimated above 500 bp) than those associated with non-crossover events. Highly accurate long-read sequencing combined with the classification of reads to specific cell types provides a new, powerful way to make individual, detailed maps of gene conversion and crossovers for any species.

evolutionary biology↗

bioRxiv2023

TRAILS: tree reconstruction of ancestry using incomplete lineage sorting

Genome-wide genealogies of multiple species carry detailed information about demographic and selection processes on individual branches of the phylogeny. Here, we introduce TRAILS, a hidden Markov model that accurately infers time-resolved population genetics parameters, such as ancestral effective population sizes and speciation times, for ancestral branches using a multi-species alignment of three species and an outgroup. TRAILS leverages the information contained in incomplete lineage sorting fragments by modelling genealogies along the genome as rooted three-leaved trees, each with a topology and two coalescent events happening in discretized time intervals within the phylogeny. Posterior decoding of the hidden Markov model can be used to infer the ancestral recombination graph for the alignment and details on demographic changes within a branch. Since TRAILS performs posterior decoding at the base-pair level, genome-wide scans based on the posterior probabilities can be devised to detect deviations from neutrality. Using TRAILS on a human-chimp-gorilla-orangutan alignment, we recover speciation parameters and extract information about the topology and coalescent times at high resolution. Author summaryDNA sequences can be compared to reconstruct the evolutionary history of different species. While the ancestral history is usually represented by a single phylogenetic tree, speciation is a more complex process, and, due to the effect of recombination, different parts of the genome might follow different genealogies. For example, even though humans are more closely related to chimps than to gorillas, around 15% of our genome is more similar to the gorilla genome than to the chimp one. Even for those parts of the genome that do follow the same human-chimp topology, we might encounter a last common ancestor at different time points in the past for different genomic fragments. Here, we present TRAILS, a new framework that utilizes the information contained in all these genealogies to reconstruct the speciation process. TRAILS infers unbiased estimates of the speciation times and the ancestral effective population sizes, improving the accuracy when compared to previous methods. TRAILS also reconstructs the genealogy at the highest resolution, inferring, for example, when common ancestry was found for different parts of the genome. This information can also be used to detect deviations from neutrality, effectively inferring natural selection that happened millions of years ago. We validate the method using extensive simulations, and we apply TRAILS to a human-chimp-gorilla multiple genome alignment, from where we recover speciation parameters that are in good agreement with previous estimates.

evolutionary biology↗

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↗

bioRxiv2023

De novo mutation rates in sticklebacks

Mutation rate is a fundamental parameter in population genetics. Apart from being an important scaling parameter for demographic and phylogenetic inference, it allows one to understand at what rate new genetic diversity is generated and what is the expected level of genetic diversity in a population at equilibrium. However, except for well-established model organisms, accurate estimates of de novo mutation rates are available for a very limited number of organisms from the wild. We estimated mutation rates ({micro}) in two marine populations of the nine-spined stickleback (Pungitius pungitius) with the aid of several 2- and 3-generational family pedigrees, deep (>50x) whole genome re-sequencing and a high-quality reference genome. After stringent filtering, we discovered 295 germline mutations from 106 offspring translating to {micro} = 4.64 x 10-9 and {micro} = 4.08 x 10-9 per base, per generation, in the two populations, respectively. Twenty percent of the mutations were shared by full-sibs showing that the level of parental mosaicism was relatively high. Since the estimated {micro} was 3.2 times smaller than the commonly used substitution rate, recalibration with {micro} led to substantial increase in estimated divergence times between different stickleback species. Our estimates of de novo mutation rate should provide a useful resource for research focused on fish population genetics and that of sticklebacks in particular.

genomics↗

bioRxiv2022

Single-cell analysis maps distinct cellular responses to rhizobia and identifies the novel infection regulator SYMRKL1 in Lotus japonicus

Legume-rhizobium signaling during establishment of symbiotic nitrogen fixation restricts rhizobium colonization to specific cells. A limited number of root hair cells allow infection threads to form, and only a fraction of the epidermal infection threads progress to cortical layers to establish functional nodules. Here we use single-cell analysis to define the epidermal and cortical cell populations that respond to and facilitate rhizobium infection. We then identify high-confidence nodulation gene candidates based on their specific expression in these populations, pinpointing genes stably associated with infection across genotypes and time points. We show that one of these, which we name SYMRKL1, encodes a protein with an ectodomain predicted to be nearly identical to that of SYMRK and is required for normal infection thread formation. Our work disentangles cellular processes and transcriptional modules that were previously confounded due to lack of cellular resolution, providing a more detailed understanding of symbiotic interactions.

plant biology↗

bioRxiv2022

Worldwide late-Quaternary population declines in extant megafauna are due to Homo sapiens rather than climate

The worldwide loss of large animal species over the past 100,000 years is evident from the fossil record, with climate and human impact as the most likely causes of megafauna extinctions. To help distinguish between these two scenarios, we analysed whole-genome sequence data of 142 species to infer their population size histories during the Quaternary. We modelled differences in population dynamics among species using ecological factors, paleoclimate and human presence as covariates. We report a significant population decline towards the present time in more than 90% of species, with larger megafauna experiencing the strongest decline. We find that population decline became ubiquitous approximately 100,000 years ago, with the majority of species experiencing their lowest population sizes during this period. We assessed the relative impact of climate fluctuations and human presence on megafauna dynamics and found that climate has limited explanatory power for late-Quaternary shifts in megafauna population sizes, which are largely explained by Homo sapiens arrival times. As a consequence of megafauna decline, total biomass and metabolic input provided by these species has drastically reduced to less than 25% compared to 100,000 years ago. These observations imply that the worldwide expansion of H. sapiens caused a major restructuring of ecosystems at global scale.

evolutionary biology↗

bioRxiv2021

The molecular evolution of spermatogenesis across mammals

The testis is a key male reproductive organ that produces gametes through the process of spermatogenesis. Testis morphologies and spermatogenesis evolve rapidly in mammals, presumably due to the evolutionary pressure on males to be reproductively successful1,2. The rapid evolution of the testis was shown to be reflected at the molecular level based on bulk-tissue work3-8, but the molecular evolution of individual spermatogenic cell types across mammalian lineages remains largely uncharacterized. Here we report evolutionary analyses of single-nucleus transcriptome data for testes from eleven species that cover the three major mammalian lineages (eutherians, marsupials, egg-laying monotremes) and birds (the evolutionary outgroup), and include seven key primates. Our analyses reveal that the rapid evolution of the testis is driven by accelerated fixation rates of gene expression changes, amino acid altering substitutions, and newly emerged genes in late spermatogenic stages - likely facilitated by reduced pleiotropic constraints, haploid selection, and a transcriptionally permissive chromatin environment. We identify temporal expression changes of individual genes across species, which may have contributed to the emergence of species-specific phenotypes, but also conserved expression programs underlying ancestral spermatogenic processes. Sex chromosome analyses show that genes predominantly expressed in spermatogonia (i.e., germ cells fueling spermatogenesis) and Sertoli cells (i.e., somatic supporting cells) independently accumulated on X chromosomes across mammals during evolution, presumably due to male-beneficial selective forces. Further work uncovered that the process of meiotic sex chromosome inactivation (MSCI) also occurs in monotremes and hence is common to the different mammalian sex chromosome systems, contrary to previous inferences9. Thus, the general mechanism of meiotic silencing of unsynapsed chromatin (MSUC), which underlies MSCI, represents an ancestral mammalian feature. Together, our study illuminates the cellular and molecular evolution of mammalian spermatogenesis and associated selective forces, and provides a resource for investigating the biology of the testis across mammals.

evolutionary biology↗

bioRxiv2021

Evolutionary dynamics of pseudoautosomal region 1 in humans and great apes

The pseudoautosomal region 1 (PAR1) is a 2.7 Mb telomeric region of human sex chromosomes. As the largest point of contact between the X and Y, PAR1 has a crucial role in ensuring proper segregation of sex chromosomes during male meiosis, exposing it to extreme recombination and associated mutational processes. We investigate PAR1 evolution using population genomic datasets of extant humans, eight populations of great apes and two archaic human genome sequences. We find that the PAR1 sequence is closer to nucleotide equilibrium than autosomal telomeric sequences. We detect a difference between long-term substitution patterns and extant diversity in PAR1 that is mainly driven by the conflict between strong mutation and recombination-associated fixation bias at CpG sites. Additionally, we detect excess C[->]G mutations in PAR1 of all great ape species, specific to the mutagenic effect of male recombination. Analysis of differences between frequencies of alleles segregating in females and males provided no evidence for sexually antagonistic selection in this region. Furthermore, despite recent evidence for Y chromosome introgression from humans into Neanderthals, we find that the Neanderthal PAR1 retained similarity to the Denisovan sequence, as is the case for the X chromosome and the autosomes. Lastly, we study repeat content and double-strand break hotspot regions in PAR1 and find that they may play roles in ensuring the obligate X-Y recombination event during male meiosis. Our study provides an unprecedented quantification of population genetic forces and insight into evolutionary processes governing PAR1 biology.

evolutionary biology↗

bioRxiv2021

Mutationathon: towards standardization in estimates of pedigree-based germline mutation rates

In the past decade, several studies have estimated the human per-generation germline mutation rate using large pedigrees. More recently, estimates for various non-human species have been published. However, methodological differences among studies in detecting germline mutations and estimating mutation rates make direct comparisons difficult. Here, we describe the many different steps involved in estimating pedigree-based mutation rates, including sampling, sequencing, mapping, variant calling, filtering, and how to appropriately account for false-positive and false-negative rates. For each step, we review the different methods and parameter choices that have been used in the recent literature. Additionally, we present the results from a "Mutationathon", a competition organized among five research labs to compare germline mutation rate estimates for a single pedigree of rhesus macaques. We report almost a two-fold variation in the final estimated rate among groups using different post-alignment processing, calling, and filtering criteria and provide details into the sources of variation across studies. Though the difference among estimates is not statistically significant, this discrepancy emphasizes the need for standardized methods in mutation rate estimations and the difficulty in comparing rates from different studies. Finally, this work aims to provide guidelines for computational and statistical benchmarks for future studies interested in identifying germline mutations from pedigrees.

evolutionary biology↗

bioRxiv2021

Different historical generation intervals in human populations inferred from Neanderthal fragment lengths and patterns of mutation accumulation

After the main out-of-Africa event, humans interbred with Neanderthals leaving 1-2% of Neanderthal DNA scattered in small fragments in all non-African genomes today1,2. Here we investigate the size distribution of these fragments in non-African genomes3. We find consistent differences in fragment length distributions across Eurasia with 11% longer fragments in East Asians than in West Eurasians. By comparing extant populations and ancient samples, we show that these differences are due to a different rate of decay in length by recombination since the Neanderthal admixture. In line with this, we observe a strong correlation between the average fragment length and the accumulation of derived mutations, similar to what is expected by changing the ages at reproduction as estimated from trio studies4. Altogether, our results suggest consistent differences in the generation interval across Eurasia, by up to 20% (e.g. 25 versus 30 years), over the past 40,000 years. We use sex-specific accumulations of derived alleles to infer how these changes in generation intervals between geographical regions could have been mainly driven by shifts in either male or female age of reproduction, or both. We also find that previously reported variation in the mutational spectrum5 may be largely explained by changes to the generation interval and not by changes to the underlying mutational mechanism. We conclude that Neanderthal fragment lengths provide unique insight into differences of a key demographic parameter among human populations over the recent history.

evolutionary biology↗

bioRxiv2020

Population dynamics of GC-changing mutations in humans and great apes

BackgroundThe nucleotide composition of the genome is a balance between origin and fixation rates of different mutations. For example, it is well-known that transitions occur more frequently than transversions, particularly at CpG sites. Differences in fixation rates of mutation types are less explored. Specifically, recombination-associated GC-biased gene conversion (gBGC) may differentially impact GC-changing mutations, due to differences in their genomic distributions and efficiency of mismatch repair mechanisms. Given that recombination evolves rapidly across species, we explore gBGC of different mutation types across human populations and among great ape species. ResultsWe report a stronger correlation between GC frequency and recombination for transitions than for transversions. Notably, CpG transitions are most strongly affected by gBGC. We show that the strength of gBGC differs for transitions and transversions but that its overall strength is positively correlated with effective population sizes of human populations and great ape species, with some notable exceptions, such as a stronger effect of gBGC on non-CpG transitions in populations of European descent. We study the dependence of gBGC dynamics on flanking nucleotides and show that some mutation types evolve in opposition to the gBGC expectation, likely due to hypermutability of specific nucleotide contexts. ConclusionsDifferences in GC-biased gene conversion are evident between different mutation types, and dependent on sex-specific recombination, population size and flanking nucleotide context. Our results therefore highlight the importance of different gBGC dynamics experienced by GC-changing mutations and their impact on nucleotide composition evolution.

evolutionary biology↗

bioRxiv2020

The germline mutational process in rhesus macaque and its implications for phylogenetic dating

Understanding the rate and pattern of germline mutations is of fundamental importance for understanding evolutionary processes. Here we analyzed 19 parent-offspring trios of rhesus macaques (Macaca mulatta) at high sequencing coverage of ca. 76X per individual, and estimated an average rate of 0.77 x 10-8 de novo mutations per site per generation (95 % CI: 0.69 x 10-8 - 0.85 x 10-8). By phasing 50 % of the mutations to parental origins, we found that the mutation rate is positively correlated with the paternal age. The paternal lineage contributed an average of 81 % of the de novo mutations, with a trend of an increasing male contribution for older fathers. About 3.5 % of de novo mutations were shared between siblings, with no parental bias, suggesting that they arose from early development (postzygotic) stages. Finally, the divergence times between closely related primates calculated based on the yearly mutation rate of rhesus macaque generally reconcile with divergence estimated with molecular clock methods, except for the Cercopithecidae/Hominoidea molecular divergence dated at 52 Mya using our new estimate of the yearly mutation rate.

evolutionary biology↗