Biology subjects

Pond, S. L. K.

Publications and source records attributed to Pond, S. L. K..

9 recordsLinked to original sources

bioRxiv2025

Dynamics of natural selection preceding human viral epidemics and pandemics.

Using a phylogenetic framework to characterize natural selection, we investigate the hypothesis that zoonotic viruses require adaptation prior to zoonosis to sustain human-to-human transmission. Examining the zoonotic emergence of Ebola virus, Marburg virus, influenza A virus, SARS-CoV, and SARS-CoV-2, we find no evidence of a change in the intensity of natural selection immediately prior to a host switch, compared with typical selection within reservoir hosts. We conclude that extensive pre-zoonotic adaptation is not necessary for human-to-human transmission of zoonotic viruses. In contrast, the reemergence of H1N1 influenza A virus in 1977 showed a change in selection, consistent with the hypothesis of passage in a laboratory setting prior to its reintroduction into the human population, purportedly during a vaccine trial. Holistic phylogenetic analysis of selection regimes can be used to detect evolutionary signals of host switching or laboratory passage, providing insight into the circumstances of past and future viral emergence.

evolutionary biology↗

bioRxiv2024

Minus the Error: Estimating dN/dS and Testing for Natural Selection in the Presence of Residual Alignment Errors

Positive selection is an evolutionary process which increases the frequency of advantageous mutations because they confer a fitness benefit. Inferring the past action of positive selection on protein-coding sequences is fundamental for deciphering phenotypic diversity and the emergence of novel traits. With the advent of genome-wide comparative genomic datasets, researchers can analyze selection not only at the level of individual genes but also globally, delivering systems-level insights into evolutionary dynamics. However, genome-scale datasets are generated with automated pipelines and imperfect curation that does not eliminate all sequencing, annotation, and alignment errors. Positive selection inference methods are highly sensitive to such errors. We present BUSTED-E: a method designed to detect positive selection for amino acid diversification while concurrently identifying some alignment errors. This method builds on the flexible branch-site random effects model (BUSTED) for fitting distributions of dN/dS, with a critical modification: it incorporates an "error-sink" component to represent an abiological evolutionary regime. Using several genome-scale biological datasets that were extensively filtered using state-of-the art automated alignment tools, we show that BUSTED-E identifies pervasive residual alignment errors, produces more realistic estimates of positive selection, reduces bias, and improves biological interpretation. The BUSTED-E model promises to be a more stringent filter to identify positive selection in genome-wide contexts, thus enabling further characterization and validation of the most biologically relevant cases.

evolutionary biology↗

bioRxiv2024

A new comparative framework for estimating selection on synonymous substitutions.

Selection on synonymous codon usage is a well known and widespread phenomenon, yet existing models often do not account for it or its effect on synonymous substitution rates. In this article, we develop and expand the capabilities of Multiclass Synonymous Substitution (MSS) models, which account for such selection by partitioning synonymous substitutions into two or more classes and estimating a relative substitution rate for each class, while accounting for important confounders like mutation bias. We identify extensive heterogeneity among relative synonymous substitution rates in an empirical dataset of [~]12,000 gene alignments from twelve Drosophila species. We validate model performance using data simulated under a forward population genetic simulation, demonstrating that MSS models are robust to model misspecification. MSS rates are significantly correlated with other covariates of selection on codon usage (population-level polymorphism data and tRNA abundance data), suggesting that models can detect weak signatures of selection on codon usage. With the MSS model, we can now study selection on synonymous substitutions in diverse taxa, independent of any a priori assumptions about the forces driving that selection.

bioinformatics↗

bioRxiv2024

Enhanced Diversifying Selection on Polymerase Genes in H5N1 Clade 2.3.4.4b: A Key Driver of Altered Species Tropism and Host Range Expansion

Highly pathogenic avian influenza H5N1 clade 2.3.4.4b viruses have shown unprecedented host range and pathogenicity, including infections in cattle, previously not susceptible to H5N1. We investigated whether selection pressures on clade 2.3.4.4b viral genes could shed light on their unique epidemiological features. Our analysis revealed that while the gene products of clade 2.3.4.4b H5N1 primarily undergo purifying selection, there are notable instances of episodic diversifying selection. Specifically, the polymerase genes PB2, PB1, and PA exhibit significantly greater selection pressures in clade 2.3.4.4b than all earlier H5N1 virus clades. Polymerases play critical roles in influenza virus adaptation, including viral fitness, interspecies transmission, and virulence. Our findings provide evidence that significant selection pressures have shaped the evolution of the H5N1 clade 2.3.4.4b viruses, facilitating their expanded host tropism and the potential for further adaptation to mammalian hosts. We discuss how exogenous factors, such as altered bird migration patterns and increased host susceptibility, may have contributed to the expanded host range. As H5N1 viruses continue to infect new hosts, there is a greater risk of emergent novel variants with increased pathogenicity in humans and animals. Thus, comprehensive One Health surveillance is critical to monitor transmission among avian and mammalian hosts.

evolutionary biology↗

bioRxiv2023

The Complete Sequence and Comparative Analysis of Ape Sex Chromosomes

Apes possess two sex chromosomes--the male-specific Y and the X shared by males and females. The Y chromosome is crucial for male reproduction, with deletions linked to infertility1. The X chromosome carries genes vital for reproduction and cognition2. Variation in mating patterns and brain function among great apes suggests corresponding differences in their sex chromosomes. However, due to their highly repetitive nature and incomplete reference assemblies, ape sex chromosomes have been challenging to study. Here, using the methodology developed for the telomere-to-telomere (T2T) human genome, we produced gapless assemblies of the X and Y chromosomes for five great apes (chimpanzee, bonobo, gorilla, Bornean and Sumatran orangutans) and a lesser ape, the siamang gibbon. These assemblies allowed us to untangle the intricacies of ape sex chromosome evolution. We found that, compared to the Xs, the ape Ys vary greatly in size and have low alignability and high levels of structural rearrangements. This divergence on the Y arises from the accumulation of lineage-specific ampliconic regions, palindromes, transposable elements, and satellites. Our analysis of Y chromosome genes revealed expansions of multi-copy gene families and signatures of purifying selection. Thus, the Y exhibits dynamic evolution, while the X is more stable. Mapping short-read sequencing data to these assemblies revealed diversity and selection patterns on sex chromosomes of >100 great ape individuals. These reference assemblies are expected to inform human evolution and conservation genetics of nonhuman apes, all of which are endangered species.

genomics↗

bioRxiv2023

Evolutionary analysis of mammalian Rem2, a member of the RGK (Rem, Rem2, Rad, and Gem/Kir) family of small GTPases, reveals the role of selection and epistasis in shaping protein functional constraints.

Rad And Gem-Like GTP-Binding Protein 2 (Rem2), is a member of the RGK family of Ras-like GTPases and has been identified in various mammalian species. Rem2 has been implicated in Huntingtons disease and Long QT Syndrome and is highly expressed in the brain and in endocrine cells. In this study, we examined the evolutionary history of Rem2 across mammals, focusing on the role of purifying selection and epistasis in shaping its sequence and structure. In our analysis of Rem2 sequences across 175 mammalian species, we found evidence for strong purifying selection in 70% of non-invariant codon sites of the protein, characteristic of essential proteins that play critical roles in biological processes and is consistent with Rem2s role in the regulation of neuronal development and function. We inferred epistatic effects in 49 pairs of coevolving codon sites in Rem2, some of which are predicted to have deleterious effects on human health. Additionally, we reconstructed the ancestral evolutionary history of mammalian Rem2 using protein structure prediction of extinct and extant sequences. This analysis revealed the dynamics of how substitutions that change the genetic distance of Rem2 can impact protein structure in variable regions while maintaining core functional mechanisms. By understanding the selective pressures, protein- and genetic-interactions that have shaped the sequence and structure of the Rem2 protein, we may gain a stronger understanding of its biological and functional constraints.

neuroscience↗

bioRxiv2022

High-throughput single-cell sequencing for retroviral reservoir characterization

During the course of infection, human immunodeficiency virus (HIV) maintains a stably integrated reservoir of replication-competent viruses within the host genome that are unaffected by antiretroviral therapy. Curative advancements rely heavily on targeting the anatomical reservoirs, though determinants of their evolutionary origins through phyloanatomic inference remain ill-supported through current sequencing and sequence analysis strategies. The vast replication-defective genomic landscape that comprises the HIV DNA population is often discarded in these evolutionary endeavors, despite key information regarding competent ancestry that can be gained from captured genomic regions outside the historically used viral envelope gene. Here, we describe the application of small-amplicon, single-cell DNA sequencing to blood and lymph node samples from a treatment-interrupted S[imian]IV-infected animal model and evaluate the contribution of genome coverage and inclusion on phylogenetic resolution and phyloanatomic inference. Findings from this study point to incomplete genomes as a significant source of phylogenetic information on movement of virus between tissue reservoirs during therapy.

genomics↗

bioRxiv2021

Coronavirus Resistance Database (CoV-RDB): SARS-CoV-2 susceptibility to monoclonal antibodies, convalescent plasma, and plasma from vaccinated persons

As novel SARS-CoV-2 variants with different patterns of spike mutations have emerged, the susceptibility of these variants to neutralization by antibodies has been rapidly assessed. However, neutralization data are generated using different approaches and are scattered across different publications making it difficult for these data to be located and synthesized. The Stanford Coronavirus Resistance Database (CoV-RDB; https://covdb.stanford.edu) is designed to house comprehensively curated published data on the neutralizing susceptibility of SARS-CoV-2 variants and spike mutations to monoclonal antibodies (mAbs), convalescent plasma (CP), and vaccinee plasma (VP). As of October 2021, CoV-RDB contains 186 publications including 64 (34%) containing 7,328 neutralizing mAb susceptibility results, 96 (52%) containing 11,390 neutralizing CP susceptibility results, and 125 (68%) containing 20,872 neutralizing VP results. The database also records which spike mutations are selected during in vitro passage of SARS-CoV-2 in the presence of mAbs and which emerge in persons receiving mAbs as treatment. The CoV-RDB interface interactively displays neutralizing susceptibility data at different levels of granularity by filtering and/or aggregating query results according to one or more experimental conditions. The CoV-RDB website provides a companion sequence analysis program that outputs information about mutations present in a submitted sequence and that also assists users in determining the appropriate mutation-detection thresholds for identifying non-consensus amino acids. The most recent data underlying the CoV-RDB can be downloaded in its entirety from a Github repository in a documented machine-readable format.

bioinformatics↗

bioRxiv2017

Relative evolutionary rate inference in HyPhy with LEISR

We introduce LEISR (Likehood Estimation of Individual Site Rates, pronounced \"laser\"), a convenient implementation in HyPhy to infer relative evolutionary rates from protein and nucleotide data. LEISR is based on the popular Rate4Site (1) approach for inferring relative site-wise evolutionary rates from protein data. We extend the original method by allowing for rate inference on both protein and nucleotide data, and we further overcome data-size limitations in Rate4Site. LEISR is available in HyPhy starting with version 2.3.7.

bioinformatics↗