Sudhir Kumar

Temple University | TU · Institute for Genomics and Evolutionary Medicine

We integrate evolutionary predictions based on the neutral theory of molecular evolution with protein dynamics to generate mechanistic insight into the molecular adaptations of the SARS-COV-2 spike (S) protein. With this approach, we first identified candidate adaptive polymorphisms (CAPs) of the SARS-CoV-2 S protein and assessed the impact of thes...

Phylogenomic analyses of long sequences, consisting of many genes and genomic segments, infer organismal relationships with high statistical confidence. But, these relationships can be sensitive to excluding just a few sequences. Currently, there is no direct way to identify fragile relationships and the associated individual gene sequences in spec...

We integrate evolutionary predictions based on the neutral theory of molecular evolution with protein dynamics to generate mechanistic insight into the molecular adaptations of the SARS-COV-2 Spike (S) protein. With this approach, we first identified Candidate Adaptive Polymorphisms (CAPs) of the SARS-CoV-2 Spike protein and assessed the impact of...

In cancer, somatic mutations occur continuously, causing cell populations to evolve. These somatic mutations result in the evolution of cellular gene expression patterns that can also change due to epigenetic modifications and environmental changes. By exploring the concordance of gene expression changes with molecular evolutionary trajectories of...

When students think of evolution, they might imagine T. rex, or perhaps an abiotic scene of sizzling electrical storms and harsh reducing atmospheres, an Earth that looks like a lunar landscape. Natural selection automatically elicits responses that include “survival of the fittest,” and “descent with modification,” and with these historical biolog...

A classic population genetic prediction is that alleles experiencing directional selection should swiftly traverse allele frequency space, leaving detectable reductions in genetic variation in linked regions. However, despite this expectation, identifying clear footprints of beneficial allele passage has proven to be surprisingly challenging. We ad...

A classic population genetic prediction is that alleles experiencing directional selection should swiftly traverse allele frequency space, leaving detectable reductions in genetic variation in linked regions. However, despite this expectation, identifying clear footprints of beneficial allele passage has proven to be surprisingly challenging. We ad...

An individual’s chronological age does not always correspond to the health of different tissues in their body, especially in cases of disease. Therefore, estimating and contrasting the physiological age of tissues with an individual’s chronological age may be a useful tool to diagnose disease and its progression. Here, we present novel metrics to q...

The primate infraorder Simiiformes, comprising Old and New World monkeys and apes, includes the most well-studied species on earth. Their most comprehensive molecular timetree, assembled from thousands of published studies, is found in the TimeTree database and contains 268 simiiform species. It is, however, missing 38 out of 306 named species in t...

We integrate evolutionary predictions based on the neutral theory of molecular evolution with protein dynamics to generate mechanistic insight into the molecular adaptations of the SARS-COV-2 Spike (S) protein. With this approach, we first identified Candidate Adaptive Polymorphisms (CAPs) of the SARS-CoV-2 Spike protein and assessed the impact of...

We integrate evolutionary predictions based on the neutral theory of molecular evolution with protein dynamics to generate mechanistic insight into the molecular adaptations of the SARS-COV-2 Spike (S) protein. With this approach, we first identified Candidate Adaptive Polymorphisms (CAPs) of the SARS-CoV-2 Spike protein and assessed the impact of...

A classic population genetic prediction is that alleles experiencing directional selection should swiftly traverse allele frequency space, leaving detectable reductions in genetic variation in linked regions. However, despite this expectation, identifying clear footprints of beneficial allele passage has proven to be surprisingly challenging. We ad...

Understanding the biology of hearing and hearing loss requires not only examination of the existing structure and function of the auditory system but also consideration of its evolutionary legacy. In this context, research in my group, in collaboration with others, utilizes a comparative approach to investigate hearing and hearing loss in various r...

We integrate evolutionary predictions based on the neutral theory of molecular evolution with protein dynamics to generate mechanistic insight into the molecular adaptations of the SARS-COV-2 Spike (S) protein. With this approach, we first identified Candidate Adaptive Polymorphisms (CAPs) of the SARS-CoV-2 Spike protein and assessed the impact of...

The origin of eukaryotes was among the most important events in the history of life, spawning a new evolutionary lineage that led to all complex multicellular organisms. However, the timing of this event, crucial for understanding its environmental context, has been difficult to establish. The fossil and biomarker records are sparse and molecular c...

A common practice in molecular systematics is to infer phylogeny and then scale it to time by using a relaxed clock method and calibrations. This sequential analysis practice ignores the effect of phylogenetic uncertainty on divergence time estimates and their confidence/credibility intervals. An alternative is to infer phylogeny and times jointly...

The study of tumor evolution is being revolutionalized by single-cell sequencing technologies that survey the somatic variation of cancer cells. In these endeavors, reliable inference of the evolutionary relationship of single cells is a key step. However, single-cell sequences contain many errors and missing bases, which necessitate advancing stan...

Repeated runs of the same program can generate different molecular phylogenies from identical datasets under the same analytical conditions. This lack of reproducibility of inferred phylogenies casts a long shadow on downstream research employing these phylogenies in areas such as comparative genomics, systematics, and functional biology. We have a...

Bulk sequencing is commonly used to characterize the genetic diversity of cancer cell populations in tumors and the evolutionary relationships of cancer clones. However, bulk sequencing produces aggregate information on nucleotide variants and their sample frequencies, necessitating computational methods to predict distinct clone sequences and thei...

Motivation Despite recent advances in sequencing technologies, genome-scale datasets continue to have missing bases and genomic segments. Such incomplete datasets can undermine downstream analyses, such as disease risk prediction and association studies. Consequently, the imputation of missing information is a common pre-processing step for which m...

Sequencing of the protein coding genome has revealed many different missense mutations of human proteins and different population frequencies of corresponding haplotypes, which consist of different sets of those mutations. Here, we present evidence for pairwise intramolecular epistasis (i.e. nonadditive interactions) between many such mutations thr...

Motivation: Timetrees depict evolutionary relationships between species and the geological times of their divergence. Hundreds of research articles containing timetrees are published in scientific journals every year. The TimeTree project has been manually locating, curating, and synthesizing timetrees from these articles for almost two decades in...

Through the artistic planning tool known to comic book artists and animators as storyboarding, students will embark on comic book–style adventures to plan, describe, and visualize the complex life of genes through the non-Mendelian concept of epistasis. Using storyboard templates, conceptual layouts, sketch booking, and cut-out genetic elements, st...

Objective Breast Cancer (BC) is one of the deadliest diseases in women, causing thousands of deaths annually despite the advent of high-throughput genomic platforms in the recent past. Microarray-based gene expression profiling with different statistical methods have been extensively used to understand the disease at the molecular level. We plan to...

The selection of the optimal substitution model of molecular evolution imposes a high computational burden for long sequence alignments in phylogenomics. We discovered that the analysis of multiple tiny subsamples of site patterns from a full sequence alignment recovers the correct optimal substitution model when sites in the subsample are upsample...

Dispersal routes of metastatic cells are not medically detected or even visible. A molecular evolutionary analysis of tumor variation provides a way to retrospectively infer metastatic migration histories and answer questions such as whether the majority of metastases are seeded from clones within primary tumors or seeded from clones within pre-exi...

We present the fifth edition of the TimeTree of Life resource (TToL5), a product of the timetree of life project that aims to synthesize published molecular timetrees and make evolutionary knowledge easily accessible to all. Using the TToL5 web portal, users can retrieve published studies and divergence times between species, the timeline of a spec...

We introduce biology to the artist’s design tool, the storyboard. This versatile organizing and visualizing artistic platform is introduced into the biology classroom to aid in an inventive and focused discovery process. Almost all biological concepts are dynamic, and storyboards offer biology, lecture, wet and computational labs, flexibility, inve...

As a reference laboratory for measles and rubella surveillance in Lombardy, we evaluated the association between SARS-CoV-2 infection and measles-like syndromes, providing preliminary evidence for undetected early circulation of SARS-CoV-2. Overall, 435 samples from 156 cases were investigated. RNA from oropharyngeal swabs (N = 148) and urine (N =...

Cancer cell genomes change continuously due to mutations, and mutational processes change over time in patients, leaving dynamic signatures in the accumulated genomic variation in tumors. Many computational methods detect the relative activities of known mutation signatures. However, these methods may produce erroneous signatures when applied to in...

Invariant sites are a common feature of amino acid sequence evolution. The presence of invariant sites is frequently attributed to the need to preserve function through site-specific conservation of amino acid residues. Amino acid substitution models without a provision for invariant sites often fit the data significantly worse than those that allo...

Many pathogenic missense mutations are found in protein positions that are neither well-conserved nor fall in any known functional domains. Consequently, we lack any mechanistic underpinning of dysfunction caused by such mutations. We explored the disruption of allosteric dynamic coupling between these positions and the known functional sites as a...

In cancer, somatic mutations occur continuously, causing cell populations to evolve. These somatic mutations result in the evolution of cellular gene expression patterns that can also change due to epigenetic modifications and environmental changes. By exploring the concordance of gene expression changes with molecular evolutionary trajectories of...

Motivation: Building reliable phylogenies from very large collections of sequences with a limited number of phylogenetically informative sites is challenging because sequencing errors and recurrent/backward mutations interfere with the phylogenetic signal, confounding true evolutionary relationships. Massive global efforts of sequencing genomes an...

Molecular evolutionary analyses require computationally intensive steps such as aligning multiple sequences, optimizing substitution models, inferring evolutionary trees, testing phylogenies by bootstrap analysis, and estimating divergence times. With the rise of large genomic data sets, phylogenomics is imposing a big carbon footprint on the envir...

Two years after the start of the COVID-19 pandemic, key questions about the emergence of its aetiological agent (SARS-CoV-2) remain a matter of considerable debate. Identifying when SARS-CoV-2 began spreading among people is one of those questions. Although the current canonically accepted timeline hypothesises viral emergence in Wuhan, China, in N...

Biodiversity analyses of phylogenomic timetrees have produced many high-profile examples of shifts in the rate of speciation across the tree of life. Temporally correlated events in ecology, climate, and biogeography are frequently invoked to explain these rate shifts. In a re-examination of 15 genomic timetrees and 25 major published studies of th...

Motivation Building reliable phylogenies from very large collections of sequences with a limited number of phylogenetically informative sites is challenging because sequencing errors and recurrent/backward mutations interfere with the phylogenetic signal, confounding true evolutionary relationships. Massive global efforts of sequencing genomes and...

Integration of ecological and evolutionary features has begun to understand tumor heterogeneity, tumor microenvironment, and metastatic potential. Developing a theoretical framework is intrinsic to deciphering tumors' tremendous spatial and longitudinal genetic variation patterns in patients. Here, we propose that tumors can be considered evolution...

Objective: Databases and softwares are important to manage modern high-throughput laboratories and store clinical and genomic information for quality assurance. Commercial softwares are expensive with proprietary code issue while academic versions have adaptation issue. Our aim was to develop an adaptable in-house software that can stores specimen...

The molecular clock hypothesis originally rested on the assumption of rate constancy across lineages of a phylogeny, which would produce an approximately steady rate of accumulation of deoxyribonucleic acid or amino acid changes through time. This assumption has been questioned on the basis of increasingly large data sets, which have shown signific...

Rapid relaxed-clock dating methods are frequently applied to analyze phylogenomic datasets containing hundreds to thousands of sequences because of their accuracy and computational efficiency. However, the relative performance of different rapid dating methods is yet to be compared on the same datasets, and, thus, the power and pitfalls of selectin...

Background Among the most consequential unknowns of the devastating COVID-19 pandemic are the durability of immunity and time to likely reinfection. There are limited direct data on SARS-CoV-2 long-term immune responses and reinfection. The aim of this study is to use data on the durability of immunity among evolutionarily close coronavirus relativ...

Many pathogenic missense mutations are found in protein positions that are neither well-conserved nor belong to any known functional domains. Consequently, we lack any mechanistic underpinning of dysfunction caused by such mutations. We explored the disruption of allosteric dynamic coupling between these positions and the known functional sites as...

Predictive modeling is useful but very challenging in biological image analysis due to the high cost of obtaining and labeling training data. For example, in the study of gene interaction and regulation in Drosophila embryogenesis, the analysis is most biologically meaningful when in situ hybridization (ISH) gene expression pattern images from the...

Felsenstein’s bootstrap approach is widely used to assess confidence in species relationships inferred from multiple sequence alignments. It resamples sites randomly with replacement to build alignment replicates of the same size as the original alignment and infers a phylogeny from each replicate dataset. The proportion of phylogenies recovering t...

Malignant cells leave their initial tumor of growth and disperse to other tissues to form metastases. Dispersals also occur in nature when individuals in a population migrate from their area of origin to colonize other habitats. In cancer, phylogenetic biogeography is concerned with the source and trajectory of cell movements. We examine the suitab...

ssrn.com/abstract=3883274 Background: Skin manifestations have been reported in patients with SARS-CoV-2 infection. As a reference laboratory for measles and rubella surveillance in Lombardy, we evaluated the association between SARS-CoV-2 infection and measles-like symptomatology while providing evidence for undetected early circulation of SARS-C...

We introduce a supervised machine learning approach with sparsity constraints for phylogenomics, referred to as evolutionary sparse learning (ESL). ESL builds models with genomic loci—such as genes, proteins, genomic segments, and positions—as parameters. Using the Least Absolute Shrinkage and Selection Operator (LASSO), ESL selects only the most i...

Cancer progression has been attributed to somatic changes in single-nucleotide variants, copy-number aberrations, loss of heterozygosity, chromosomal instability, epistatic interactions, and the tumor microenvironment. It is not entirely clear which of these changes are essential and which are ancillary to cancer. The dynamic nature of cancer evolu...

Felsenstein's bootstrap resampling approach, applied in thousands of research articles, imposes a high computational burden for very long sequence alignments. We show that the bootstrapping of a collection of little subsamples, coupled with median bagging of subsample confidence limits, produces accurate bootstrap confidence for phylogenetic relati...

A bstract We introduce a supervised machine learning approach with sparsity constraints for phylogenomics, referred to as evolutionary sparse learning (ESL). ESL builds models with genomic loci—such as genes, proteins, genomic segments, and positions—as parameters. Using the Least Absolute Shrinkage and Selection Operator (LASSO), ESL selects only...

Motivation Precise time calibrations needed to estimate ages of species divergence are not always available due to fossil records' incompleteness. Consequently, clock calibrations available for Bayesian dating analyses can be few and diffused, i.e. phylogenies are calibration-poor, impeding reliable inference of the timetree of life. We examined th...

Background Matrices of morphological characters are frequently used for dating species divergence times in systematics. In some studies, morphological and molecular character data from living taxa are combined, whereas others use morphological characters from extinct taxa as well. We investigated whether morphological data produce time estimates th...

Global sequencing of hundreds of thousands of genomes of Severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, has continued to reveal new genetic variants that are the key to unraveling its early evolutionary history and tracking its global spread over time. Here, we present the heretofore cryptic mutational history and spatiotemporal dynam...

The Molecular Evolutionary Genetics Analysis (MEGA) software has matured to contain a large collection of methods and tools of computational molecular evolution. Here, we describe new additions that make MEGA a more comprehensive tool for building timetrees of species, pathogens, and gene families using rapid relaxed-clock methods. Methods for esti...

Mutational processes in somatic cancer cell populations are constantly changing, leaving their signatures in the accumulated genomic variation in tumors. The inference of mutational signatures from the observed genetic variation enables spatiotemporal tracking of tumor mutational processes that evolve due to cellular environmental changes, mutation...

Motivation Precise time calibrations needed to estimate ages of species divergence are not always available due to fossil records’ incompleteness. Consequently, clock calibrations available for Bayesian dating analyses can be few and diffused, i.e., phylogenies are calibration-poor, impeding reliable inference of the timetree of life. We examined t...

We present a drawing discovery lab that crosscuts multiple disciplines in biology and links concepts in genetics and evolutionary thinking to enhance understanding of the genotype-to-phenotype transformation. These combined concepts are also linked to ecological frameworks in nature through the model of biological plasticity. Students and teachers...

Pharmacogenomics holds the promise of personalized drug efficacy optimization and drug toxicity minimization. Much of the research conducted to date, however, suffers from an ascertainment bias towards European participants. Here, we leverage publicly available, whole genome sequencing data collected from global populations, evolutionary characteri...

Metastases cause a vast majority of cancer morbidity and mortality. Metastatic clones are formed by dispersal of cancer cells to secondary tissues, and are not medically detected or visible until later stages of cancer development. Clone phylogenies within patients provide a means of tracing the otherwise inaccessible dynamic history of migrations...

Motivation As the number and diversity of species and genes grow in contemporary datasets, two common assumptions made in all molecular dating methods, namely the time-reversibility and stationarity of the substitution process, become untenable. No software tools for molecular dating allow researchers to relax these two assumptions in their data an...

Evolutionary evidence is important scientific background for appreciating the theory of evolution. We describe a STEAM-based lesson plan that uses paleontological drawings and a modern evolutionary database to explore and understand fossil, morphological, and molecular evidence. Together, with a focus on arthropods and the Cambrian explosion, stude...

From the first day of 2021, all manuscripts published in the journal Molecular Biology and Evolution (MBE) will be freely accessible online without a subscription. This exciting change will make all the MBE content available to all readers immediately upon publication.

Motivation Expression quantitative trait loci (eQTL) harbor genetic variants modulating gene transcription. Fine mapping of regulatory variants at these loci is a daunting task due to the juxtaposition of causal and linked variants at a locus as well as the likelihood of interactions among multiple variants. This problem is exacerbated in genes wit...

Molecular phylogenetics deals with the inference of evolutionary relationships among individuals, populations, species and higher taxonomic entities using molecular data. By modelling patterns of molecular change in protein and deoxyribonucleic acid (DNA) sequences over time, scientists now routinely reconstruct evolutionary histories of species an...

Predictive modeling is useful but very challenging in biological image analysis due to the high cost of obtaining and labeling training data. For example, in the study of gene interaction and regulation in Drosophila embryogenesis, the analysis is most biologically meaningful when in situ hybridization (ISH) gene expression pattern images from the...

Severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, was quickly identified as the cause of COVID-19 disease soon after its earliest reports. The knowledge of the contemporary evolution of SARS-CoV-2 is urgently needed not only for a retrospective on how, when, and why COVID-19 has emerged and spread, but also for creating remedies through...

Background: Prostate cancer (PC) risk increases with African ancestry and a history of sexually transmitted infections (STIs). Also, single-nucleotide polymorphisms (SNPs) in toll-like receptor (TLR) genes influence PC risk. This pilot study explores interactions between STIs and TLR-related SNPs in relation to PC risk among Jamaican men. Methods...

Simultaneous molecular dating of population and species divergences is essential in many biological investigations, including phylogeography, phylodynamics, and species delimitation studies. In these investigations, multiple sequence alignments consist of both intra‐ and inter‐species samples (mixed samples). As a result, the phylogenetic trees con...

Identifying the origin of SARS-CoV-2, the etiological agent of the current COVID-19 pandemic, may help us to avoid future epidemics of coronavirus and other zoonoses. Several theories about the zoonotic origin of SARS-CoV-2 have recently been proposed. Although Betacoronavirus found in Rhinolophus bats from China have been broadly implicated, their...

Naked mole-rats are highly vocal, eusocial, subterranean rodents with, counterintuitively, poor hearing. The causes underlying their altered hearing are unknown. Moreover, whether altered hearing is degenerate or adaptive to their unique lifestyles is controversial. We used various methods to identify the factors contributing to altered hearing in...

Metastases form by dispersal of cancer cells to secondary tissues. They cause a vast majority of cancer morbidity and mortality. Metastatic clones are not medically detected or visible until later stages of cancer development. Thus, clone phylogenies within patients provide a means of tracing the otherwise inaccessible dynamic history of migrations...

Motivation As the number and diversity of species and genes grow in contemporary datasets, two common assumptions made in all molecular dating methods, namely the time-reversibility and stationarity of the substitution process, become untenable. No software tools for molecular dating allow researchers to relax these two assumptions in their data an...

Long-lived rodents have become an attractive model for the studies on aging. To understand evolutionary paths to long life, we prepare chromosome-level genome assemblies of the two longest-lived rodents, Canadian beaver (Castor canadensis) and naked mole rat (NMR, Heterocephalus glaber), which were scaffolded with in vitro proximity ligation and ch...

Motivation Expression quantitative trait loci (eQTL) harbor genetic variants modulating gene transcription. Fine mapping of regulatory variants at these loci is a daunting task due to the juxtaposition of causal and linked variants at a locus as well as the likelihood of interactions among multiple variants. This problem is exacerbated in genes wit...

Background: Matrices of morphological characters are frequently used for dating species divergence times in systematics. In some studies, morphological and molecular character data from living taxa are combined, whereas others use morphological characters from extinct taxa as well. We investigated whether morphological data produce time estimates t...

Background: Matrices of morphological characters are frequently used for dating species divergence times in systematics. In some studies, morphological and molecular character data from living taxa are combined, whereas others use morphological characters from extinct taxa as well. We investigated whether morphological data produce time estimates t...

Background: Matrices of morphological characters are frequently used for dating species divergence times in systematics. In some studies, morphological and molecular character data from living taxa are combined, whereas others use morphological characters from extinct taxa as well. We investigated whether morphological data produce time estimates t...

Advances in sequencing techniques and statistical methods have made it possible not only to predict sequences of ancestral proteins but also to identify thousands of mutations in the human exome, some of which are disease associated. These developments have motivated numerous theories and raised many questions regarding the fundamental principles b...

The conventional wisdom in molecular evolution is to apply parameter-rich models of nucleotide and amino acid substitutions for estimating divergence times. However, the actual extent of the difference between time estimates produced by highly complex models compared to those from simple models is yet to be quantified for contemporary datasets that...

Motivation: Functions of cancer driver genes vary substantially across tissues and organs. Distinguishing passenger genes, oncogenes (OGs) and tumor-suppressor genes (TSGs) for each cancer type is critical for understanding tumor biology and identifying clinically actionable targets. Although many computational tools are available to predict putat...

Tumors harbor extensive genetic heterogeneity in the form of distinct clone genotypes that arise over time and across different tissues and regions in cancer. Many computational methods produce clone phylogenies from population bulk sequencing data collected from multiple tumor samples from a patient. These clone phylogenies are used to infer mutat...

The conventional wisdom in molecular evolution is to apply parameter-rich models of nucleotide and amino acid substitutions for estimating divergence times. However, the actual extent of the difference between time estimates produced by highly complex models compared to those from simple models is yet to be quantified for contemporary datasets that...