Biology subjects

Vazquez, J. M.

Publications and source records attributed to Vazquez, J. M..

11 recordsLinked to original sources

bioRxiv2026

Molecular signatures and cellular responses underlying hypoxic adaptation in sea turtles

Hypoxia-inducible factors (HIFs) are transcriptional regulators that orchestrate the canonical response to low-oxygen tension in animal cells. Vertebrates possess three HIF- isoforms, which arose from two gene duplication events of the ancestral HIF-1 gene. Here, we examined whether the HIF gene family (HIF-1, HIF-2, HIF-3, and HIF-1N inhibitor) shows evidence of positive selection in hypoxia-tolerant reptiles (Testudines), compared evolutionary patterns within the family, and assessed the transcriptional response to hypoxia in primary cells derived from a hypoxia-tolerant (Caretta caretta) and a non-tolerant (Sceloporus occidentalis) reptile. We found that HIF-1, HIF-2, and HIF-1N are highly conserved across reptiles, whereas HIF-3 is under positive selection in Testudines. We also identified multiple novel regulatory motifs unique to Testudines. Transcriptional signatures of hypoxia exposure indicated stark differences between lizards and turtles. Whereas lizard cells exhibited a canonical response to hypoxia, characterized by enriched cell-survival pathways, sea turtle cells exhibit a robust, distinctive transcriptional response involving enriched pathways related to protein synthesis, quality maintenance, and mitochondrial integrity. Surprisingly, cis-regulatory element analysis did not show HIFs as key regulators of the transcriptional response in either species. Instead, TFDP1 in lizard cells and E2F1 in sea turtle cells emerged as potential key regulators. TFDP1 regulates the cell cycle, specifically DNA synthesis and cell cycle progression, while E2F regulates DNA-damage response, apoptosis, metabolism, and fatty acid biosynthesis. These results suggest that the reptilian response to hypoxia is shaped by transcriptional plasticity, while highlighting key regulatory mechanisms driving hypoxic adaptation in sea turtle cells. However, positive selection of HIF-3 and novel HIF motifs suggest a combined, but yet to be uncovered, contribution of regulatory and coding sequence evolutionary mechanisms shaping hypoxia tolerance in Testudines.

molecular biology↗

bioRxiv2025

Avid lysosomal acidification in fibroblasts of the Mediterranean mouse Mus spretus

Failures of the lysosome-autophagy system are a hallmark of aging and many disease states. As a consequence, interventions that enhance lysosome function are of keen interest in the context of drug development. Throughout the biomedical literature, evolutionary biologists have found cases in which challenges faced by humans in clinical settings have been resolved by non-model organisms adapting to wild environments. Here, we used a primary cell culture approach to survey lysosomal characteristics in species of the genus Mus. We found that fibroblasts from M. spretus, a wild Mediterranean mouse, exhibited elevated lysosomal mass and enzyme activity along with reduced activity of {beta}-galactosidase, a classical marker of cellular senescence, compared to those from M. musculus, a related species adapted to human-associated environments. We propose that classic laboratory models of lysosome function and senescence may reflect characters that diverge from the phenotypes of wild mice. The M. spretus phenotype may ultimately serve as a blueprint for interventions that ameliorate lysosomal dysfunction under conditions of stress and disease.

evolutionary biology↗

bioRxiv2024

Extensive longevity and DNA virus-driven adaptation in nearctic Myotis bats

Summary ParagraphThe genus Myotis is one of the largest clades of bats, and exhibits some of the most extreme variation in lifespans among mammals alongside unique adaptations to viral tolerance and immune defense1-3. To study the evolution of these phenotypes we generated cell lines and near-complete genome assemblies for eight closely related Myotis species. Using genome-wide screens of positive selection, analyses of structural variation, and functional experiments in primary cells, we identify patterns of adaptation contributing to longevity, cancer resistance, and viral interactions. We demonstrate distinct modes of adaptation to DNA and RNA viruses compared to all other mammals, with bats exhibiting genome-wide overrepresentation of positive selection for DNA virus-interacting proteins and elevated rates of copy number variation for RNA virus-interacting proteins. Characterization of Myotis-specific duplications of the key immune factor protein kinase R (PKR) reveals multiple ancient segregating trans-species copy number polymorphisms. We show that the recurrent evolution of longevity seen in Myotis is associated with positive selection in cancer pathways, and demonstrate a unique response to DNA damage in primary cells of the long-lived M. lucifugus. Together, our results suggest that bats remarkable longevity and immunity are linked through pleiotropic adaptations to viruses and aging-related disease.

genomics↗

bioRxiv2023

Hypoxia blunts angiogenic signaling and upregulates the antioxidant system in elephant seal endothelial cells

Elephant seals experience extreme hypoxemia during diving bouts. Similar depletions in oxygen availability characterize pathologies including myocardial infarction and ischemic stroke in humans, but seals manage these repeated episodes without injury. However, the real-time assessment of the molecular changes underlying protection against hypoxic injury in seals remains restricted by their at-sea inaccessibility. Hence, we developed a proliferative arterial endothelial cell culture system to assess the molecular response to prolonged hypoxia. Seal and human cells exposed to 1% O2 for up to 6 h demonstrated differential responses to both acute and prolonged hypoxia. Seal cells decouple stabilization of the hypoxia-sensitive transcriptional regulator HIF-1 from angiogenic signaling at both the transcriptional and cellular level. Rapid upregulation of genes involved in the glutathione (GSH) metabolism pathway supported maintenance of GSH pools and increases in intracellular succinate in seal but not human cells during hypoxia exposure. High maximal and spare respiratory capacity in seal cells after hypoxia exposure occurred in concert with increasing mitochondrial branch length and independent from major changes in extracellular acidification rate, suggesting seal cells recover oxidative metabolism without significant glycolytic dependency after hypoxia exposure. In sum, our studies show that in contrast to human cells, seal cells adapt to hypoxia exposure by dampening angiogenic signaling, increasing antioxidant protection, and maintaining mitochondrial morphological integrity and function.

physiology↗

bioRxiv2022

Expanding the stdpopsim species catalog, and lessons learned forrealistic genome simulations

Simulation is a key tool in population genetics for both methods development and empirical research, but producing simulations that recapitulate the main features of genomic data sets remains a major obstacle. Today, more realistic simulations are possible thanks to large increases in the quantity and quality of available genetic data, and to the sophistication of inference and simulation software. However, implementing these simulations still requires substantial time and specialized knowledge. These challenges are especially pronounced for simulating genomes for species that are not well-studied, since it is not always clear what information is required to produce simulations with a level of realism sufficient to confidently answer a given question. The community-developed framework stdpopsim seeks to lower this barrier by facilitating the simulation of complex population genetic models using up-to-date information. The initial version of stdpopsim focused on establishing this framework using six well-characterized model species (Adrion et al., 2020). Here, we report on major improvements made in the new release of stdpopsim (version 0.2), which includes a significant expansion of the species catalog and substantial additions to simulation capabilities. Features added to improve the realism of the simulated genomes include non-crossover recombination and provision of species-specific genomic annotations. Through community-driven efforts, we expanded the number of species in the catalog more than three-fold and broadened coverage across the tree of life. During the process of expanding the catalog, we have identified common sticking points and developed best practices for setting up genome-scale simulations. We describe the input data required for generating a realistic simulation, suggest good practices for obtaining the relevant information from the literature, and discuss common pitfalls and major considerations. These improvements to stdpopsim aim to further promote the use of realistic whole-genome population genetic simulations, especially in non-model organisms, making them available, transparent, and accessible to everyone.

bioinformatics↗

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↗

bioRxiv2021

Tissue-specific impacts of aging and genetics on gene expression patterns in humans

Age is the primary risk factor for many common human diseases including heart disease, Alzheimers dementias, cancers, and diabetes. Determining how and why tissues age differently is key to understanding the onset and progression of such pathologies. Here, we set out to quantify the relative contributions of genetics and aging to gene expression patterns from data collected across 27 tissues from 948 humans. We show that age impacts the predictive power of expression quantitative trait loci across several tissues. Jointly modelling the contributions of age and genetics to transcript level variation we find that the heritability (h2) of gene expression is largely consistent among tissues. In contrast, the average contribution of aging to gene expression variance varied by more than 20-fold among tissues with [Formula] in 5 tissues. We find that the coordinated decline of mitochondrial and translation factors is a widespread signature of aging across tissues. Finally, we show that while in general the force of purifying selection is stronger on genes expressed early in life compared to late in life as predicted by Medawars hypothesis, a handful of highly proliferative tissues exhibit the opposite pattern. These non-Medawarian tissues exhibit high rates of cancer and age-of-expression associated somatic mutations in cancer. In contrast, gene expression variation that is under genetic control is strongly enriched for genes under relaxed constraint. Together we present a novel framework for predicting gene expression phenotypes from genetics and age and provide insights into the tissue-specific relative contributions of genes and the environment to phenotypes of aging.

genetics↗

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↗

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↗

bioRxiv2017

A zombie LIF gene in elephants is up-regulated by TP53 to induce apoptosis in response to DNA damage

Large bodied organisms have more cells that can potentially turn cancerous than smallbodied organisms with fewer cells, imposing an increased risk of developing cancer. This expectation predicts a positive correlation between body size and cancer risk, however, there is no correlation between body size and cancer risk across species ( Petos Paradox). Here we show that elephants and their extinct relatives (Proboscideans) may have resolved Petos Paradox in part through re-functionalizing a leukemia inhibitory factor pseudogene (LIF6) with pro-apoptotic functions. The LIF6 gene is transcriptionally up-regulated by TP53 in response to DNA damage, and translocates to the mitochondria where it induces apoptosis. Phylogenetic analyses of living and extinct Proboscidean LIF6 genes indicates its TP53 response element evolved coincident with the evolution of large body sizes in the Proboscidean stem-lineage. These results suggest that re-functionalizing of a pro-apoptotic LIF pseudogene may have been permissive (though not sufficient) for the evolution of large body sizes in Proboscideans.

evolutionary biology↗