Biology subjects

Smith, M. L.

Publications and source records attributed to Smith, M. L..

At least 19 recordsLinked to original sources

bioRxiv2026

Disruption of a CCR5-like immunoglobulin gene is linked to plague susceptibility in black-footed ferrets

Black-footed ferrets (Mustela nigripes) are among the worlds most endangered mammals and remain highly vulnerable to sylvatic plague caused by Yersinia pestis, yet the genetic basis of this susceptibility has remained unknown. Current conservation strategies rely on vaccination of captive-bred animals and large-scale flea control with insecticides, approaches that are costly, labor-intensive, and difficult to implement across the species natural range. Several closely related mustelid species, including the domestic ferret, are substantially more resistant to plague, providing an opportunity to identify naturally evolved immune mechanisms through comparative immunogenomics. Here we identify a conserved class of immunoglobulin lambda variable genes encoding unusually long antigen-binding loops with CCR5-mimicking sequence features that are widespread among Caniformia species. Because CCR5 has been implicated in host interactions with Yersinia species, we hypothesized that antibodies encoded by these germline genes contribute to plague resistance through receptor-like molecular mimicry. Consistent with this hypothesis, we show that these genes are under strong purifying selection in mustelids, are actively expressed in antibody repertoires, and monoclonal antibodies encoded by them reduced intracellular Y. pestis survival in macrophages. In contrast, all analyzed black-footed ferrets carried a frameshifting deletion resulting in loss of gene expression. These findings identify a naturally disrupted germline antibody gene as a candidate determinant of plague susceptibility in black-footed ferrets, demonstrating that variation in germline immunoglobulin genes can influence susceptibility to a lethal infectious disease. Ultimately, these findings lay the groundwork for genetically informed conservation management and the development of new antibody-based anti-plague strategies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/734856v2_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@19d8ac1org.highwire.dtl.DTLVardef@a37aorg.highwire.dtl.DTLVardef@1ecd1e0org.highwire.dtl.DTLVardef@c6fd67_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2026

DNA 6mA marks transcriptionally active chromatin in malaria parasites

DNA N6-methyladenine (6mA) has emerged as a significant epigenetic modification across a broad range of eukaryotes, from unicellular protists to metazoa. However, its role in unicellular eukaryotic parasites with highly AT-rich genomes, such as malaria-causing Plasmodium falciparum, remains unclear. Using mass spectrometry, South-western blotting, and Single Molecule Real-Time sequencing (Pacific Biosciences) across four stages of P. falciparum intra-erythrocytic development (IED), we confirmed that 0.02-0.04% of genomic adenines are modified to 6mA, with over 60% of the sites being stably maintained during the IED cycle. Notably, 6mA is enriched at transcription start sites, with genes bearing 6mA marks within their 5 and 3 untranslated regions exhibiting significantly elevated steady-state transcript levels. Consistent with this, 6mA loci show a strong positive correlation with activating histone post-translational modifications, while showing no significant association with repressive histone marks. Furthermore, in contrast to unicellular ciliates such as Oxytricha and Tetrahymena - organisms that share ancestry with Plasmodium - 6mA-marked genomic regions do not occlude nucleosomes. Lastly, we identified a putative 6mA methyltransferase belonging to the METTL4 family in P. falciparum, PfN6AMT encoded by the PF3D7_1303100 gene, and demonstrate that recombinant PfN6AMT exhibits robust methyltransferase activity in vitro, with mutation of its active site residues abolishing catalytic activity. Collectively, our findings demonstrate that 6mA is a low-abundance, yet reproducible, feature of the P. falciparum epigenome that is associated with transcriptionally active chromatin, and that the molecular mechanisms governing DNA adenine methylation may have undergone substantial evolutionary divergence, even among closely related eukaryotic lineages.

genomics↗

bioRxiv2026

An integrated human immunoglobulin germline resource linking allele diversity to expressed repertoire structure

Human immunoglobulin (IG) loci are highly polymorphic, yet existing germline resources remain noisy and incomplete, limiting our ability to link inherited variation to antibody repertoires. Here, we integrate high-fidelity long-read genomic sequencing with matched adaptive immune receptor repertoire sequencing (AIRR-seq) to construct HUSA, a population-scale, evidence-resolved germline resource. Using a conservative allele inference framework, HUSA expands current references more than three-fold, identifying over 1300 alleles while preserving allele-level evidence provenance across genomic and repertoire data. By linking genotype and expressed repertoires within individuals, we show that coding-region similarity predicts the structure of adjacent recombination signal sequences and leader regions, revealing that IG alleles are organized as linked cis-regulatory units associated with differences in recombination context and allele usage. These results define key germline constraints shaping repertoire formation and establish a robust, genotype-aware foundation for the analysis of immune receptor repertoires.

immunology↗

bioRxiv2026

Transcriptomes resolve phylogenetic relationships and reveal undescribed diversity in taildropper slugs (Genus Prophysaon)

The temperate rainforests of the Pacific Northwest of North America harbor many endemic taxa whose evolutionary histories have been shaped by major climatic and geologic events. The enigmatic taildropper slugs (genus Prophysaon) are one example, notable for their ability to autonomize their tails to escape predators. Despite extensive work uncovering the evolutionary history of individual lineages, relationships among the nine recognized species of Prophysaon remain poorly understood due to insufficient molecular data. To address this, we collected transcriptomes for six of the nine currently accepted species of Prophysaon. Using these data, we were able to resolve species relationships, calling into question the existing subgeneric classification based on morphology. We also detected undescribed phenotypic diversity within the P. andersonii--P. foliolatum species complex, with molecular data supporting the distinctness of two phenotypically distinct populations from Washington. Finally, our transcriptomic data suggest a moderate role of introgression in shaping the evolutionary history of Prophysaon. Here, we synonymize the subgenus Mimetarion with nominotypical Prophysaon. Future work should further investigate whether the undescribed diversity detected here represents species level differentiation.

evolutionary biology↗

bioRxiv2026

My Gut Feels Your Pain - The Social Transfer of Pain Remodels the Gut Microbiome

BackgroundThe "social transfer of pain" is a phenomenon where a mouse experiencing injury-induced hyperalgesia can trigger hyperalgesia in a mouse briefly housed in the same environment ( bystander). The peripheral mechanisms underlying social transfer of pain in mice are not yet well described. As gut microbes are associated with social interactions, pain states, and pain attenuation via the gut-brain axis, we hypothesized that the bystander gut microbiome may respond to the social transfer of pain. MethodsTo induce the social transfer of pain, complete Freunds adjuvant (CFA) was injected into the hindpaw of a mouse which then underwent social interaction with a bystander for one hour. Mechanical sensitivity was assessed using the Von Frey mechanical sensitivity test. Stool samples and mechanical thresholds were taken prior to social interaction, 4 hours post-social interaction, and 24 hours post-social interaction. Metagenomic sequencing characterized the taxonomic and predicted functional gene response of the gut microbiome to CFA-induced pain, social transfer of pain and control groups. ResultsAt 4 hours post-social interaction, bystander animals experienced increased mechanical sensitivity comparable to CFA-injected animals and significantly lower than controls, indicating enhanced hyperalgesia. Compared to baseline, fecal community composition analyses at 4 hours and 24 hours post-interaction showed significant differences in Unweighted Unifrac in both CFA-injected and bystander animals but not in controls. Differential abundance analyses using Maaslin2 identified significant increases in the relative abundances of short chain fatty acid producing taxa like Lachnospiraceae, Ruminococcaceae, Oscillospiraceae and decreases in commensal mouse gut microbes like Muribaculaceae from baseline to 4 hours and 24 hours post-interaction in both bystanders and CFA-injected animals but not in controls. Functional analysis revealed increased abundance of pathways related to short-chain fatty acid production including pyruvate to butanoate and L-lysine fermentation to acetate and butanoate. The altered gut microbiome of bystanders strongly resembles that observed in CFA-injected animals at 4 hours and 24 hours post-injection, with the addition of a unique bystander bloom in several species of Lachnospiraceae. ConclusionsThe changes in the gut microbiome of bystander animals suggest that the social transfer of pain alters bystander peripheral physiology. These results are the first evidence of the potential for such a link.

microbiology↗

bioRxiv2025

Germline polymorphism in the immunoglobulin kappa and lambda loci explain variation in the expressed light chain antibody repertoire

Variation in antibody (Ab) responses contributes to variable disease outcomes and therapeutic responsiveness, the determinants of which are incompletely understood. This study demonstrates that polymorphisms in immunoglobulin (IG) light chain loci dictate the composition of the Ab repertoire, establishing fundamental baseline differences that preclude functional Ab-mediated responses. Using long-read genomic sequencing of the IG kappa (IGK) and IG lambda (IGL) loci, we comprehensively resolved genetic variation, including novel structural variants, single nucleotide variants, and gene alleles. By integrating these genetic data with Ab repertoire profiling, we found that all forms of IG germline variation contributed to inter-individual gene usage differences for >70% of light chain genes in the repertoire, directly impacting the amino acids of expressed light chain transcripts, including complementarity determining region domains. The genomic locations of usage - associated variants in both intergenic and coding regions indicated that IG polymorphisms modulate gene usage via diverse mechanisms, likely including the modulation of V(D)J recombination, heavy and light chain pairing biases, and transcription/translation. Finally, relative to IGL, IGK was characterized by more extensive linkage disequilibrium and genetic co-regulation of gene usage, illuminating differential regulatory and evolutionary features between the two light chain loci. These results firmly establish the critical contribution of IG light chain polymorphism in Ab repertoire diversity, with important implications for investigating Ab responses in health and disease.

immunology↗

bioRxiv2025

Development and validation of HIV SMRTcap for the characterization of HIV-1 reservoirs across tissues and subtypes

Human Immunodeficiency Virus type 1 (HIV-1) is responsible for the global HIV/AIDS epidemic and the establishment of an integrated HIV-1 reservoir remains the primary obstacle to cure. Upon therapy interruption, reactivation of the persistent HIV-1 reservoir propagates viral rebound and mediates continued immunological decline. While furthering understanding of the HIV-1 reservoir is essential for HIV-1 cure, commonly used sequencing strategies are often limited by the reliance on short-read sequencing across separate assays to determine integration sites and proviral integrity - something that does not always adequately resolve complex human genomic repeats or low complexity regions. Simultaneous identification of proviral integration sites and proviral integrity at the single molecule level would enable HIV-1 reservoir characterization with minimal imputation or bioinformatic reconstruction. Here we present HIV Single Molecule Real Time Capture (HIV SMRTcap), a novel molecular and computational pipeline that directly and simultaneously identifies HIV-1 integration sites, defines proviral integrity, and characterizes clonal expansion of HIV-1 provirus-containing cells with single molecule resolution. In combination with long-read, single-molecule, real-time (SMRT) sequencing and custom analytic pipelines, HIV SMRTcap enables a highly comprehensive characterization of HIV-1 reservoirs. Moreover, we demonstrate here that HIV SMRTcap performs robustly across the major global subtypes (HIV-1 subtype A, B, C, D and A/D recombinant viruses), and can use both cell- and tissue-derived inputs, including samples from antiretroviral therapy (ART) treated individuals with undetectable viral loads. Our results demonstrate that HIV SMRTcap serves as a comprehensive, robust method for unbiased HIV-1 reservoir characterization. Used alone, or in combination with single-cell based methods, HIV SMRTcap will enable novel exploration of viral reservoirs across subtypes and in tissue-specific compartments, providing critical information needed to inform HIV-1 cure.

genomics↗

bioRxiv2025

Reducing the impact of HaHV-1 in Australian abalone: the role of age and immune priming

Abalone (Haliotis sp.) are marine organisms of significant ecological and economic importance. However, disease outbreaks, particularly caused by Haliotid herpesvirus (HaHV-1), pose a major threat to the global aquaculture industry. HaHV-1 causes Abalone Viral Ganglioneuritis (AVG) and has led to significant economic losses due to mass mortality in farmed and wild abalone in regions such as China, Taiwan, and Australia. The current study investigated the effect of age on the susceptibility of Australian hybrid abalone to HaHV-1 and the potential of immune priming as a strategy to protect abalone from HaHV-1 infection. Using a co-housed immersion challenge model, we found that abalone less than one year of age were significantly less susceptible to HaHV-1 infection and exhibit less pronounced clinical signs of HaHV-1 infection when compared to adults. Additionally, immune priming adult abalone with poly(I:C) prior to viral challenge provided protection against HaHV-1 when compared to abalone primed with a bacterial antigen, Flagellin-A and unprimed controls. We also determined that the use of pedal swabs is a less invasive method for confirming positive HaHV-1 infections, but not for determining comparative viral loads. These findings are pivotal in developing preventative strategies against HaHV-1 in aquaculture and highlight the need for further research on immune priming and age-related susceptibility in abalone.

microbiology↗

bioRxiv2025

Energy calculations for atomic oxygen liberation from hypohalous acids biosynthesized by mammalian peroxidases

The ultimate process of the mammalian immunological system is destruction of invasive microbes by peroxidase (PO) activities. Three enzymes, lactoperoxidase (LPO), eosinophil peroxidase (EPO) and myeloperoxidase (MPO) require two substrates for this task. The first is H2O2 and the second either I-, Br-, Cl- or SCN-. All POs are able to synthesize hypoiodous acid and OSCN- but two can create HOBr (EPO and MPO) and only MPO can biosynthesize HOCl. Using density-functional theory (DFT) and following first principles of molecular modelling we investigated the energetics of hypohalous acid breakdowns by calculating the internal energy differences between the reactants and products. Atomic oxygen (ATOX) and simple halide acids are the energetically favoured products with halide cations and hydroxide ion being minor products. There is nothing subtle about ATOX, it is a very destructive species. ATOX production explains the documented ability of POs to indiscriminately and rapidly destroy invasive microbes and the role of MPO initiating inflammation. Previously unrecognised, the biosynthesis of ATOX also explains why mammalian POs are restricted to surfaces or special cells which are themselves destroyed after PO activation. This chemistry is the probable reason why dietary iodine, uniquely provided by the Japanese diet, helped to significantly reduce deaths from the SARS-CoV-2 viral agent during the COVID-19 pandemic in Japan. HighlightsO_LIThe energetics of hypohalous acid, HOI, HOBr and HOCl, breakdown into atomic oxygen (ATOX) or halide cation were calculated using density-functional theory C_LIO_LIThe release of neutral ATOX from all three hypohalous acids is greatly preferred over halide cation and hydroxide production C_LIO_LIATOX produced by mammalian peroxidases is incredibly powerful and largely responsible for the ultimate destruction of most invasive, especially airborne microbes C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=160 SRC="FIGDIR/small/645784v2_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@12f9c2aorg.highwire.dtl.DTLVardef@b5a7c1org.highwire.dtl.DTLVardef@1889e9org.highwire.dtl.DTLVardef@1063ab7_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

The human immunoglobulin heavy chain constant gene locus is enriched for large complex structural variants and coding polymorphisms that vary in frequency among human populations

The human immunoglobulin heavy chain constant (IGHC) domain of antibodies (Ab) is responsible for effector functions critical to immunity. This domain is encoded by genes in the IGHC locus, where descriptions of genomic diversity remain incomplete. We utilized long-read sequencing to build an IGHC haplotype/variant catalog from 105 individuals of diverse ancestry. We discovered uncharacterized single nucleotide variants (SNV) and large structural variants (SVs, n=7), representing new genes and alleles enriched for non-synonymous substitutions, highlighting potential functional effects. Of the 221 identified IGHC alleles, 192 were novel. SNV, SV, and gene allele/genotype frequencies revealed population differentiation, including (i) hundreds of SNVs in African and East Asian populations exceeding a fixation index (FST) of 0.3, and (ii) an IGHG4 haplotype carrying coding variants uniquely enriched in Asian populations. Our results illuminate missing signatures of IGHC diversity and establish a new foundation for investigating IGHC germline variation in Ab function and disease.

genomics↗

bioRxiv2025

The reasonable effectiveness of domain adaptation for inference of introgression

Supervised machine learning approaches have proven powerful in population genetics. To use such approaches, training data with known inputs and outputs are required. Since such data are generally unavailable in population genetics, researchers typically rely on simulations under the models of interest to train machine learning algorithms. While powerful, this approach depends heavily on the models used to generate training data. Because of the variety and complexity of processes shaping genetic variation, it is inevitable that not all processes important in an empirical system will be included when generating training data. This leads to a mismatch between the data used to train a machine learning algorithm and the data to which the trained model is ultimately applied--i.e., a domain shift-- and can negatively impact inference. Here, we train a Convolutional Neural Network (CNN) to detect introgression between sister populations and demonstrate that it has near perfect accuracy when applied to data generated under the models used for training. To evaluate the impacts of domain shifts on inference, we generated new data with introgression from a third, unsampled population into one of the two focal populations (i.e., ghost introgression), and accuracy was substantially reduced on these data. Finally, we used domain adaptation, which aims to train a network that performs well in the presence of a domain shift. Notably, this requires no knowledge of the target or empirical domain. Our domain adaptation network was able to accurately detect introgression, even in the presence of unmodelled ghost introgression. We also applied this approach to empirical data to detect introgression between ABC Island brown bears and other populations of brown bears. Previous work has suggested that introgression between ABC Island bears and polar bears can mislead tests of introgression between populations of brown bears. We found that using domain adaptation reduced support for introgression between geographically isolated populations of brown bears, suggesting that our approach reduces false inferences of introgression due to ghost introgression.

evolutionary biology↗

bioRxiv2024

Ultra-long sequencing for contiguous haplotype resolution of the human immunoglobulin heavy chain locus

Genetic diversity within the human immunoglobulin heavy chain (IGH) locus influences the expressed antibody repertoire and susceptibility to infectious and autoimmune diseases. However, repetitive sequences and complex structural variation pose significant challenges for large-scale characterization. Here, we introduce a method using Oxford Nanopore ultra-long sequencing and adaptive sampling, coupled with a bioinformatic pipeline, to generate haplotype-resolved single-contig IGH assemblies. We compared our method to a well-established IGH characterization framework using Pacific Biosciences HiFi sequencing in four donors and observed almost complete sequence congruence between our haplotype-resolved assemblies and the HiFi reads. Applying our approach to the HG002 reference material revealed no base differences to the Telomere-to-Telomere genome benchmark over the IGH locus. Importantly, among the four donors, our approach uncovered 30 novel alleles and previously uncharacterized large structural variants, including a 120 kb segmental duplication spanning IGHE to IGHA1 and an expanded seven-copy IGHV3-23 gene haplotype.

immunology↗

bioRxiv2024

Using paralogs for phylogenetic inference mitigates the effects of long-branch attraction

Traditionally, the inference of species trees has relied on orthologs, or genes related through speciation events, to the exclusion of paralogs, or genes related through duplication events. This has led to a focus on using only gene families with a single gene-copy per species, as these families are likely to be composed of orthologs. However, recent work has demonstrated that phylogenetic inference using paralogs is both accurate and allows researchers to take advantage of more data. Here, we investigate a case in which using larger gene families actually increases accuracy compared to using single-copy genes alone. Long-branch attraction is a phenomenon in which taxa with long branches may be incorrectly inferred as sister taxa due to homoplasy. The most common solution to long-branch attraction is to increase taxon sampling to break up long branches. Sampling additional taxa is not always feasible, possibly due to extinction or limited access to high-quality DNA. We propose the use of larger gene families with additional gene copies to break up long branches. Using simulations, we demonstrate that using larger gene families mitigates the impacts of long-branch attraction across large regions of parameter space, especially when either maximum parsimony or maximum likelihood with a misspecified substitution model is used for inference. We also analyze data from Chelicerates, with a focus on assessing support for a sister relationship between scorpions and pseudoscorpions. Previous work has suggested that the failure to recover this relationship is due to long-branch attraction between pseudoscorpions and other lineages. Using data from larger gene families increases support for a clade uniting scorpions and pseudoscorpions, although other resolutions of this relationship continue to have higher support. Together, this work highlights the potential utility of larger gene families in phylogenetic inference.

evolutionary biology↗

bioRxiv2024

Diverse priming outcomes under conditions of very rare precursor B cells

Rare B cells can have special pathogen-recognition features giving them the potential to make outsized contributions to protective immunity. However, rare naive B cells infrequently participate in immune responses. We investigated how germline-targeting vaccine antigen delivery and adjuvant selection affect priming of exceptionally rare BG18-like HIV broadly neutralizing antibody-precursor B cells (~1 in 50 million) in non-human primates. Only escalating dose (ED) priming immunization using the saponin adjuvant SMNP elicited detectable BG18-like cells in germinal centers (GCs). All groups had strong GC responses, but only ED+SMNP and bolus+SMNP induced BG18-like memory B cells in >50% of animals. One group had vaccine-specific GC responses equivalent to ED+SMNP, but BG18-like memory B cells were rarely detected. Following homologous boosting, BG18-like memory B cells were more frequent in a bolus priming group, but had lower somatic hypermutation and affinities. This outcome was inversely associated with post-prime antibody titers, suggesting antibody feedback can significantly influence rare precursor B cell responses.

immunology↗

bioRxiv2024

Collective flow of circadian clock information in honeybee colonies

Honeybee colonies exhibit a collective circadian rhythm reflecting the periodic dynamics of the environment. Thousands of workers, including those engaged in in-hive tasks, must synchronize in various processes that may be rhythmic, such as nectar inflows, or non-rhythmic, such as brood care but it remains unknown how those different rhythms are integrated into a colony-level circadian rhythm. Using an AI-driven automated tracking system, we obtained uninterrupted long-term tracking of all individuals in two honeybee colonies. We demonstrate that circadian rhythmicity is present across all age groups and that this rhythm is entrained into all individuals, however, with peak activity shifting by up to 2 hours in workers furthest from the entrance. Extensive data analysis and an agent-based model suggest that mechanical interactions between individuals facilitate the transfer of movement speed, and hence Zeitgeber information. Finally, we show that this speed transfer leads to a collective slow wave of activity that initiates at the nest entrance, spreading throughout the nest. This simple mechanism, workers bumping into each other, enables colonies to entrain their rhythm to the daily cycle of the external environment and, because of the spatial organization of the nest, activates different groups of workers sequentially. The speed transfer interactions demonstrate a tightly-tuned mechanism that underlines the elegant self-organization of the superorganism.

animal behavior and cognition↗

bioRxiv2024

Short lifespan is one's fate, long lifespan is one's achievement: lessons from Daphnia

Studies of longevity and senescence rely on baseline life expectancy of reference genotypes measured in standardized conditions such as food level and group size. Variation in baseline lifespan data across labs and protocols and among genotypes can make longevity intervention studies difficult to compare, particularly when GxE interactions exist. Furthermore, extending the lifespan of a short-lived genotype or of any genotype under suboptimal conditions may be of a lesser theoretical and translational value than extending the maximal possible lifespan. Daphnia is rapidly becoming a model organism of choice for longevity research complementing data obtained on traditional models. In this study we report baseline longevity of several genotypes (parthenogenetic clones) of a long-lived species D. magna under a variety of laboratory protocols, aiming to document the highest possible lifespan, factors reducing it, and physiological parameters that change with age and correlate with longevity. Combining data from 25 different experiments across two labs we report strong differences among clones of different geographic origin, moderate effects of group size and medium composition on longevity, and strong GxE with respect to food level. Specifically, short-lived clones that tend to originate from small intermittent habitats show little or no caloric restriction (CR) longevity extension, while long-lived ones expand their lifespan even further when maintained at 25% of the ad libitum food. We find no evidence of any trade-offs between longevity and fecundity across clones or correlations with age-specific feeding rate. We find that in the short-lived, CR non-responsive clones show little correlation between longevity and two measures of lipid peroxidation (LPO: lipid hydroperoxides and MDA abundance). In contrast, the long-lived, CR-responsive clones show a positive longevity correlation with lipid hydroperoxide abundance at any age, and a negative correlation with MDA concentration measured at about median lifespan. This indicates differences among genotypes in longevity-related accumulation of LPO targets, efficiency of detoxification of LPO products, and/or their effects on longevity. Our observations support the hypothesis that a long lifespan can be affected by food availability and levels of oxidative damage, while genetically determined short lifespan remains short regardless. We suggest a set of condition and genotypes to be used as a reference for longevity studies in Daphnia.

ecology↗

bioRxiv2023

reconcILS: A gene tree-species tree reconciliation algorithm that allows for incomplete lineage sorting

Reconciliation algorithms infer the evolutionary history of individual gene trees given a species tree. Many reconciliation algorithms consider only duplication and loss events (and sometimes horizontal transfer), ignoring effects of the coalescent process, including incomplete lineage sorting (ILS). Here, we present a new heuristic algorithm for carrying out reconciliation that accurately accounts for ILS by treating it as a series of nearest neighbor interchange (NNI) events. For discordant branches of the gene tree identified by last common ancestor (LCA) mapping, our algorithm recursively chooses the optimal history by comparing the cost of duplication and loss to the cost of NNI and loss. We demonstrate the accuracy of our new method, which we call reconcILS, using a new simulation engine (dupcoal) that generates gene trees produced by the interaction of duplication, loss, and ILS under the MSC-DL model. Despite being a heuristic method, reconcILS is much more accurate than models that ignore ILS, and at least as accurate or better than leading methods that can model ILS, while also able to handle much larger datasets. We demonstrate the use of reconcILS by applying it to a dataset of 23 primate genomes, highlighting its accuracy compared to standard methods in the presence of large amounts of ILS.

bioinformatics↗

bioRxiv2023

Selection leads to false inferences of introgression using popular methods

Detecting introgression between closely related populations or species is a fundamental objective in evolutionary biology. Existing methods for detecting migration and inferring migration rates from population genetic data often assume a neutral model of evolution. Growing evidence of the pervasive impact of selection on large portions of the genome across diverse taxa suggests that this assumption is unrealistic in most empirical systems. Further, ignoring selection has previously been shown to negatively impact demographic inferences (e.g., of population size histories). However, the impacts of biologically realistic selection on inferences of migration remain poorly explored. Here, we simulate data under models of background selection, selective sweeps, balancing selection, and adaptive introgression. We show that ignoring selection sometimes leads to false inferences of migration in popularly used methods that rely on the site frequency spectrum (SFS). Specifically, balancing selection and some models of background selection result in the rejection of isolation-only models in favor of isolation-with-migration models and lead to elevated estimates of migration rates. BPP, a method that analyzes sequence data directly, showed false positives for all conditions at recent divergence times, but balancing selection also led to false positives at medium divergence times. Our results suggest that such methods may be unreliable in some empirical systems, such that new methods that are robust to selection need to be developed. Article SummaryDetecting migration between closely related populations is a central objective in many evolutionary biology studies. However, popular methods for detecting migration assume a simplified model of evolution. Here, we evaluate the impacts of biologically realistic natural selection, recombination, and mutation on three methods for detecting migration. We find that biological complexity leads to false inferences of migration, suggesting that results should be interpreted with caution and that new methods are needed to make robust inferences of migration across empirical systems.

evolutionary biology↗