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Soni, V.

Publications and source records attributed to Soni, V..

At least 19 recordsLinked to original sources
bioRxiv2026

Inferring the relative contributions of evolutionary processes shaping X chromosome dynamics in the common marmoset (Callithrix jacchus) in the presence of twinning and hematopoietic chimerism

The common marmoset (Callithrix jacchus) is a biomedically important species that is characterized by two unusual biological traits -- a high frequency of twin births and hematopoietic chimerism -- that preclude the application of many commonly used population genomic approaches for quantifying evolutionary processes. In this study, we directly account for both factors in order to estimate fine-scale mutation and recombination rate maps, as well as to infer the demographic and selective processes shaping variation, on the common marmoset X chromosome. Comparing our findings to estimates recently inferred on the autosomes of this species, we find reduced rates of mutation and recombination on the X, as expected. Furthermore, population sex ratios are inferred to be nearly equal, and the appropriately rescaled autosomal population history fits the X chromosome well. Finally, we report evidence of recent selective sweeps targeting a number of X-linked genes, including several of significant biomedical relevance. Overall, these analyses provide novel insights into the evolutionary processes shaping X chromosome evolution in this biomedically-relevant primate model.

evolutionary biology↗
bioRxiv2026

Inferring the demographic history of Chinese and Indian rhesus macaque (Macaca mulatta) populations from PacBio HiFi long-read sequencing data

The rhesus macaque (Macaca mulatta) is one of the most widely used animal models in biomedical research, both as it resembles humans in key biological aspects and as it is characterized by a broad geographic range. Most of the individuals housed in U.S. research colonies have been sampled from either China or India, though notably the source population of these animals has significantly shifted over time. Given the substantial genetic and immunological differences between these populations, a deeper understanding of the underlying population structure is critically important for biomedical interpretation. Despite this, the demographic histories of these two populations remain poorly resolved. Here, we present an analysis of whole-genome, PacBio HiFi long-read sequencing data from ten unrelated individuals of each population, applying four related model- and non-model based demographic inference approaches, in order to reconstruct their ancestral history. We evaluated the fit of the subsequently estimated models against the empirical data, and incorporated underlying uncertainty in the mutation rates used for scaling. We inferred a well-fitting population history characterized by substantial structure between Chinese and Indian populations, with a split time [~]140,000 generations ago from an ancestral population of [~]65,000 individuals. We additionally inferred the subsequent history of size change within, and gene flow between, these populations, reaching the current estimated sizes of [~]220,000 individuals in the Chinese population and [~]14,000 individuals in the Indian population. The robust baseline demographic model established in this study will serve as a valuable resource for future research on this species, including for improved fine-scale recombination mapping, selection inference, and association studies.

evolutionary biology↗
bioRxiv2026

Comparing fine-scale mutation and recombination landscapes in rhesus macaque (Macaca mulatta) populations of Chinese and Indian descent inferred from both short- and long-read sequencing data

Genomic diversity amongst primates is fundamentally shaped by species- and population-specific rates of mutation and recombination. In this study, we infer fine-scale mutation and recombination rate maps for the rhesus macaque (Macaca mulatta) -- the most widely used non-human primate model in biomedical research -- leveraging both short-(Illumina) and long-(PacBio HiFi) read sequencing data from two distinct populations of Chinese and Indian descent. Thereby, we draw comparisons between the rates estimated from each dataset, highlighting both biologically meaningful variation between these populations as well as artefactual discrepancies likely arising from systematic biases and differences in the utilized sequencing technologies. Consistent with previous observations in humans, broad-scale features of the recombination landscape are well-conserved between the two populations, but significant differences exist at the finer scales. Notably, we find evidence for a high rate of turnover in recombination hotspots over a short evolutionary time span, resulting in population-specific recombination maps in which the vast majority of the >30,000 identified recombination hotspots in one population are inactive in the other population. Given that mutation and recombination rates are necessary components for the interpretation of other diversity-shaping processes and events, including those characterizing both the underlying demographic and selective histories, the incorporation of these population-specific maps into future models will improve our understanding of the evolutionary genomics of the species. Additionally, these maps will serve as a fundamental component of future genome-wide association and fine-mapping studies of disease traits in this biomedical model system.

evolutionary biology↗
bioRxiv2026

Inferring patterns of purifying, positive and balancing selection in the coppery titi monkey (Plecturocebus cupreus) utilizing a well-fit evolutionary baseline model

Despite the coppery titi monkey (Plecturocebus cupreus) being a model system for the study of neurodevelopment and behavior, the evolutionary forces shaping observed levels and patterns of genetic variation in the species have remained poorly studied. In order to illuminate the pervasive eCects of purifying and background selection, we have fit a distribution of fitness eCects of newly arising exonic mutations, utilizing patterns of polymorphism and divergence based on a recently published high-quality genome assembly. To further characterize episodically acting selective processes, we additionally performed the first whole-genome scans for recent positive and balancing selection in this species, reducing false-positive rates by incorporating the demographic history of the population into an evolutionary null model. These scans identified a small number of biomedically-relevant genes with strong statistical support for having experienced recent selective sweeps or long-term balancing selection. In addition, we identified four genomic deletions bearing the signatures of balancing selection. Taken together, this study provides the first insights into patterns of persistent and episodic selective processes in this species.

evolutionary biology↗
bioRxiv2026

Inferring fine-scale rates of mutation and recombination in the coppery titi monkey (Plecturocebus cupreus)

Despite being a primate of considerable biomedical interest, particularly as a model for social behavior and neurobiology, the evolutionary processes shaping genetic variation in the coppery titi monkey (Plecturocebus cupreus) remain largely uncharacterized. Utilizing divergence and polymorphism data together with a recently published high-quality, annotated genome, we here infer the first fine-scale maps of mutation and recombination rates in this platyrrhine. We find a mean genome-wide mutation rate of between 0.93 x 10-8 and 1.61 x 10-8 per site per generation and a mean genome-wide recombination rate of 0.975 cM/Mb, in line with fine-scale rates estimated in other primates. In addition to providing novel biological insights into the mutation and recombination rates in this emerging model species for behavioral research, these fine-scale maps also improve our understanding of how the processes of mutation and recombination shape genetic variation in the coppery titi monkey genome, and their incorporation into evolutionary models will be a necessary aspect of future downstream inference of other evolutionary processes required to elucidate the genetic factors underlying the phenotypic traits studied in this species.

evolutionary biology↗
bioRxiv2026

Inferring the demographic history of coppery titi monkeys (Plecturocebus cupreus) from high-quality, whole-genome, population-level data

Despite being an important biomedical model species for social behavior, the natural population history of the coppery titi monkey (Plecturocebus cupreus) remains largely uncharacterized, in part due to the scarcity of genomic resources available for the species. Apart from the inherent interest in the demographic dynamics of this abundant platyrrhine native to the Amazon forest of Brazil and Peru, this quantification will also serve as a central component of future genotype-to-phenotype studies, given the ability of historical population size change and structure to generate genetic associations. In this study, we deep-sequenced the genomes of six unrelated individuals and inferred a baseline demographic model based on observed levels and patterns of variation in the non-coding regions of the genome. In characterizing these demographic dynamics, we found that estimated population size changes correspond well to previously described speciation times as well as to large-scale climatic changes relating to glaciation patterns.

evolutionary biology↗
bioRxiv2025

RNA polymerase-mediated regulation of intrinsic antibiotic resistance and bacterial cell division

Rifampin is a frontline antibiotic that inhibits the RNA polymerase of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). Unlike most antibiotics, rifampin has an unusual ability to shorten the duration of treatment needed to cure TB that is not simply explained by its antimicrobial potency. We sought specific secondary effects of rifampins inhibition of Mtb RNA polymerase that may mediate this activity. We discovered that rifampin elicited a cell division arrest that was mediated through its inhibition of RNA polymerase. This arrest resulted in a downstream inhibition of the MtrAB two-component regulatory system, a mediator of intrinsic antibiotic resistance in Mtb. This inhibition is broadly conserved in other bacteria and represents a novel form of antimicrobial activity, termed adjunctive sensitization, that can mediate synergy and may contribute to rifampins unusual treatment shortening activity.

microbiology↗
bioRxiv2025

Investigating the effects of chimerism on the inference of selection: quantifying genomic targets of purifying, positive, and balancing selection in common marmosets (Callithrix jacchus)

The common marmoset (Callithrix jacchus) is of considerable biomedical importance, yet there remains a need to characterize the evolutionary forces shaping empirically observed patterns of genomic variation in the species. However, two uncommon biological traits potentially prevent the use of standard population genetic approaches in this primate: a high frequency of twin-births and the prevalence of hematopoietic chimerism. Here we characterize the impact of these biological features on the inference of natural selection, and directly model twinning and chimerism when performing inference of the distribution of fitness effects to characterize general selective dynamics as well as when scanning the genome for loci shaped by the action of episodic positive and balancing selection. Results suggest a generally increased degree of purifying selection relative to human populations, consistent with the larger estimated effective population size of common marmosets. Furthermore, genomic scans based on an appropriate evolutionary baseline model reveal a small number of genes related to immunity, sensory perception, and reproduction to be strong sweep candidates. Notably, two genes in the major histocompatibility complex were found to have strong evidence of being maintained by balancing selection, in agreement with observations in other primate species. Taken together, this work, presenting the first whole-genome characterization of selective dynamics in the common marmoset, thus provides important insights into the landscape of both persistent and episodic selective forces in this species.

evolutionary biology↗
bioRxiv2025

Inferring the landscapes of mutation and recombination in the common marmoset (Callithrix jacchus) in the presence of twinning and hematopoietic chimerism

The common marmoset (Callithrix jacchus) is an important model in biomedical and clinical research, particularly for the study of age-related, neurodegenerative, and neurodevelopmental disorders (due to their biological similarities with humans), infectious disease (due to their susceptibility to a variety of pathogens), as well as developmental biology (due to their short gestation period relative to many other primates). Yet, while being one of the most commonly used non-human primate models for research, the population genomics of the common marmoset remains relatively poorly characterized, despite the critical importance of this knowledge in many areas of research including genome-wide association studies, models of polygenic risk scores, and scans for the targets of selection. This neglect owes, at least in part, to two biological peculiarities related to the reproductive mode of the species -- frequent twinning and sibling chimerism -- which are likely to affect standard population genetic approaches relying on assumptions underlying the Wright-Fisher model. Using high-quality population genomic data, we here infer the rates and landscapes of mutation and recombination -- two fundamental processes dictating the levels and patterns of genetic variability -- in the presence of these biological features, and discuss our findings in light of recent work in primates. Our results suggest that, while the species exhibits relatively low neutral mutation rates, rates of recombination are in the range of those observed in other anthropoids. Moreover, the recombination landscape of common marmosets, like that of many vertebrates, is dominated by PRDM9-mediated hotspots, with artificial intelligence-based models predicting an intricate 3D-structure of the species-specific PRDM9-DNA binding complex in silico. Apart from providing novel insights into the population genetics of common marmosets, given the importance of the availability of fine-scale maps of mutation and recombination for evolutionary inference, this work will also serve as a valuable resource to aid future genomic research in this widely studied system.

evolutionary biology↗
bioRxiv2025

Can ancient DNA and other forms of time-sampled data aid in the inference of negative frequency dependent selection?

Negative frequency-dependent selection (NFDS) is commonly viewed as the most efficacious form of balancing selection. Despite this, inferring NFDS remains challenging, and questions remain as to its relative importance in maintaining genetic variation in populations. Recent advances in both sequencing and genotyping technologies have resulted in a considerable increase in the number of publicly available human ancient DNA datasets, creating new opportunities for development of methods for the inference of NFDS from time-sampled data. In this perspective, I present three brief simulation studies to show how time-sampled data can aid improve inference power. First, I show how multiple time points can help us distinguish between recent NFDS and partial selective sweeps, as well as other forms of balancing selection, based on allele frequency trajectories. I then demonstrate how selective effects can be distinguished from population history based on changes in genetic variation and the site frequency spectrum over time. Finally, I apply an approximate Bayesian computation approach to compare the power of multiple and single time point datasets in estimating the time for which NFDS has been shaping variation. Thus, I argue that data from multiple timepoints can facilitate the generation of new methodological approaches for better inference of NFDS.

genomics↗
bioRxiv2025

Accounting for chimerism in demographic inference: reconstructing the history of common marmosets (Callithrix jacchus) from high-quality, whole-genome, population-level data

As a species of considerable biomedical importance, characterizing the evolutionary genomics of the common marmoset (Callithrix jacchus) is of significance across multiple fields of research. However, at least two peculiarities of this species potentially preclude commonly utilized population genetic modeling and inference approaches: a high frequency of twin births and hematopoietic chimerism. We here investigate these effects within the context of demographic inference, demonstrating via simulation that neglecting these biological features results in significant mis-inference of the underlying population history. Based upon this result, we develop a novel approximate Bayesian inference approach accounting for both common twin-births as well as chimeric sampling. In addition, we present novel population genomic data from 15 individuals sequenced to high-coverage, and utilize gene-level annotations to identify neutrally evolving intergenic regions appropriate for demographic inference. Applying our developed methodology, we estimate a well-fitting population history for this species, which suggests robust ancestral and current population sizes, as well as a size reduction roughly 7,000 years ago likely associated with a shift from arboreal to savanna vegetation in north-eastern Brazil during this period.

evolutionary biology↗
bioRxiv2025

Interpreting patterns of X chromosomal relative to autosomal diversity in aye-ayes(Daubentonia madagascariensis)

We here present high-quality, population-level sequencing data from the X chromosome of the highly-endangered aye-aye, Daubentonia madagascariensis. Using both polymorphism- and divergence-based inference approaches, we quantify fine-scale mutation and recombination rate maps, study the demographic and selective processes additionally shaping variation on the X chromosome, and compare these estimates to those recently inferred from the autosomes in this species. Results suggest that an equal sex ratio is most consistent with observed patterns of variation, and that no sex-specific demographic patterns are needed to fit the empirical site frequency spectrum. Further, reduced rates of recombination were observed relative to the autosomes as would be expected, whereas mutation rates were inferred to be similar. Utilizing the estimated population history together with the mutation and recombination rate maps, we evaluated evidence for both recent and recurrent selective sweeps as well as balancing selection across the X chromosome, finding no significant evidence supporting the action of these episodic processes. Overall, these analyses provide new insights into the evolution of the X chromosome in this species, which represents one of the earliest splits in the primate clade.

evolutionary biology↗
bioRxiv2025

Estimating the distribution of fitness effects in aye-ayes (Daubentonia madagascariensis),accounting for population history as well as mutation and recombination rate heterogeneity

The distribution of fitness effects (DFE) characterizes the range of selection coefficients from which new mutations are sampled, and thus holds a fundamentally important role in evolutionary genomics. To date, DFE inference in primates has been largely restricted to haplorrhines, with limited data availability leaving the other suborder of primates, strepsirrhines, largely under-explored. To advance our understanding of the population genetics of this important taxonomic group, we here map exonic divergence in aye-ayes (Daubentonia madagascariensis) - the only extant member of the Daubentoniidae family of the Strepsirrhini suborder. We further infer the DFE in this highly-endangered species, utilizing a recently published high-quality annotated reference genome, a well-supported model of demographic history, as well as both direct and indirect estimates of underlying mutation and recombination rates. The inferred distribution is generally characterized by a greater proportion of deleterious mutations relative to humans, providing evidence of a larger long-term effective population size. In addition however, both immune-related and sensory-related genes were found to be amongst the most rapidly evolving in the aye-aye genome.

evolutionary biology↗
bioRxiv2024

Inferring fine-scale mutation and recombination rate maps in aye-ayes (Daubentonia madagascariensis)

The rate of input of new genetic mutations, and the rate at which that variation is reshuffled, are key evolutionary processes shaping genomic diversity. Importantly, these rates vary not just across populations and species, but also across individual genomes. Despite previous studies having demonstrated that failing to account for rate heterogeneity across the genome can bias the inference of both selective and neutral population genetic processes, mutation and recombination rate maps have to date only been generated for a relatively small number of organisms. Here, we infer such fine-scale maps for the aye-aye (Daubentonia madagascariensis) - a highly endangered strepsirrhine that represents one of the earliest splits in the primate clade, and thus stands as an important outgroup to the more commonly-studied haplorrhines - utilizing a recently released fully-annotated genome combined with high-quality population sequencing data. We compare our indirectly inferred rates to previous pedigree-based estimates, finding further evidence of relatively low mutation and recombination rates in aye-ayes compared to other primates.

evolutionary biology↗
bioRxiv2024

Integration of multi-modal measurements identifies critical mechanisms of tuberculosis drug action

Treatments for tuberculosis remain lengthy, motivating a search for new drugs with novel mechanisms of action. However, it remains challenging to elucidate the direct targets of a drug, and even more so, to determine which disrupted cellular processes lead to bacterial killing. We developed a computational tool, DECIPHAER (DEcoding Cross-modal Information of PHarmacologies via AutoEncodeRs), to select the important correlated transcriptional and morphological responses of Mycobacterium tuberculosis to drug treatments. By finding a reduced feature space from these measurements, DECIPHAER highlighted essential features of Mtb cellular damage such as phosphosugar stress and inhibition of translation and DNA replication. After training, DECIPHAER provides cell-death-relevant insight into single-modal datasets, enabling interrogation of drug treatment responses for which transcriptional data are unavailable. Using morphological data alone with DECIPHAER, we discovered that respiration inhibition by the poly-pharmacological drugs, SQ109 and BM212, can influence cell death more than their effects on the cell wall. This study demonstrates that DECIPHAER can extract the critical shared information from multi-modal measurements to identify cell death-relevant mechanisms of TB drugs.

microbiology↗
bioRxiv2024

Sugar phosphate-mediated inhibition of peptidoglycan precursor synthesis

Antibiotic tolerance, the widespread ability of diverse pathogenic bacteria to sustain viability in the presence of typically bactericidal antibiotics for extended time periods, is an understudied steppingstone towards antibiotic resistance. The Gram-negative pathogen Vibrio cholerae, the causative agent of cholera, is highly tolerant to {beta}-lactam antibiotics. We previously found that the disruption of glycolysis, via deletion of pgi (vc0374, glucose-6-phosphate isomerase), resulted in significant cell wall damage and increased sensitivity towards {beta}-lactam antibiotics. Here, we uncover the mechanism of this resulting damage. We find that glucose causes growth inhibition, partial lysis, and a damaged cell envelope in {Delta}pgi. Supplementation with N-acetylglucosamine, but not other carbon sources (either from upper glycolysis, TCA cycle intermediates, or cell wall precursors) restored growth, re-established antibiotic resistance towards {beta}-lactams, and recovered cellular morphology of a pgi mutant exposed to glucose. Targeted metabolomics revealed the cell wall precursor synthetase enzyme GlmU (vc2762, coding for the bifunctional enzyme that converts glucosamine-1P to UDP-GlcNAc) as a critical bottleneck and mediator of glucose toxicity in {Delta}pgi. In vitro assays of GlmU revealed that sugar phosphates (primarily glucose-1-phosphate) inhibit the acetyltransferase activity of GlmU (likely competitively), resulting in compromised PG and LPS biosynthesis. These findings identify GlmU as a critical branchpoint enzyme between central metabolism and cell envelope integrity and reveal the molecular mechanism of {Delta}pgi glucose toxicity in Vibrio cholerae. ImportanceSugar-phosphate toxicity is a well characterized phenomenon that is seen within diverse bacterial species, and yet the molecular underpinnings remain elusive. We previously discovered that disrupting Vibrio choleraes ability to eat glucose (by disrupting the pgi gene), also resulted in a damaged cell envelope. Upon deletion of pgi, glucose-phosphate levels rapidly build and inhibit the enzymatic activity of GlmU, a key step of bacterial peptidoglycan precursor synthesis. GlmU inhibition causes enhanced killing by antibiotics and a pronounced cell envelope defect. Thus, GlmU serves as a prime target for novel drug development. This research opens new routes through which central metabolism and sugar-phosphate toxicity modulate antibiotic susceptibility.

microbiology↗
bioRxiv2024

Inferring the demographic history of aye-ayes (Daubentonia madagascariensis) from high-quality, whole-genome, population-level data

The nocturnal aye-aye, Daubentonia madagascariensis, is one of the most elusive lemurs on the island of Madagascar. The timing of its activity and arboreal lifestyle has generally made it difficult to obtain accurate assessments of population size using traditional census methods. Therefore, alternative estimates provided by population genetic inference are essential for yielding much needed information for conservation measures and for enabling ecological and evolutionary studies of this species. Here, we utilize genomic data from 17 unrelated individuals -- including 5 newly sequenced, high-coverage genomes -- to estimate this history. Essential to this estimation are recently published annotations of the aye-aye genome which allow for variation at putatively neutral genomic regions to be included in the estimation procedures, and regions subject to selective constraints, or in linkage to such sites, to be excluded owing to the biasing effects of selection on demographic inference. By comparing a variety of demographic estimation tools to develop a well-supported model of population history, we find strong support for the species to consist of two demes, separating northern Madagascar from the rest of the island. Additionally, we find that the aye-aye has experienced two severe reductions in population size. The first occurred rapidly, approximately 3,000 to 5,000 years ago, and likely corresponded with the arrival of humans to Madagascar. The second occurred over the past few decades and is likely related to substantial habitat loss, suggesting that the species is still undergoing population decline and remains at great risk for extinction.

evolutionary biology↗