Biology subjects

Hernandez, F.

Publications and source records attributed to Hernandez, F..

17 recordsLinked to original sources

bioRxiv2026

Single-Cell RNA Sequencing Reveals Distinct Cellular and Molecular Features of Steroid-Induced Osteonecrosis of the Femoral Head Compared to Alcohol-Induced Osteonecrosis and Hip Osteoarthritis

Osteonecrosis of the femoral head (ONFH) remains a devastating complication of glucocorticoid therapy and alcohol abuse, yet the pathophysiology is poorly understood. Using single-cell RNA sequencing, we analyzed femoral head specimens from patients undergoing total hip arthroplasty due to steroid-induced ONFH, alcohol-induced ONFH, or hip osteoarthritis (OA). Our comprehensive analysis across conditions revealed etiology-specific cellular compositions and transcriptional profiles. Steroid-induced ONFH demonstrated a distinctive immunological signature characterized by a neutrophil-predominant, elevated innate-to-adaptive immune cell ratio compared to alcohol-induced ONFH or OA. T cell analysis revealed impaired maturation in steroid-induced ONFH, with abundant naive T cells but reduced mature CD4+ T cells and CD4+ memory T cells compared to both alcohol-induced ONFH and OA. In addition, compared to alcohol-induced ONFH, steroid-induced ONFH was associated with an increase in exhausted/dysfunctional CD8+ T cells which suggests an impaired response to stress and reflects chronic immune dysfunction. Within stromal cell populations, steroid-induced ONFH demonstrated an increase in pericytes, endothelial cells, and mesenchymal cell with osteogenic features as compared to both alcohol-induced ONFH or OA. These findings collectively reveal novel cellular mechanisms underlying steroid-induced ONFH which may contribute to further investigation of etiology-specific pathogenesis and treatment strategies.

genomics↗

bioRxiv2026

Harnessing historical collections to reconstruct the invasion history of Microstegium vimineum (Poaceae)

The evolutionary processes underlying successful invasions are often difficult to disentangle. Historical collections provide a temporal perspective, offering great potential to reconstruct invasion histories and identify the processes driving invasions. Japanese stiltgrass (Microstegium vimineum) is an invasive C4 grass introduced to eastern North America over a century ago and now established in 31 USA states. To reconstruct its invasion history, we leveraged low-coverage whole-genome sequencing of 142 herbarium and 330 contemporary samples spanning the temporal and spatial extent of the North American invasion and the native range in Asia. We identified three independent introductions in the USA: an awnless form in the South and two independent introductions of awned forms in the North, with limited admixture among introductions across space and time. In both regions, we observed high genetic diversity in the earliest available collections despite demographic bottlenecks and identified several putative selective sweeps in or near flowering-time genes, suggesting rapid evolution in the introduced range. Our analyses support separate invasions in the USA, likely facilitated by standing genetic variation and selection, but provide little support for admixture playing a major role. Our study highlights the power of historical collections to uncover the processes and mechanisms underlying successful biological invasions.

evolutionary biology↗

bioRxiv2026

Genomic offsets predict observed kelp declines and suggest benefits of assisted migration in the Northeast Pacific

Kelp forests are widely distributed along temperate and polar coastlines worldwide and are among the worlds most productive and diverse marine ecosystems. Yet, due in part to ocean warming, they are declining and even disappearing in many parts of the world. While genomic tools can identify local adaptation and predict species responses to global change, these predictions have rarely been validated in the field, hampering their widespread use in conservation practice. Here, we applied a seascape genomics approach to investigate environmental adaptation in the two main canopy-forming species of the Northeast Pacific, Macrocystis tenuifolia and Nereocystis luetkeana. We leveraged whole-genome sequences of 598 individuals across 94 sites along the British Columbia and Washington coasts, together with 37 environmental variables. Both species showed genomic signatures of local adaptation, with distinct environmental drivers shaping adaptation in each species despite their co-occurrence across much of the studied area. Using gradient forests, we modelled the genetic turnover across environmental gradients and predicted populations vulnerability (genomic offset) under projected environmental conditions. Genomic offsets differed greatly among regions and were positively correlated with kelp declines observed to date, especially in Macrocystis, validating the link between genomic models and outcomes in the field and allowing us to translate genomic predictions into an ecologically meaningful metric: the risk of extirpation under global change. Our models predict that assisted migration could significantly attenuate kelps vulnerability to global change. Across environmentally heterogenous coastlines, short-distance migration can often substantially reduce future genomic-environmental mismatches, but in many cases, long-distance migration would be most beneficial. Our results highlight the potential of seascape genomics to predict vulnerability of populations to global change. Importantly, the validated link between our genomic models and ecological outcomes allows quantification of climate-driven extirpation risk and can inform conservation strategies to improve the resilience and sustainable management of these vulnerable ecosystems.

evolutionary biology↗

bioRxiv2026

Herbarium genomics reveal signatures of colonization history, lineage turnover, and adaptation during invasion

O_LIA key challenge in invasion biology is dissecting the roles of colonization history, admixture, and selection on invasion success. However, it is often difficult to determine the sources and locations of introduction events as well as the timing and magnitude of gene flow and selection using genomics datasets from contemporary samples. C_LIO_LIWe disentangle the evolutionary processes acting during the North American invasion of Trifolium repens (white clover) using low-coverage whole genome sequencing from 513 herbarium specimens originally collected between 1838-2018. C_LIO_LIIntroduction history paralleled European colonization patterns. The earliest collected samples had predominantly Belgian and British ancestry, with increasing French and Spanish contributions over time in the Mid-Atlantic and South. Genomic diversity increased significantly through time likely driven by admixture between independently introduced lineages. In lowest latitude regions, there is a strong shift in dominant ancestry with limited admixture (i.e., lineage turnover). Putatively adaptive loci exhibited protracted shifts in allele frequency during the invasion, consistent with contemporary clines. C_LIO_LIOur study demonstrates the power of herbarium genomics to provide spatiotemporal insight into recent evolutionary history. We find a complex invasion history that includes multiple introductions, lineage turnover, and admixture that increased genetic diversity and likely facilitated adaptation in this now cosmopolitan plant. C_LI

plant biology↗

bioRxiv2025

A New Aneurysm Rupture-Prone Marfan Mouse Model with FBN1Q2467X Nonsense Mutation Reveals Adventitial Inflammation

Marfan syndrome (MFS) is a genetic disorder caused by mutations in fibrillin-1(FBN1), which encodes FBN1, a key structural component of the extracellular matrix. Mutations in FBN1 influence the severity of aortic disease and therapeutic responses, with aortic aneurysm being the leading cause of mortality in patients with MFS. To investigate the mechanisms driving aneurysm progression, we generated a mouse model (Fbn1Q2469X/+) carrying the FBN1Q2467X nonsense mutation identified in MFS patients. This mutation results in FBN1 deficiency. Although Fbn1Q2469X/+ mice appear normal, showing only mild, nonprogressive dilation of the aortic root and ascending aorta with minor reductions in blood pressure, homozygous Fbn1Q2469X/Q2469X mice develop spontaneous thoracic aortic aneurysms (TAA) that progress to rupture between 10 and 25 days of age, with 100% penetrance. Histopathology shows progressive vessel wall degeneration characterized by disorganized vascular smooth muscle cells, collagen loss, and elastic fiber fragmentation from early to late stages. RNA-seq analysis identifies inflammation as the dominant process in late-stage aneurysms. Immunofluorescence assay reveals inflammatory cells prominently localized to the adventitia near rupture sites, linking adventitial inflammation to aneurysm progression. This genetically modified Fbn1Q2469X/Q2469X mouse model consistently develops progressive aortic aneurysms and provides a reliable, cost-effective platform to investigate the molecular mechanisms of aneurysm progression and to evaluate therapeutic strategies in aneurysm diseases, including Marfan syndrome and related disorders.

genetics↗

bioRxiv2025

Comprehensively Testing the Function of Missense Variation in the STK11 Tumour Suppressor

The tumor suppressor gene STK11 encoding Serine/Threonine Kinase 11 (STK11) is associated with Peutz-Jeghers Syndrome (PJS), a heritable gastrointestinal disease that increases lifetime cancer risk, and with somatic variation that contributes to [~]30% of lung and 20% of cervical cancers. Although identifying pathogenic variants is clinically actionable, over 94% of STK11 missense variants that have been observed clinically lack a definitive classification. We therefore measured the impact of STK11 variants at scale in a mammalian cell-based assay, scoring 6,026 (73% of all possible) amino acid substitutions across the full-length gene. Functional scores--which were consistent with biochemical properties, smaller-scale assays, and pathogenicity annotations--identified a subset of PJS patients with germline STK11 variants diagnosed later in life, as well as somatic STK11 variants found in cancer patients that had comparable overall survival estimates to wild-type STK11. Our scores provided new evidence for 350 annotated VUS STK11 missense variants and [~]80% of missense variants that have not yet been reported clinically, but we might expect to observe in the future. Thus, our effect map provides a proactive resource for gaining sequence-structure-function insights and evidence for actionable interpretation of clinical missense variants.

cancer biology↗

bioRxiv2025

Saturation mapping of MUTYH variant effects using DNA repair reporters

Variants of uncertain significance (VUS) limit the actionability of genetic testing. A prominent example is MUTYH, a base excision repair factor associated with polyposis and colorectal cancer, which has a pathogenic variant carrier rate approaching 1 in 50 individuals in some populations. To systematically interrogate variant function in MUTYH, we coupled deep mutational scanning with a DNA repair reporter containing its lesion substrate, 8OG:A. Our variant-to-function map covers >97% of all possible MUTYH point variants (n=10,941) and achieves 100% accuracy classifying the pathogenicity of known clinical variants (n=247). Leveraging a large clinical registry, we observe significant associations with colorectal polyps and cancer, with more severely impaired missense variants conferring greater risk. We recapitulate known functional differences between pathogenic founder alleles, and highlight sites of complete missense intolerance, including residues that intercalate DNA and coordinate essential Zn2+ or Fe-S clusters. This map provides a resource to resolve the 1,032 existing missense VUS and 90 variants with conflicting interpretations in MUTYH, and demonstrates a scalable strategy to interrogate other clinically relevant DNA repair factors.

genomics↗

bioRxiv2024

Admixture with cultivated sunflower likely facilitated establishment and spread of wild sunflower (H. annuus) in Argentina

A better understanding of the genetic and ecological factors underlying successful invasions is critical to mitigate the negative impacts of invasive species. Here, we study the invasion history of Helianthus annuus populations from Argentina, with particular emphasis on the role of post-introduction admixture with cultivated sunflower (also H. annuus) and climate adaptation driven by large haploblocks. We conducted genotyping-by-sequencing of samples of wild populations as well as Argentinian cultivars and compared them with wild (including related annual Helianthus species) and cultivated samples from the native range. We also characterized samples for 11 known haploblocks associated with environmental variation in native populations to test whether haploblocks contributed to invasion success. Population genomics analyses supported two independent geographic sources for Argentinian populations, the central United States and Texas, but no significant contribution of related annual Helianthus species. We found pervasive admixture with cultivated sunflower, likely as result of post-introduction hybridization. Genomic scans between invasive populations and their native sources identified multiple genomic regions with evidence of selection in the invaded range. These regions significantly overlapped between the two native-invasive comparisons and showed disproportionally high crop ancestry, suggesting that crop alleles contributed to invasion success. We did not find evidence of climate adaptation mediated by haploblocks, yet outliers of genome scans were enriched in haploblock regions and, for at least two haploblocks, the cultivar haplotype was favored in the invaded range. Our results show that admixture with cultivated sunflower played a major role in the establishment and spread of H. annuus populations in Argentina.

evolutionary biology↗

bioRxiv2024

Involvement of the cellular prion protein in seeding and spreading of sarkosyl-derived fractions of Alzheimer's disease in Prnp mutant mice and in the P301S transgenic tauopathy mice model

The natural cellular prion protein is known to play several roles during development and adult brain. Far from its pathological roles in prionopathies, the non-pathogenic cellular prion protein has been described as a receptor for several amyloid in oligomeric and prefibrillar forms. For some amyloids, specific domains of the protein play a crucial role in modulating amyloids cellular uptake and seeding properties. In most studies, the functions and the role of putative amyloid receptors have been analyzed by using brain extracts derived from human neurodegenerative patients. Another strategy has been to modify the genetic dosage of the natural prion protein in genetic models of different diseases. In this study, we take advantage of both approaches to examine whether this protein plays a role in the seeding and spreading of pathogenic tau. Our results point to a role of the natural prion protein in the emergence of pathogenic tau in a mouse model overexpressing the mutation P301S of the human tau gene. In contrast, its role is minor when sarkosyl-derived brain samples of Alzheimers disease are used. In fact, our results indicate that the use of this type of sample is not adequate to determine the role of a putative receptor in tau seeding and spreading.

neuroscience↗

bioRxiv2023

Multiple Pleistocene refugia for Arctic White Heather (Cassiope tetragona) supported by population genomics analyses of contemporary and Little-Ice-Age samples

AimArctic plants survived the Pleistocene glaciations in unglaciated refugia, but the number of these refugia is often unclear. We use high-resolution genomic data from present-day and Little-Ice-Age populations of Arctic White Heather (Cassiope tetragona) to re-evaluate the biogeography of this species and determine whether it had multiple independent refugia or a single refugium in Beringia. LocationCircumpolar Arctic and Coastal British Columbia (BC) alpine TaxonCassiope tetragona L., subspecies saximontana and tetragona, outgroup C. mertensiana (Ericaceae) MethodsWe built genotyping-by-sequencing (GBS) libraries using Cassiope tetragona tissue from 36 Arctic locations, including two [~]250-500-year-old populations collected under glacial ice on Ellesmere Island, Canada. We assembled a de novo GBS reference and called variants in dDocent. Population structure, genetic diversity, and demography were inferred from PCA, ADMIXTURE, fastsimcoal2, SplitsTree, and several population genomics statistics. ResultsPopulation structure analyses identified 4-5 clusters that align with geographic locations. Nucleotide diversity was highest in Beringia and decreased eastwards across Canada. Demographic coalescent analysis of the site-frequency-spectrum dated the following splits from Alaska: BC subspecies saximontana (6 mya), Russia (1.5 mya), Europe (>300-600 kya), Greenland (100 kya). Northern Canada populations appear to be from the current interglacial (7-9 kya). Genetic variants from Alaska appeared more frequently in present-day than historic plants on Ellesmere Island. ConclusionsDemographic analyses show BC, Alaska, Russia, Europe, and Greenland all had separate refugia during the last major glaciations. Northern Canadian populations appear to be founded during the current interglacial with genetic contributions from Alaska, Europe, and Greenland. On Ellesmere Island, there is evidence for continued, recent gene flow with foreign variants introduced in the last 250-500 years. These results suggest that a re-analysis of other Arctic species with shallow population structure using higher resolution genomic markers and demographic analyses may help reveal deeper structure and other circumpolar glacial refugia.

genomics↗

bioRxiv2023

Lamivudine (3TC), a nucleoside reverse transcriptase inhibitor, prevents the neuropathological alterations present in mutant tau transgenic mice

The dysregulation of transposable elements contributes to neurodegenerative disorders. Previous studies have reported an increase in retrotransposon transcription in Drosophila models, as well as in human tauopathies. In this context, here we tested the possible protective effects of a reverse transcriptase inhibitor, namely lamivudine (also known as 3TC), in P301S mice, an animal model of Alzheime[r]s disease based on FTDP-17-tau overexpression. Transgenic P301S mice administered lamivudine through drinking water showed a decrease in the following histopathological marks typical of tauopathies: tau phosphorylation; inflammation; neuronal death; and hippocampal atrophy. Lamivudine treatment attenuated motor deficits (Rotarod test) and improved short-term memory (Y-maze test). To evaluate the role of tau in retrotransposition, we cotransfected HeLa cells with a plasmid containing a complete LINE-1 sequence and a neomycin reporter cassette designed for retrotransposition assays, and a plasmid with the tau sequence. LINE-1 insertion increased considerably in the cotransfection compared to the transfection without tau. In addition, lamivudine inhibited the insertion of LINE-1. Our data suggest that the progression of the tauopathy can be attenuated by the administration of lamivudine upon the first symptoms of neuropathology. HighlightsO_LILamivudine treatment in drinking water inhibited a tau-associated pathology in a mouse model of tauopathy. C_LIO_LITau promotes the insertion of transposable elements LINE-1 in vitro. LINE-1 insertion in vitro is inhibited by lamivudine. C_LIO_LILamivudine attenuates memory and motor deficits in tau transgenic mice. C_LI

neuroscience↗

bioRxiv2023

The role of intraspecific crop-weed hybridization in the evolution of weediness and invasiveness: cultivated and feral radish (Raphanus sativus L.) as a case study

PREMISECrop-wild/weed hybrids usually exhibit intermediate and maladapted phenotypes compared to their parents; however, hybridization has sometimes been associated with increased fitness, potentially leading to enhanced weediness and invasiveness. Since the ecological context and maternal genetic effects may affect hybrid fitness, they could influence the evolutionary outcomes of hybridization. Here, we evaluated the performance of first-generation crop-weed hybrids of Raphanus sativus L. and their parents under two contrasting ecological conditions. METHODSUsing experimental hybridization and common garden experiments under field conditions, we assessed the differences in time to flowering, survival to maturity, plant biomass and reproductive components between bidirectional crop-weed hybrids and their parents, under two contrasting ecological conditions, agrestal (wheat cultivation, fertilization, weeding) and ruderal (human-disturbed uncultivated area) over two years. RESULTSCrop, weeds and bidirectional hybrids overlapped -at least partially-during the flowering period, indicating a high probability of gene flow. Hybrids survived to maturity at rates at least as successful as their parents and showed higher plant biomass and fecundity, which resulted in higher fitness compared to their parents in both contrasting environments, without any differences associated with the direction of the hybridization. CONCLUSIONSIntraspecific crop-weed hybridization, regardless of the cross direction, has the potential to promote weediness in weedy R. sativus both in agrestal and ruderal environments, increasing the chances of the introgression of crop alleles into weed populations. This is the first report of intraspecific crop-weed hybridization in R. sativus.

evolutionary biology↗

bioRxiv2023

Folate-based in vivo reprogramming of dentate gyrus improves cognitive function in old mice

In this work, we have studied the effect of small compounds in the partial rejuvenation of dentate gyrus cells by measuring the improvement of cognitive functions in elderly mice. Aging has been related to a change in DNA methylation and some one-carbon metabolites linked to that methylation process, like vitamin B12, folate or methionine have been involved in cognitive performance during aging. However, their role in this process and the possible mechanisms behind its cognitive effects are still unclear. Through direct infusion of these molecules in the dentate gyrus we have tested their effects on cognition in elderly mice. Only positive results were found for folate. A partial rejuvenation of dentate gyrus cells related to an increase in neuroplasticity by reorganizing extracellular matrix structures and rising the expression of juvenile genes like GluN2B was found. Since folate is involved in several cellular pathways in addition to DNA methylation, we have focused in its interaction with its folate receptor alpha (FR), a protein that is present at the cell nucleus, acting as transcription factor. We have found that most of folate effects on brain would be mediated by the activation of FR. In addition, we propose that the mechanism for cell rejuvenation by folate, or other FR binding molecules, may involve the expression of proteins, like SOX2, a Yamanaka factor present in young neurons. Thus, the use of molecules that activate the FR pathway could constitute an interesting strategy to be considered for the study of brain rejuvenation.

neuroscience↗

bioRxiv2022

Persistence of cultivar alleles in wild carrot (Daucus carota L.) populations in the United States

Cultivated species and their wild relatives often hybridize in the wild and crop-wild hybrids can survive and reproduce in some environments. However, it is unclear whether crop alleles are permanently incorporated into the wild genomes in the long run or whether they are purged by natural selection. This question is key to accurately assessing the risk of escape and spread of cultivar genes into wild populations. Here, we use genomic data and population genomic methods to study hybridization and introgression between cultivated and wild carrots (Daucus carota L.) in the United States. We used single nucleotide polymorphisms (SNPs) obtained via genotyping by sequencing for 450 wild individuals from 29 wild georeferenced populations in seven states and 144 cultivars from the United States, Europe, and Asia. Cultivated and wild carrots formed two well differentiated groups, and evidence of crop-wild admixture was detected in several but not all the wild populations in the United States. Two regions were identified where cultivar alleles were introgressed into wild carrots: California and the Nantucket Island, in Massachusetts. In these areas, we found no support for adaptive (or maladaptive) introgression, instead, most crop alleles seemed to be neutral. Surprisingly, there was no evidence of introgression in some populations with a long-known history of sympatry with the crop, suggesting that post-hybridization barriers might prevent introgression in some areas. Further studies are needed to better delineate the geographic patterns of introgression, but our results support the introgression and persistence of cultivar genes in wild carrot populations.

evolutionary biology↗

bioRxiv2021

Rapid evolution of weedy traits during sunflower de-domestication: the importance of hybridization and standing genetic variation

Hybridization between crops and their wild relatives may promote the evolution of de-domesticated (feral) weeds. Wild sunflower (Helianthus annuus L.) is typically found in ruderal environments, but crop-wild hybridization may facilitate the evolution of weedy populations. Using one crop-specific mitochondrial marker (CMS-PET1) and 14 nuclear SSR markers, we studied the origin and genetic diversity of a recently discovered weedy population of sunflower (named BRW). Then, using a resurrection approach, we tested for rapid evolution of weedy traits (seed dormancy, herbicide resistance, and competitive ability) by sampling weedy and wild populations 10 years apart (2007 and 2017). All the weedy plants present the CMS-PET1 cytotype, confirming their feral origin. At the nuclear markers, BRW showed higher genetic diversity than the cultivated lines and low differentiation with one wild population, suggesting that wild hybridization increased their genetic diversity. We found support for rapid evolution towards higher seed dormancy, but not for higher competitive ability or herbicide resistance. Our results highlight the importance of seed dormancy during the earliest stages of adaptation and show that crop-wild hybrids can evolve quickly in agricultural environments.

plant biology↗

bioRxiv2020

Ecological fitness cost associated with the AHAS Trp574Leu mutation in feral Raphanus sativus

Gene mutations endowing herbicide resistance may have negative pleiotropic effects on plant fitness. Quantifying these effects is critical for predicting the evolution of herbicide resistance and developing management strategies for herbicide-resistant weeds. This study reports the effects of the acetohydroxyacid synthase (AHAS) Trp574Leu mutation throughout the life cycle of the weed feral radish (Raphanus sativus L.). Resistant and susceptible biotypes responded differently to light and water treatments in relation to germination and emergence. Under light exposure, the resistant biotype showed higher germination and emergence, but no differences were found in seed dormancy, germination in darkness and emergence from buried seeds or pods. The resistant biotype showed delayed and reduced seedling emergence relative to the susceptible biotype under rainfed conditions, but these differences between the biotypes were not detected in irrigated soil. The biotypes showed similar relative growth rates and vegetative biomass. However, under wheat interference, resistant plants had 36-46% less total above-ground biomass, 26-47% less seeds per plant, and 36-53% less plant yield than susceptible ones, and these differences were more evident at higher plant density. This study provides a better understanding of the ecological fitness cost associated with the AHAS Trp574Leu mutation in feral R. sativus. The fitness costs could reduce the frequency of the resistant allele in areas untreated with AHAS inhibiting herbicides.

evolutionary biology↗

bioRxiv2020

Maternal control of early life history traits affects overwinter survival and seedling phenotypes in sunflower (Helianthus annuus L.)

When cultivated and wild plants hybridize, hybrids often show intermediate phenotypic traits relative to their parents, which make them unfit in natural environments. However, maternal genetic effects may affect the outcome of hybridization by controlling the expression of the earliest life history traits. Here, using wild, cultivated, and reciprocal crop-wild sunflower (Helianthus annuus L.) hybrids, we evaluated the maternal effects on emergence timing and seedling establishment in the field, and on seedling traits under controlled conditions. In the field, we evaluated reciprocal crop-wild hybrids between two wild populations with contrasting dormancy (the high dormant BAR and the low dormant DIA) and one cultivar (CROP) with low dormancy. Under controlled conditions, we evaluated reciprocal crop-wild hybrids between two wild populations (BAR and RCU) and one CROP under three contrasting temperature treatments. In the field, BAR overwintered as dormant seeds whereas DIA and CROP showed high autumn emergence ([~]50% of planted seeds), resulting in differential overwinter survival and seedling establishment in the spring. Reciprocal crop-wild hybrids resembled their female parents in emergence timing and success of seedling establishment. Under controlled conditions, we observed large maternal effects on most seedling traits across temperatures. Cotyledon size explained most of the variation in seedling traits, suggesting that the maternal effects on seed size have cascading effects on seedling traits. Maternal effects on early life history traits affect early plant survival and phenotypic variation of crop-wild hybrids, thus, they should be addressed in hybridization studies, especially those involving highly divergent parents like cultivated species and their wild ancestors.

plant biology↗