Biology subjects

de Manuel, M.

Publications and source records attributed to de Manuel, M..

14 recordsLinked to original sources

bioRxiv2025

What sets the mutation rate of a cell type in an animal species?

Germline mutation rates per generation are strikingly similar across animals, despite vast differences in life histories. Analogously, in at least one somatic cell type, mutation rates at the end of lifespan are comparable across mammals. These observations point to a key role for natural selection in shaping mutation rates. In this essay, we summarize the patterns identified to date and outline existing theories for how selection pressures might shape mutation rates in animal germline and soma. We argue that an understanding of what sets the mutation rate of a given cell type in a species requires better integration of genetics and development with population processes of selection and genetic drift.

evolutionary biology↗

bioRxiv2025

Sex differences in transcription-associated mutagenesis in the human germline

In humans, germline mutation rates are three- to four-fold higher in males than females, for largely unknown reasons. We investigated whether transcription, a well-documented source of both DNA damage and repair in somatic tissues, is associated with sex differences in germline mutations. To this end, we used expression data from male and female germline cells and phased de novo germline mutations from pedigrees. Focusing on protein-coding genes, we found no relationship between the male mutation rate and gene expression levels in the fetal germline or in adult testis tissue, despite evidence for transcriptional asymmetry. Individual stages of spermatogenesis differ in their contribution to mutation, however: expression levels in spermatogonial stem cells are significantly positively associated with paternal mutation rates, while those in primary spermatocytes are significantly negatively associated. Thus, transcription may have varying effects over male gametogenesis that are not readily detected from its cumulative effect on the total germline mutation rate. In females, by contrast, mutation rates increase significantly with transcription levels in the fetal germline, adult oocytes and adult ovary tissues, consistent with widespread transcription asymmetry. We confirm the difference between the sexes by analyzing phased mutations from three-generation pedigrees and the lack of an association in males by analyzing paternal mutations from seminiferous tubules and sperm. Thus, transcription has distinct effects on the mutation rate in the two sexes, leading to an increase in mutations in females but not males, in contrast to what one might expect from the overall paternal bias in germline mutations.

genetics↗

bioRxiv2025

Collateral mutagenesis funnels multiple sources of DNA damage into a ubiquitous mutational signature

Mutations reflect the net effects of myriad types of damage, replication errors, and repair mechanisms, and are therefore expected to differ across cell types with distinct exposures to mutagens, division rates, and cellular programs. Yet when mutations in humans are decomposed into a set of "signatures", one single base substitution signature, SBS5, is present across cell types and tissues, and predominates in post-mitotic neurons as well as male and female germlines [1-3]. The etiology of SBS5 is unknown. By modeling the processes by which mutations arise, we infer that SBS5 is the footprint of errors in DNA synthesis triggered by distinct types of DNA damage. Supporting this hypothesis, we find that SBS5 rates increase with signatures of endogenous and exogenous DNA damage in cancerous and non-cancerous cells and co-vary with repair rates along the genome, as expected from model predictions. These analyses indicate that SBS5 captures the output of a "funnel", through which multiple sources of damage result in a similar mutation spectrum. As we further show, SBS5 mutations arise not only from translesion synthesis but also from DNA repair, suggesting that both mechanisms occasionally trigger the same mutagenic process.

genomics↗

bioRxiv2024

Conservation of mutation and recombination parameters between mammals and zebra finch

Most of our understanding of the fundamental processes of mutation and recombination stems from a handful of disparate model organisms and pedigree studies of mammals, with little known about other vertebrates. To gain a broader comparative perspective, we focused on the zebra finch (Taeniopygia castanotis), which, like other birds, differs from mammals in its karyotype (which includes many micro-chromosomes), in the mechanism by which recombination is directed to the genome, and in aspects of ontogenesis. We collected genome sequences from three generation pedigrees that provide information about 80 meioses, inferring 202 single-point de novo mutations, 1,174 crossovers, and 275 non-crossovers. On that basis, we estimated a sex-averaged mutation rate of 5.0 x 10-9 per base pair per generation, on par with mammals that have a similar generation time ([~]2-3 years). Also as in mammals, we found a paternal germline mutation bias at later stages of gametogenesis (of 1.7:1) but no discernible difference between sexes in early development. Examining recombination patterns, we found that the sex-averaged crossover rate on macro-chromosomes (1.05 cM/Mb) is again similar to values observed in mammals, as is the spatial distribution of crossovers, with a pronounced enrichment near telomeres. In contrast, non-crossover rates are more uniformly distributed. On micro-chromosomes, sex-averaged crossover rates are substantially higher (4.21 cM/Mb), as expected from crossover homeostasis, and both crossover and non-crossover events are more uniformly distributed. At a finer scale, recombination events overlap CpG islands more often than expected by chance, as expected in the absence of PRDM9. Despite differences in the mechanism by which recombination events are specified and the presence of many micro-chromosomes, estimates of the degree of GC-biased gene conversion (59%), the mean non-crossover conversion tract length ([~]32 bp), and the non-crossover-to-crossover ratio (5.4:1) are all comparable to those reported in primates and mice. The similarity of mutation and recombination properties in zebra finch to those in mammals suggest that they are conserved by natural selection.

evolutionary biology↗

bioRxiv2023

Disentangling sources of clock-like mutations in germline and soma

The rates of mutations vary across cell types. To identify causes of this variation, mutations are often decomposed into a combination of the single base substitution (SBS) "signatures" observed in germline, soma and tumors, with the idea that each signature corresponds to one or a small number of underlying mutagenic processes. Two such signatures turn out to be ubiquitous across cell types: SBS signature 1, which consists primarily of transitions at methylated CpG sites caused by spontaneous deamination, and the more diffuse SBS signature 5, which is of unknown etiology. In cancers, the number of mutations attributed to these two signatures accumulates linearly with age of diagnosis, and thus the signatures have been termed "clock-like." To better understand this clocklike behavior, we develop a mathematical model that includes DNA replication errors, unrepaired damage, and damage repaired incorrectly. We show that mutational signatures can exhibit clocklike behavior because cell divisions occur at a constant rate and/or because damage rates remain constant over time, and that these distinct sources can be teased apart by comparing cell lineages that divide at different rates. With this goal in mind, we analyze the rate of accumulation of mutations in multiple cell types, including soma as well as male and female germline. We find no detectable increase in SBS signature 1 mutations in neurons and only a very weak increase in mutations assigned to the female germline, but a significant increase with time in rapidly-dividing cells, suggesting that SBS signature 1 is driven by rounds of DNA replication occurring at a relatively fixed rate. In contrast, SBS signature 5 increases with time in all cell types, including post-mitotic ones, indicating that it accumulates independently of cell divisions; this observation points to errors in DNA repair as the key underlying mechanism. Thus, the two "clock-like" signatures observed across cell types likely have distinct origins, one set by rates of cell division, the other by damage rates.

genetics↗

bioRxiv2023

Patterns of recombination in snakes reveal a tug of war between PRDM9 and promoter-like features

In vertebrates, there are two known mechanisms by which meiotic recombination is directed to the genome: in humans, mice, and other mammals, recombination occurs almost exclusively where the protein PRDM9 binds, while in species lacking an intact PRDM9, such as birds and canids, recombination rates are elevated near promoter-like features. To test if PRDM9 also directs recombination in non-mammalian vertebrates, we focused on an exemplar species, the corn snake (Pantherophis guttatus). Unlike birds, this species possesses a single, intact PRDM9 ortholog. By inferring historical recombination rates along the genome from patterns of linkage disequilibrium and identifying crossovers in pedigrees, we found that PRDM9 specifies the location of recombination events outside of mammals. However, we also detected an independent effect of promoter-like features on recombination, which is more pronounced on macrothan microchromosomes. Thus, our findings reveal that the uses of PRDM9 and promoter-like features are not mutually-exclusive, and instead reflect a tug of war, which varies in strength along the genome and is more lopsided in some species than others. One sentence summaryWhile the localization of meiotic recombination in vertebrates was previously thought to occur using one of two distinct mechanisms, our analysis of recombination in corn snakes reveals that they and likely other vertebrates use both of these mechanisms.

evolutionary biology↗

bioRxiv2022

Ghost admixture in eastern gorillas

Archaic admixture has had a significant impact on human evolution with multiple events across different clades, including from extinct hominins such as Neanderthals and Denisovans into modern humans. Within the great apes archaic admixture has been identified in chimpanzees and bonobos, but the possibility of such events has not been explored in other species. Here, we address this question using high-coverage whole genome sequences from all four extant gorilla subspecies, including six newly sequenced eastern gorillas from previously unsampled geographic regions. Using Approximate Bayesian Computation (ABC) with neural networks to model the demographic history of gorillas, we find a signature of admixture from an archaic ghost lineage into the common ancestor of eastern gorillas, but not western gorillas. We infer that up to 3% of the genome of these individuals is introgressed from an archaic lineage that diverged more than 3 million years ago from the common ancestor of all extant gorillas. This introgression event took place before the split of mountain and eastern lowland gorillas, likely more than 40 thousand years ago, and may have influenced perception of bitter taste in eastern gorillas. When comparing the introgression landscapes of gorillas, humans and bonobos, we find a consistent depletion of introgressed fragments on the X chromosome across these species. However, depletion in protein-coding content is not detectable in eastern gorillas, possibly as a consequence of stronger genetic drift in this species.

evolutionary biology↗

bioRxiv2022

Genomics reveals introgression and purging of deleterious mutations in the Arabian leopard (Panthera pardus nimr)

Low genetic variation and high levels of inbreeding are usually a consequence of recent population declines in endangered species. From a conservation point of view, it is essential to genetically screen endangered populations to help assess their vulnerability to extinction and to properly create informed management actions towards their conservation efforts. The leopard, Panthera pardus, is a highly generalist predator with currently eight different subspecies inhabiting a wide range of habitats. Yet, genomic data is still lacking for the Critically Endangered Arabian leopard (P. p. nimr). Here, we sequenced the whole genome of two specimens of Arabian leopard and assembled the most complete genomic dataset for leopards to date, including genomic data for all current subspecies. Our phylogenomic analyses show that leopards are divided into two deeply divergent clades, one including the only African subspecies and a second one including all seven subspecies of Asian leopards. Interestingly, the Arabian leopard represents a well-differentiated lineage sister to the rest of Asian subspecies. The demographic history, genomic diversity, Runs of Homozygosity (RoHs), and mutational load in the Arabian leopard indicate a prolonged population decline, which has led to an increase in inbreeding and RoHs, with consequent purging of deleterious mutations. Our study represents the first attempt to genetically inform captive breeding programs for this Critically Endangered subspecies. Still, more genomes, particularly from wild individuals, are needed to fully characterise the genetic makeup of this singular and iconic subspecies.

genomics↗

bioRxiv2022

A paternal bias in germline mutation is widespread across amniotes and can arise independently of cell divisions

In humans and other mammals, germline mutations are more likely to arise in fathers than in mothers. Although this sex bias has long been attributed to DNA replication errors in spermatogenesis, recent evidence from humans points to the importance of mutagenic processes that do not depend on cell division, calling into question our understanding of this basic phenomenon. Here, we infer the ratio of paternal-to-maternal mutations, , in 42 species of amniotes, from putatively neutral substitution rates of sex chromosomes and autosomes. Despite marked differences in gametogenesis, physiologies and environments across species, fathers consistently contribute more mutations than mothers in all the species examined, including mammals, birds and reptiles. In mammals, is as high as 4 and correlates with generation times; in birds and snakes, appears more stable around 2. These observations are consistent with a simple model, in which mutations accrue at equal rates in both sexes during early development and at a higher rate in the male germline after sexual differentiation, with a conserved paternal-to-maternal ratio across species. Thus, may reflect the relative contributions of two or more developmental phases to total germline mutations, and is expected to depend on generation time even if mutations do not track cell divisions.

evolutionary biology↗

bioRxiv2020

Historical population declines prompted significant genomic erosion in the northern and southern white rhinoceros (Ceratotherium simum)

Large vertebrates are extremely sensitive to anthropogenic pressure, and their populations are declining fast. The white rhinoceros (Ceratotherium simum) is a paradigmatic case: this African megaherbivore suffered a remarkable population reduction in the last 150 years due to human activities. The two white rhinoceros subspecies, the northern (NWR) and the southern white rhinoceros (SWR), however, underwent opposite fates: the NWR vanished quickly after the onset of the decline, while the SWR recovered after a severe bottleneck. Such demographic events are predicted to have an erosive effect at the genomic level, in connection with the extirpation of diversity, and increased genetic drift and inbreeding. However there is currently little empirical data available that allows us to directly reconstruct the subtleties of such processes in light of distinct demographic histories. Therefore to assess these effects, we generated a whole-genome, temporal dataset consisting of 52 re-sequenced white rhinoceros genomes, that represents both subspecies at two time windows: before and during/after the bottleneck. Our data not only reveals previously unknown population substructure within both subspecies, but allowed us to quantify the genomic erosion undergone by both, with post-bottleneck white rhinoceroses harbouring significantly fewer heterozygous sites, and showing higher inbreeding coefficients than pre-bottleneck individuals. Moreover, the effective population size suffered a decrease of two and three orders of magnitude in the NWR and SWR respectively, due to the recent bottleneck. Our data therefore provides much needed empirical support for theoretical predictions about the genomic consequences of shrinking populations, information that is relevant for understanding the process of population extinction. Furthermore, our findings have the potential to inform management approaches for the conservation of the remaining white rhinoceroses.

evolutionary biology↗

bioRxiv2019

Plasmodium vivax Malaria viewed through the lens of an eradicated European strain

The protozoan Plasmodium vivax is responsible for 42% of all cases of malaria outside Africa. The parasite is currently largely restricted to tropical and subtropical latitudes in Asia, Oceania and the Americas. Though, it was historically present in most of Europe before being finally eradicated during the second half of the 20th century. The lack of genomic information on the extinct European lineage has prevented a clear understanding of historical population structuring and past migrations of P. vivax. We used medical microscope slides prepared in 1944 from malaria-affected patients from the Ebro Delta in Spain, one of the last footholds of malaria in Europe, to generate a genome of a European P. vivax strain. Population genetics and phylogenetic analyses placed this strain basal to a cluster including samples from the Americas. This genome allowed us to calibrate a genomic mutation rate for P. vivax, and to estimate the mean age of the last common ancestor between European and American strains to the 15th century. This date points to an introduction of the parasite during the European colonisation of the Americas. In addition, we found that some known variants for resistance to anti-malarial drugs, including Chloroquine and Sulfadoxine, were already present in this European strain, predating their use. Our results shed light on the evolution of an important human pathogen and illustrate the value of antique medical collections as a resource for retrieving genomic information on pathogens from the past.

genetics↗

bioRxiv2019

Estimates of genetic load in small populations suggest extensive purging of deleterious alleles

It is commonly thought that declining populations will experience negative genetic consequences as a result of increased inbreeding. Here we estimated the average deleteriousness of derived alleles in a range of mammals and found that species with historically small population size and low genetic diversity often have lower genetic load than species with large population sizes. This is likely the result of genetic purging - the more efficient removal of partially deleterious recessive alleles from inbred populations. Our findings suggest that genetic purging occurs over long evolutionary time frames, and therefore rapid population declines are likely to dis-proportionally increase mutational load in species with high diversity, as they carry many deleterious alleles that can reach fixation before genetic purging can remove them.

genomics↗

bioRxiv2019

Evidence that viruses, particularly SIV, drove genetic adaptation in natural populations of eastern chimpanzees

All four subspecies of chimpanzees are endangered. Differing in their demographic histories and geographical ranges within sub-Saharan Africa, they have likely adapted to different environmental factors. We show that highly differentiated SNPs in eastern chimpanzees are uniquely enriched in genic sites in a way that is expected under recent adaptation. These sites are enriched for genes that differentiate the immune response to infection by simian immunodeficiency virus (SIV) in natural vs. non-natural host species. Conversely, central chimpanzees exhibit selective sweeps at the cytokine receptors CCR3, CCR9 and CXCR6 - paralogs of CCR5 and CXCR4, the two major receptors utilized by HIV to enter human cells. Thus, we infer that SIV may be eliciting distinctive adaptive responses in different chimpanzee subspecies. Since central chimpanzee SIV is the source of the global HIV/AIDS pandemic, understanding the mechanisms that limit pathogenicity of SIV in chimpanzees can broaden our understanding of HIV infection in humans.

evolutionary biology↗

bioRxiv2018

Unbiased whole genomes from mammalian feces using fluorescence-activated cell sorting

Ecological flexibility, extended lifespans, and large brains, have long intrigued evolutionary biologists, and comparative genomics offers an efficient and effective tool for generating new insights into the evolution of such traits. Studies of capuchin monkeys are particularly well situated to shed light on the selective pressures and genetic underpinnings of local adaptation to diverse habitats, longevity, and brain development. Distributed widely across Central and South America, they are inventive and extractive foragers, known for their sensorimotor intelligence. Capuchins have the largest relative brain size of any monkey and a lifespan that exceeds 50 years, despite their small (3-5 kg) body size. We assemble a de novo reference genome for Cebus imitator and provide the first genome annotation of a capuchin monkey. Through high-depth sequencing of DNA derived from blood, various tissues and feces via fluorescence activated cell sorting (fecalFACS) to isolate monkey epithelial cells, we compared genomes of capuchin populations from tropical dry forests and lowland rainforests and identified population divergence in genes involved in water balance, kidney function, and metabolism. Through a comparative genomics approach spanning a wide diversity of mammals, we identified genes under positive selection associated with longevity and brain development. Additionally, we provide a technological advancement in the use of non-invasive genomics for studies of free-ranging mammals. Our intra- and interspecific comparative study of capuchin genomics provides new insights into processes underlying local adaptation to diverse and physiologically challenging environments, as well as the molecular basis of brain evolution and longevity. SIGNIFICANCESurviving challenging environments, living long lives, and engaging in complex cognitive processes are hallmark characteristics of human evolution. Similar traits have evolved in parallel in capuchin monkeys, but their genetic underpinnings remain unexplored. We developed and annotated a reference assembly for white-faced capuchin monkeys to explore the evolution of these phenotypes. By comparing populations of capuchins inhabiting rainforest versus dry forests with seasonal droughts, we detected selection in genes associated with kidney function, muscular wasting, and metabolism, suggesting adaptation to periodic resource scarcity. When comparing capuchins to other mammals, we identified evidence of selection in multiple genes implicated in longevity and brain development. Our research was facilitated by our new method to generate high- and low-coverage genomes from non-invasive biomaterials.

genomics↗