Biology subjects

Lynch, V. J.

Publications and source records attributed to Lynch, V. J..

At least 19 recordsLinked to original sources

bioRxiv2025

Loss of the cytosolic DNA-sensing genes cGAS and STING1 inarmadillos (Cingulata)

The principal sensor of intracellular double-stranded DNA (dsDNA) is cyclic GMP-AMP synthase (CGAS), which generates the second messenger cyclic GMP-AMP that binds stimulator of interferon genes (STING1), leading to the expression of type I interferon genes. CGAS and STING1 also play essential roles in maintaining genome integrity and the initiation and progression of cancer. Here we show that CGAS and STING1 were pseudogenized in the ancestral armadillo branch 45 to 70 million years ago. The complete loss of the CGAS-STING1 pathway in armadillos suggests this lineage has evolved alternate ways to sense intracellular double-stranded DNA, which may be related to their extreme cancer resistance.

evolutionary biology↗

bioRxiv2024

Pervasive loss of regulated necrotic cell death genes in elephants, hyraxes, and sea cows (Paenungualta)

Gene loss can promote phenotypic differences between species, for example, if a gene constrains phenotypic variation in a trait, its loss allows for the evolution of a greater range of variation or even new phenotypes. Here, we explore the contribution of gene loss to the evolution of large bodies and augmented cancer resistance in elephants. We used genomes from 17 Afrotherian and Xenarthran species to identify lost genes, i.e., genes that have pseudogenized or been completely lost, and Dollo parsimony to reconstruct the evolutionary history of gene loss across species. We unexpectedly discovered a burst of gene losses in the Afrotherian stem lineage and found that the loss of genes with functions in regulated necrotic cell death modes was pervasive in elephants, hyraxes, and sea cows (Paenungulata). Among the lost genes are MLKL and RIPK3, which mediate necroptosis, and sensors that activate inflammasomes to induce pyroptosis, including AIM2, MEFV, NLRC4, NLRP1, and NLRP6. These data suggest that the mechanisms that regulate necrosis and pyroptosis are either extremely derived or potentially lost in these lineages, which may contribute to the repeated evolution of large bodies and cancer resistance in Paenungulates as well as susceptibility to pathogen infection.

evolutionary biology↗

bioRxiv2024

Rapid evolution of genes with anti-cancer functions during the origins of large bodies and cancer resistance in elephants

Elephants have emerged as a model system to study the evolution of body size and cancer resistance because, despite their immense size, they have a very low prevalence of cancer. Previous studies have found that duplication of tumor suppressors at least partly contributes to the evolution of anti-cancer cellular phenotypes in elephants. Still, many other mechanisms must have contributed to their augmented cancer resistance. Here, we use a suite of codon-based maximum-likelihood methods and a dataset of 13,310 protein-coding gene alignments from 261 Eutherian mammals to identify positively selected and rapidly evolving elephant genes. We found 496 genes (3.73% of alignments tested) with statistically significant evidence for positive selection and 660 genes (4.96% of alignments tested) that likely evolved rapidly in elephants. Positively selected and rapidly evolving genes are statistically enriched in gene ontology terms and biological pathways related to regulated cell death mechanisms, DNA damage repair, cell cycle regulation, epidermal growth factor receptor (EGFR) signaling, and immune functions, particularly neutrophil granules and degranulation. All of these biological factors are plausibly related to the evolution of cancer resistance. Thus, these positively selected and rapidly evolving genes are promising candidates for genes contributing to elephant-specific traits, including the evolution of molecular and cellular characteristics that enhance cancer resistance.

evolutionary biology↗

bioRxiv2023

Phylogenomics reveals an almost perfect polytomy among the almost ungulates (Paenungulata)

Phylogenetic studies have resolved most relationships among Eutherian Orders. However, the branching order of elephants (Proboscidea), hyraxes (Hyracoidea), and sea cows (Sirenia) (i.e., the Paenungulata) has remained uncertain since at least 1758, when Linnaeus grouped elephants and manatees into a single Order (Bruta) to the exclusion of hyraxes. Subsequent morphological, molecular, and large-scale phylogenomic datasets have reached conflicting conclusions on the branching order within Paenungulates. We use a phylogenomic dataset of alignments from 13,388 protein-coding genes across 261 Eutherian mammals to infer phylogenetic relationships within Paenungulates. We find that gene trees almost equally support the three alternative resolutions of Paenungulate relationships and that despite strong support for a Proboscidea+Hyracoidea split in the multispecies coalescent (MSC) tree, there is significant evidence for gene tree uncertainty, incomplete lineage sorting, and introgression among Proboscidea, Hyracoidea, and Sirenia. Indeed, only 8-10% of genes have statistically significant phylogenetic signal to reject the hypothesis of a Paenungulate polytomy. These data indicate little support for any resolution for the branching order Proboscidea, Hyracoidea, and Sirenia within Paenungulata and suggest that Paenungulata may be as close to a real, or at least unresolvable, polytomy as possible.

evolutionary biology↗

bioRxiv2023

Pervasive relaxed selection on spermatogenesis genes coincident with the evolution of polygyny in gorillas

Gorillas have a polygynous social system in which the highest-ranking male has almost exclusive access to females and sires most of the offspring in the troop. Such behavior results in a dramatic reduction of sperm competition, which is ultimately associated with numerous traits that cause low efficacy of gorilla spermatogenesis. However, the molecular basis behind the remarkable erosion of the gorilla male reproductive system remains unknown. Here, we explored the genetic implications of the polygynous social system in gorillas by testing for altered selection intensity across 13,310 orthologous protein-coding genes from 261 Eutherian mammals. We identified 578 genes with relaxed purifying selection in the gorilla lineage, compared with only 96 that were positively selected. Genes under relaxed purifying selection in gorillas have accumulated numerous deleterious amino acid substitutions, their expression is biased towards male germ cells and are enriched in functions related to meiosis and sperm biology. We tested the role of gorilla relaxed genes previously not implicated in male reproductive function using the Drosophila model system and identified 41 novel spermatogenesis genes required for normal fertility. Furthermore, by exploring exome/genome sequencing data of infertile men with severe spermatogenic impairment, we found that the human orthologs of the gorilla relaxed genes are enriched for loss-of-function variants in infertile men. These data provide compelling evidence that reduced sperm competition in gorillas is associated with relaxed purifying selection on genes related to male reproductive function. The accumulation of deleterious mutations in these genes likely provides the mechanistic basis behind the low efficacy of gorilla spermatogenesis and uncovers new candidate genes for human male infertility.

evolutionary biology↗

bioRxiv2022

A CDKN2C retroduplication in Bowhead whales is associated with the evolution of extremely long lifespans and alerted cell cycle dynamics

Among the constraints on the evolution of remarkably long lifespans is an increased risk of developing cancer because organisms with long lifespans have more time to accumulate cancer-causing mutations than organisms with shorter lifespans. Indeed, while there is a strong correlation between lifespan and cancer risk within species, there is no correlation between maximum lifespan and cancer risk across species ( Petos Paradox). Here we use evolutionary genomics and comparative experimental biology to explore the mechanisms by which Bowhead whales (Balaena mysticetus), which can live at least 211 years, evolved their extremely long lifespans. We found that the Bowhead whale genome encodes a species-specific retroduplicated CDKN2C (p18INK4C) gene (CDKN2CRTG). The CDKN2CRTG gene is embedded within a Cetacean-specific LINE L1 element, and is highly expressed in Bowhead whale tissues likely because it coopted an L1 promoter to drive constitutive expression. Furthermore we use a series of gain of function experiments to show how the duplicate CDKN2CRTG gene may influence cellular phenotypes such as cell cycle progression and DNA damage repair in ways that are beneficial for aging and cancer resistance. Remarkably, Bowhead and Right whales only diverged ~4-5 million years ago, suggesting the long lifespan of Bowheads may have evolved relatively recently and coincident with the origin of CDKN2CRTG. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=167 SRC="FIGDIR/small/506958v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@22cb1aorg.highwire.dtl.DTLVardef@444631org.highwire.dtl.DTLVardef@5c4c8aorg.highwire.dtl.DTLVardef@1a510d3_HPS_FORMAT_FIGEXP M_FIG C_FIG

evolutionary biology↗

bioRxiv2022

Parallel evolution of reduced cancer risk and tumor suppressor duplications in Xenarthra

The risk of developing cancer is correlated with body size and lifespan within species, but there is no correlation between cancer and either body size or lifespan between species indicating that large, long-lived species have evolved enhanced cancer protection mechanisms. Previously we showed that several large bodied Afrotherian lineages evolved reduced intrinsic cancer risk, particularly elephants and their extinct relatives (Proboscideans), coincident with pervasive duplication of tumor suppressor genes (Vazquez and Lynch 2021). Unexpectedly, we also found that Xenarthrans (sloths, armadillos, and anteaters) evolved very low intrinsic cancer risk. Here, we show that: 1) several Xenarthran lineages that independently evolved large bodies, long lifespans, and reduced intrinsic cancer risk; 2) reduced cancer risk in the stem lineages of Xenarthra and Pilosa occurred coincident with bursts of tumor suppressor gene duplications; 3) cells from sloths proliferate extremely slowly while Xenarthran cells induce apoptosis are very low levels of DNA damage; and 4) the prevalence of cancer is extremely low Xenarthrans, and cancer is nearly absent from armadillos. These data implicate the duplication of tumor suppressor genes in the evolution of remarkably large body sizes and decreased cancer risk in Xenarthrans and suggest they are a remarkably cancer resistant group of mammals. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=167 SRC="FIGDIR/small/502824v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@a98f15org.highwire.dtl.DTLVardef@1f0b859org.highwire.dtl.DTLVardef@d6ed7eorg.highwire.dtl.DTLVardef@81f3d5_HPS_FORMAT_FIGEXP M_FIG C_FIG

evolutionary biology↗

bioRxiv2022

Cancer prevalence is remarkably low in turtles and is correlated with life history traits in birds, mammals, and squamates

Identifying species with unusually low cancer prevalence can provide new insights into cancer resistance. Most studies have focused on mammals, but the genetic, physiological, and ecological diversity among vertebrates can influence cancer susceptibility. We used necropsies from over a thousand species of amphibians, birds, crocodilians, mammals, squamates, and turtles to investigate relationships between cancer prevalence, intrinsic cancer risk, body mass, and lifespan. Previous studies often relied on species averages, leading to inaccurate interpretations. Our innovative statistical approach uses raw cancer data and resampling to improve accuracy. We found remarkably low cancer prevalence in turtles, high prevalence in squamates and mammals, and lower-than-expected prevalence based on lifespan and body mass in multiple groups. Our results show lifespan influences neoplasia and malignancy transformation rates in mammals, while body mass affects neoplasia prevalence in amphibians and squamates. These data reveal a complex relationship between life history traits and cancer risk, identifying vertebrates with potential novel cancer resistance mechanisms. STATEMENT OF SIGNIFICANCEBiodiversity is an untapped natural resource for understanding cancer. Our study reveals a wide divergence in cancer prevalence among vertebrate groups, with notably low rates in turtles and high rates in squamates and mammals. These findings can lead to new breakthroughs in understanding the biology of cancer.

evolutionary biology↗

bioRxiv2022

Interpreting the Evolutionary Echoes of a Protein Complex Essential for Inner-Ear Mechanosensation

The sensory epithelium of the inner ear, found in all extant lineages of vertebrates, has been subjected to over 500 million years of evolution, resulting in the complex inner ear of modern vertebrates. Inner-ear adaptations are as diverse as the species in which they are found, and such unique anatomical variations have been well studied. However, the evolutionary details of the molecular machinery that are required for hearing are less well known. Two molecules that are essential for hearing in vertebrates are cadherin-23 and protocadherin-15, proteins whose interaction with one another acts as the focal point of force transmission when converting sound waves into electrical signals that the brain can interpret. This interaction exists in every lineage of vertebrates, but little is known about the structure or mechanical properties of these proteins in most non-mammalian lineages. Here, we use various techniques to characterize the evolution of this protein interaction. Results show how evolutionary sequence changes in this complex affect its biophysical properties both in simulations and experiments, with variations in interaction strength and dynamics among extant vertebrate lineages. Evolutionary simulations also characterize how the biophysical properties of the complex in turn constrain its evolution and provide a possible explanation for the increase in deafness-causing mutants observed in cadherin-23 relative to protocadherin-15. Together, these results suggest a general picture of tip-link evolution in which selection acted to modify the tip-link interface, while subsequent neutral evolution combined with varying degrees of purifying selection drove additional diversification in modern tetrapods.

evolutionary biology↗

bioRxiv2021

Transposable elements continuously remodel the regulatory landscape, transcriptome, and function of decidual stromal cells

Gene expression evolution underlies the origin, divergence, and conservation of biological characters including cell-types, tissues, and organ systems. Previously we showed that large-scale gene expression changes in decidual stromal cells contributed to the origins of pregnancy in eutherians and the divergence of pregnancy traits in primates, and that transposable elements likely contributed to these gene expression changes. Here we show that two large waves of TEs remodeled the transcriptome and regulatory landscape of decidual stromal cells, including a major wave in primates. Genes nearby TE-derived regulatory elements are among the most progesterone responsive in the genome and play essential roles in orchestrating progesterone responsiveness and the core function of decidual cells by donating progesterone receptor binding sites to the genome. We tested the regulatory abilities of 89 TE consensus sequences and found nearly all acted as repressors in mammalian cells, but treatment with a histone deacetylase inhibitor unmasked latent enhancer functions. These data indicate TEs have played an important role in the development, evolution, and function of primate decidual stromal cells and suggest a two-step model in which latent enhancer functions of TEs are unmasked after they lose primary repressors functions. Significance statementGene expression patterns evolved very rapidly during the evolutionary origins of pregnancy in early mammals and in primates. These episodes of gene expression evolution and linked with important processes that establish and maintain pregnancy, and appear to be driven by domestication of transposable elements.

evolutionary biology↗

bioRxiv2021

Gene expression phylogenies and ancestral transcriptome reconstruction resolves major transitions in the origins of pregnancy

Structural and physiological changes in the female reproductive system underlie the origins of pregnancy in multiple vertebrate lineages. In mammals, for example, the glandular portion of the lower reproductive tract has transformed into a structure specialized for supporting fetal development. These specializations range from relatively simple maternal provisioning in egg-laying monotremes to an elaborate suite of traits that support intimate maternal-fetal interactions in Eutherians. Among these traits are the maternal decidua and fetal component of the placenta, but there is considerable uncertainty about how these structures evolved. We identified the origins of pregnancy utilizing ancestral transcriptome reconstruction to infer functional evolution of the maternal-fetal interface. Remarkably, we found that maternal gene expression profiles are correlated with degree of placental invasion. These results indicate that an epitheliochorial-like placenta evolved early in the mammalian stem-lineage and that the ancestor of Eutherians had a hemochorial placenta, and suggest maternal control of placental invasiveness. Collectively, these data resolve major transitions in the evolution of pregnancy and indicate that ancestral transcriptome reconstruction can be used to study the function of ancestral cell, tissue, and organ systems.

evolutionary biology↗

bioRxiv2021

Concurrent evolution of anti-aging gene duplications and cellular phenotypes in long-lived turtles

There are many costs associated with increased body size and longevity in animals, including the accumulation of genotoxic and cytotoxic damage that comes with having more cells and living longer. Yet, some species have overcome these barriers and have evolved remarkably large body sizes and long lifespans, sometimes within a narrow window of evolutionary time. Here, we demonstrate through phylogenetic comparative analysis that multiple turtle lineages, including Galapagos giant tortoises, concurrently evolved large bodies, long lifespans, and reduced cancer risk. We also show through comparative genomic analysis that Galapagos giant tortoises have gene duplications related to longevity and tumor suppression. To examine the molecular basis underlying increased body size and lifespan in turtles, we treated cell lines from multiple species, including Galapagos giant tortoises, with drugs that induce different types of cytotoxic stress. Our results indicate that turtle cells, in general, are resistant to oxidative stress related to aging, while Galapagos giant tortoise cells, specifically, are sensitive to endoplasmic reticulum stress, which may give this species an ability to mitigate the effects of cellular stress associated with increased body size and longevity.

evolutionary biology↗

bioRxiv2021

Evolutionary transcriptomics implicates new genes and pathways in human pregnancy and adverse pregnancy outcomes

Evolutionary changes in the anatomy and physiology of the female reproductive system underlie the origins and diversification of pregnancy in Eutherian ("Placental") mammals. This developmental and evolutionary history constrains normal physiological functions and biases the ways in which dysfunction contributes to reproductive trait diseases and adverse pregnancy outcomes. Here, we show that gene expression changes in the human endometrium during pregnancy are associated with the evolution of human-specific traits and pathologies of pregnancy. We found that hundreds of genes gained or lost endometrial expression in the human lineage. Among these are genes that may contribute to human-specific maternal-fetal communication (HTR2B) and maternal-fetal immunotolerance (PDCD1LG2) systems, as well as vascular remodeling and deep placental invasion (CORIN). These data suggest that explicit evolutionary studies of anatomical systems complement traditional methods for characterizing the genetic architecture of disease. We also anticipate our results will advance the emerging synthesis of evolution and medicine ("evolutionary medicine") and be a starting point for more sophisticated studies of the maternal-fetal interface. Furthermore, the gene expression changes we identified may contribute to the development of diagnostics and interventions for adverse pregnancy outcomes.

evolutionary biology↗

bioRxiv2021

Return of a lost structure in the evolution of felid dentition revisited: A DevoEvo perspective on the irreversibility of evolution

There is a longstanding interest in whether the loss of complex characters is reversible (so-called "Dollos law"). Reevolution has been suggested for numerous traits but among the first was Kurten (1963), who proposed that the presence of the second lower molar (M2) of the Eurasian lynx (Lynx lynx) was a violation of Dollos law because all other Felids lack M2. While an early and often cited example for the reevolution of a complex trait, Kurten (1963) and Werdelin (1987) used an ad hoc parsimony argument to support their proposition that M2 reevolved in Eurasian lynx. Here I revisit the evidence that M2 reevolved in Eurasian lynx using explicit parsimony and maximum likelihood models of character evolution and find strong evidence that Kurten (1963) and Werdelin (1987) were correct - M2 reevolved in Eurasian lynx. Next, I explore the developmental mechanisms which may explain this violation of Dollos law and suggest that the reevolution of lost complex traits may arise from the reevolution of cis-regulatory elements and protein-protein interactions, which have a longer half-life after silencing that protein coding genes. Finally, I present a model developmental model to explain the reevolution M2 in Eurasian lynx.

evolutionary biology↗

bioRxiv2020

Pervasive duplication of tumor suppressors in Afrotherians during the evolution of large bodies and reduced cancer risk

The risk of developing cancer is correlated with body size and lifespan within species. Between species, however, there is no correlation between cancer and either body size or lifespan, indicating that large, long-lived species have evolved enhanced cancer protection mechanisms. Elephants and their relatives (Proboscideans) are a particularly interesting lineage for the exploration of mechanisms underlying the evolution of augmented cancer resistance because they evolved large bodies recently within a clade of smaller bodied species (Afrotherians). Here, we explore the contribution of gene duplication to body size and cancer risk in Afrotherians. Unexpectedly, we found that tumor suppresxssor duplication was pervasive in Afrotherian genomes, rather than restricted to Proboscideans. Proboscideans, however, have duplicates in unique pathways that may underlie some aspects of their remarkable anti-cancer cell biology. These data suggest that duplication of tumor suppressor genes facilitated the evolution of increased body size by compensating for decreasing intrinsic cancer risk.

evolutionary biology↗

bioRxiv2020

Evolutionary transcriptomics implicates HAND2 in the origins of implantation and regulation of gestation length

The developmental origins and evolutionary histories of cell types, tissues and organ systems contribute to the ways in which their dysfunction leads to disease. In mammals for example, the nature and extent of maternal-fetal interactions, how those interactions develop, and their evolutionary history likely influence diseases of pregnancy such as infertility and preterm birth. Here we show genes that evolved to be expressed at the maternal-fetal interface in Eutherian ( Placental) mammals play essential roles in the evolution of pregnancy and are associated with immune system disorders and preterm birth. Among these genes is the transcription factor HAND2, which suppresses estrogen signaling, an innovation of Eutherians, thereby allowing blastocyst implantation. We found that HAND2 is dynamically expressed in the decidua throughout the menstrual cycle and pregnancy, gradually decreasing to reach a low at term. HAND2 regulates a small but distinct set of target genes in endometrial stromal fibroblasts including the cytokine IL15, which was also dynamically expressed throughout the menstrual cycle and gestation, and promoted the migration of natural killer cells and extravillous cytotrophoblasts. Remarkably, we found that the HAND2 promoter loops to a distal enhancer containing SNPs implicated in the regulation of gestation length and birth weight. Collectively, these data connect HAND2 expression at the maternal-fetal interface with the evolution of implantation and gestation length regulation, and preterm birth.

evolutionary biology↗

bioRxiv2020

Transcriptome and regulatory maps of decidua-derived stromal cells inform gene discovery in preterm birth

While a genetic component of preterm birth (PTB) has long been recognized and recently mapped by genome-wide association studies (GWAS), the molecular determinants underlying PTB remain elusive. This stems in part from an incomplete availability of comprehensive functional genomic annotations in human cell types relevant to pregnancy and PTB. Here, we generated extensive transcriptional and chromatin annotations of cultured primary decidua-derived mesenchymal stromal/stem cells (MSCs) and in vitro differentiated decidual stromal cells (DSCs) and developed a computational framework to integrate these functional annotations with results from a GWAS of gestational duration in 56,384 women. This resulted in a significant enrichment of heritability estimates in functional noncoding regions in stromal cells, as well as in the discovery of additional loci associated with gestational duration and target genes of associated loci. Our strategy illustrates how systematic functional annotations in pregnancy-relevant cell types aid in the experimental follow-up of GWAS for PTB and, likely, other pregnancy-related conditions.

genomics↗

bioRxiv2020

Cooption of polyalanine tract into a repressor domain in the mammalian transcription factor HoxA11

An enduring problem in biology is explaining how the functions of genes originated and how those functions diverge between species. Despite detailed studies on the functional evolution of a few proteins, the molecular mechanisms by which protein functions have evolved are almost entirely unknown. Here we show that a polyalanine tract in the homeodomain transcription factor HoxA11 arose in the stem-lineage of mammals and functions as an autonomous repressor module by physically interacting with the PAH domains of SIN3 proteins. These results suggest that long polyalanine tracts, which are common in transcription factors and often associated with disease, may generally function as repressor domains and can contribute to the diversification of transcription factor functions despite the deleterious consequences of polyalanine tract expansion. Research HighlightsWe show that a polyalanine track in HoxA11 evolved into a repressor domain in mammals through an increase in alanine repeat number, indicating that transcription factors can evolve novel functions despite the potential deleterious consequences associated with amino acid repeats.

evolutionary biology↗