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bioRxiv2024

Genetic architecture of the thermal tolerance landscape of Drosophila melanogaster

Increased environmental temperatures associated with global warming strongly impact the natural populations of ectothermic species. Therefore, it is crucial to understand the genetic foundations and evolutionary potential of heat tolerance. However, heat tolerance and its genetic components depend on the methodology, making it difficult to predict the adaptive responses to global warming. Here, we measured the knockdown time for 100 lines from the Drosophila Genetic Reference Panel (DGRP) at four different static temperatures, and we estimated their thermal death time (TDT) curves, which incorporate the magnitude and the time of exposure to thermal stress. Through quantitative genetic analyses, it was observed that the knockdown time showed a significant heritability at different temperatures and that its genetic correlations decreased as temperatures were dissimilar. Significant genotype-by-sex and genotype-by-environment interactions were noted for knockdown time. We also discovered heritable variation for the two parameters of TDT: CTmax and thermal sensitivity. Taking advantage of the DGRP, we performed a GWAS and identified multiple variants positively associated with the TDT parameters, which map to genes related to signaling and developmental functions. We performed functional validations for some candidate genes using RNAi, which revealed that genes such as mam, KNCQ, or robo3 affect the knockdown time at a specific temperature but are not associated with the TDT parameters. Ultimately, the thermal tolerance landscape must possess the ability to adapt to the selective pressures caused by global warming. Genetic variation of phenotypic plasticity and sexually antagonistic pleiotropy should also facilitate the adaptive process and maintain the genetic diversity in Drosophila populations.

evolutionary biology↗

bioRxiv2024

Independent genetic mapping experiments identify diverse molecular determinants of host adaptation in a generalist herbivore

Interactions between plants and herbivores promote evolutionary change. Studying the evolution of herbivore mechanisms aimed to cope with diUerent host plant species is a critical intersection between evolutionary biology and sustainable pest management. Generalist herbivores are of particular interest, as hybridization between genetically distinct populations can increase the standing genetic variation and therefore the adaptive potential of the species. Tetranychus urticae is a generalist arthropod known for its adaptive potential, evidenced in its immense host range and ability to develop metabolic resistance to xenobiotics. However, the molecular underpinnings associated with the potential of host adaptation and the consequences of host adaptation in this and many other pests remain elusive. Here, we use two independent, empirical approaches to identify and map the genetic basis of host plant performance and adaptation in genetically distinct populations of T. urticae. In the first approach, we subject a genetically diverse mite population to tomato selection and map genomic regions linked to the phenotypic evolution of increased reproductive performance. In the second approach, we map genomic regions responsible for performance on tomato by comparing the genomes of pooled individuals from a F2 backcross between populations with high and low reproductive performance. Both approaches revealed specific and shared genomic regions associated with host plant performance and adaptation and key candidate genes were identified. Our findings highlight the power of spider mite genetic approaches to identify the complex genetic basis of host adaptation in a generalist herbivore.

evolutionary biology↗

bioRxiv2024

Genetic, natal, and spatial drivers of social phenotypes in wild great tits

In social animals, group dynamics profoundly influence collective behaviours, vital in processes like information sharing and predator vigilance. Disentangling the causes of individual-level variation in social behaviours is crucial for understanding the evolution of sociality. This requires unravelling the genetic and environmental basis of these behaviours, which is challenging in uncontrolled wild populations. In this study, we partitioned genetic, developmental and spatial environmental variation in repeatable social network traits derived from foraging events using a multigenerational pedigree and extensive observational social data from a long-term monitored great tit population. Animal models indicated minimal narrow-sense heritability (2-3%) in group size choice, further reduced when spatial location was considered, which itself explains a substantial 30% of the observed variation. Individual gregariousness also had a small genetic component, with a low heritability estimate for degree (<5%). Centrality showed heritability up to 10% in one of three years sampled, whereas betweenness showed none, indicating modest genetic variation in individual sociability, but not group-switching tendencies. These findings suggest a small, albeit detectable, genetic influence on individual sociality, but pronounced spatial effects. Furthermore, our study highlights the importance of common environment effects (natal origin and brood identity), which essentially negated genetic effects when explicitly accounted for. In addition, we demonstrate that phenotypic resemblance can be a result of similarities beyond shared genes; spatial proximity at birth and natal environmental similarity explained up to 8% of individual sociability. Our results thus emphasise the role of non-genetic factors, particularly developmental and spatial variation, in shaping individual social behavioural tendencies.

ecology↗

bioRxiv2024

Sequencing of historical plastid genomes reveal exceptional genetic diversity in early domesticated rye plants

In medieval central Europe, rye was one of the most important agricultural crops. Its properties of frost resistance, general resilience and resistance to many pathogens made it invaluable for medieval farmers. Rye has a distinct domestication history compared to other cereal crops and was not domesticated directly from its wild ancestors, like barley and wheat. Rye is considered to be a "secondary domesticate", i.e. a crop with domestication traits that initially evolved as an arable weed but eventually was intentionally sown and propagated as a crop. To study the history of rye domestication, genetic sequences of present-day plant populations as well as material from historical samples can provide insights into the temporal and spatial signatures of domestication. In this study we combined archaeobotanical methods and ancient DNA sequencing of well-preserved, historical rye material to study patterns of genetic diversity across four centuries. We first applied archaeobotanical methods to characterize rye material acquired from construction material ranging from the 14th to 18th century from different locations in Germany. Next, we extracted DNA to sequence complete chloroplast genomes of six individual samples. We compared the 115,000 bp chloroplast genomes of historical rye samples to chloroplast genomes of other cereal crops and identified 217 single nucleotide variants exclusive to historical samples. By comparing the aDNA chloroplast samples with modern rye chloroplasts, we show that the genetic variation in ancient rye populations was exceptionally high compared to samples from contemporary rye cultivars. This confirms that late domestication and selective breeding have reduced genetic variation in this important crop species only in the last few centuries. HighlightsO_LIHistorical plant material covering four centuries was obtained from half-timbered houses from five locations in Germany C_LIO_LIIntegrative archaeobotanical analyses and ancient DNA sequencing provided insights into genetic diversity of rye plants from historical farmland fields. C_LIO_LISequence analyses of complete assembled chloroplast genomes reveal expectational diversity in rye populations. C_LIO_LILate domestication of rye preserved genetic diversity over centuries. The more recent intensification of rye breeding has however conferred a considerable loss of genetic diversity in this important crop. C_LI

evolutionary biology↗

bioRxiv2024

Genomic re-sequencing reveals substantial mutational divergence across genetically engineered strains of model archaea

Because archaea are the evolutionary ancestors of eukaryotes, archaeal molecular biology has been a topic of intense recent research. The hypersaline adapted archaeal species Halobacterium salinarum and Haloferax volcanii serve as important model organisms because facile tools enable genetic manipulation. As a result, the number of strains in circulation among the haloarchaeal research community has increased over the last few decades. However, the degree of genetic divergence and effects on genetic integrity during inter-lab transfers remain unclear. To address this question, we performed whole genome re-sequencing on a cross-section of wild-type, parental, and knockout strains in both model species. Integrating these data with existing repositories of re-sequencing data, we identify mutations that have arisen in a collection of 60 strains, sampled from 2 species across 8 different labs. Independent of sequencing, we construct strain lineages, identifying branch points and significant genetic effects in strain history. Combining this with our sequencing data, we identify small clusters of mutations that definitively separate lab strains. Additionally, an analysis of gene knockout strains suggests that roughly 1 in 3 strains currently in use harbors second-site mutations of potential phenotypic impact. Overall, we find that divergence among lab strains is thus far minimal, though as the archaeal research community continues to grow, careful strain provenance and genomic re-sequencing are required to keep inter-lab divergence to a minimum, prevent the compounding of mutations into fully independent lineages, and maintain the current high degree of reproducible research between lab groups in the haloarchaeal research community. Data SummaryNovel sequencing data for this project was submitted to the National Center for Biotechnology Information (NCBI) Sequence Read Archive (SRA) and can be found under bioproject accession PRJNA1120443. SRA accessions for previously published sequencing data are available in supplementary table 1. R code for performing analysis and generating figures is available at https://github.com/andrew-soborowski/halophile_genome_resequencing. Impact StatementArchaea are important due to their shared evolutionary history with eukaryotes. As the archaeal research community grows, keeping track of the genetic integrity of archaeal strains of interest is necessary. In particular, routine genetic manipulations and the common practice of sharing strains between labs allow mutations to arise in lab stocks. If these mutations affect cellular processes, they may jeopardize the reproducibility of work between research groups and confound the results of future studies. In this work, we examine DNA sequences from 60 strains across two species of archaea. We identify shared and unique mutations occurring between and within strains. Independently, we trace the lineage of each strain, identifying which genetic manipulations lead to observed off-target mutations. While overall divergence across labs is minimal so far, our work highlights the need for labs to continue proper strain husbandry.

genomics↗

bioRxiv2024

Genetic differentiation and adaptive evolution of buff-tailed bumblebees in Asia

Bumblebees are ecologically and economically important pollinating insects, so their declines resulting from environmental changes have received intensive attention. Understanding how environmental factors shape the genetic differentiation of natural populations and identifying the genetic basis of local adaptation will provide insights into how species may cope with environmental changes. The buff-tailed bumblebee (Bombus terrestris) has a wide natural distribution range and has been successfully domesticated to produce commercial colonies for greenhouse pollination. Previous population genetics studies on B. terrestris have mainly focused on populations in Europe; however, populations in Asia, representing the eastern side of its natural distribution, have been less thoroughly sampled. To fill this gap, we collected wild B. terrestris samples from Asia, as well as wild B. terrestris from Europe and samples from domesticated colonies. We conducted whole-genome resequencing for 77 collected B. terrestris workers and performed population genomics analysis. Our results revealed significant genetic differentiation (FST= 0.076) between buff-tailed bumblebees in Europe and Asia, along with notable morphological and physiological differences. Consequently, B. terrestris in Asia represents a distinct new genetic resource. Demographic analysis suggested that the population size of buff-tailed bumblebees had increased during historic cold periods, confirming their cold-adapted characteristics. Selective sweep analysis identified 331 genes under selection in the genomes of Asian B. terrestris, likely involved in their adaptation to high ultraviolet radiation, low temperature, and low precipitation in their habitats. Our research provides insights into the population genetic structure and genetic basis of local adaptation in the buff-tailed bumblebee, which will be useful for its conservation and management.

bioinformatics↗

bioRxiv2024

Phylogeographic Insights into Lion Evolution: Unraveling the Genetic Diversity and Lineage Divergence of Panthera leo

This study investigates the genetic diversity and phylogeographic structure of lion populations (Panthera leo) across Africa and Asia, revealing significant insights into their evolutionary history. Our analysis identifies two primary clades: the North Clade comprising Asian and northern African populations identified as Panthera leo leo, and the South Clade containing East and southern African populations identified as Panthera leo melanochaita. We estimate that the lions modern lineage originated approximately 320-280 Kya, with a divergence into the North Clade around 170-130 Kya. The South Clade exhibits a deeper divergence about 290-180 Kya, suggesting a longer history of geographic isolation driven by environmental changes. These dates are older than earlier estimates, owing to new information on the time of divergence between P. leo and P. spelaea. Most famous and referenced studies used 0.55 Mya as the split time between P. leo and P. spelaea as the calibration point for their time calibrated trees but new studies demonstrated that split time between P. leo and P. spelaea is circa 1.89 Mya. Also, our findings indicate that the Indian lineage (Asian haplogroup) represents a genetically distinct group that should not be classified as a separate subspecies, as its genetic differentiation is trivial compared to that between P. l. leo and P. l. melanochaita. The results also indicate higher genetic diversity within P. l. melanochaita, suggesting a stable population structure influenced by historical environmental conditions. In contrast, P. l. leo exhibits lower genetic variability, likely due to recent anthropogenic pressures, including habitat loss and fragmentation. Demographic analyses illustrate a dramatic decline in effective population size starting in the mid-20th century, correlating with the well-documented reduction in lion range. Phylogeographic patterns in lions reflect broader trends in savannah mammals, underscoring the role of historical climatic fluctuations in shaping modern populations. Crucially, our results contest the hypothesis that the Indian lion population was bolstered by sub-Saharan lion introductions, indicating its ancient lineage. These findings highlight the necessity for targeted conservation strategies that consider the genetic and evolutionary context of lion populations, as well as the unique challenges they face in a changing landscape. Overall, this research underscores the importance of integrating genetic data into lion conservation efforts to ensure the long-term survival of this iconic species.

evolutionary biology↗

bioRxiv2024

Gaps in the global protection of terrestrial genetic diversity

In recent decades, increased anthropogenic impact has led to a global decline in genetic diversity. Before the Kunming-Montreal Global Biodiversity Framework (2022), the absence of international consensus on how to directly assess and monitor genetic diversity, hampered large-scale conservation efforts. Scarcity of assessable genetic data has hindered the evaluation of conservation policies in safeguarding genetic diversity. This study presents the first global approach for evaluating the protection of genetic diversity. By examining the global distribution of mammalian intraspecific mitochondrial DNA and protected area coverage, we identify regions with high genetic diversity and insufficient protection coverage, e.g. regions of critical importance for biodiversity in the Brazilian Atlantic Forest. Additionally, we estimate the impact of global change scenarios on genetically diverse regions with a low degree of protection, revealing high vulnerability of areas in Central Africa. Nonetheless, integrating robust analysis into conservation planning remains challenging. Incorporating Macrogenetics into conservation planning holds the potential to reverse biodiversity decline.

ecology↗

bioRxiv2024

Uncovering methylation-dependent genetic effects on regulatory element function in diverse genomes

A major goal in evolutionary biology and biomedicine is to understand the complex interactions between genetic variants, the epigenome, and gene expression. However, the causal relationships between these factors remain poorly understood. mSTARR-seq, a methylation-sensitive massively parallel reporter assay, is capable of identifying methylation-dependent regulatory activity at many thousands of genomic regions simultaneously, and allows for the testing of causal relationships between DNA methylation and gene expression on a region-by-region basis. Here, we developed a multiplexed mSTARR-seq protocol to assay naturally occurring human genetic variation from 25 individuals sampled from 10 localities in Europe and Africa. We identified 6,957 regulatory elements in either the unmethylated or methylated state, and this set was enriched for enhancer and promoter annotations, as expected. The expression of 58% of these regulatory elements was modulated by methylation, which was generally associated with decreased RNA expression. Within our set of regulatory elements, we used allele-specific expression analyses to identify 8,020 sites with genetic effects on gene regulation; further, we found that 42.3% of these genetic effects varied between methylated and unmethylated states. Sites exhibiting methylation-dependent genetic effects were enriched for GWAS and EWAS annotations, implicating them in human disease. Compared to datasets that assay DNA from a single European individual, our multiplexed assay uncovers dramatically more genetic effects and methylation-dependent genetic effects, highlighting the importance of including diverse individuals in assays which aim to understand gene regulatory processes.

genomics↗

bioRxiv2024

Genetic diversity and differentiation of a mycoheterotrophic orchid (Cymbidium macrorhizon) under urbanization

Urbanization exerts substantial pressures on genetic diversity of plant species. However, depending on species-specific life history, the direction/magnitude of urbanization impacts can vary. To elucidate relationships between life history and urbanization effects, there are needs to accumulate the knowledge on genetic diversity/differentiation along urban-rural gradients for species with unique traits. We examined these facets based on genome-wide single nucleotide polymorphisms of a mycoheterotrophic and vegetative-dormant orchid, Cymbidium macrorhizon, for eleven populations in remnant forests along an urban gradient within the Tokyo metropolitan area, Japan. The reduced inbreeding coefficient and increased genetic differentiation were observed with increased proportion of surrounding urban land-use 50 years ago rather than in recent years. This pattern might reflect lowest heterozygosity under intensive urbanization due to population bottleneck and genetic drift due to habitat shrinkage and fragmentation. The significant impacts of past landscape on the indices might indicate time lags of genetic erosion, namely intra-specific extinction debt, due to longevity and dormancy. Therefore, 30% increase of urban land-use since 1970s has not yet affected genetic erosion, resulting in its progression in the future. We emphasize the importance not only to assess genetic diversity but also to connect the assessments with life history and spatiotemporal urbanization impacts.

ecology↗

bioRxiv2024

Genetic ancestry in Puerto Rican Afro-descendants illustrates diverse histories of African diasporic populations

ObjectivesGenetic studies of contemporary Puerto Ricans reflect a demographic history characterized by admixture between Indigenous American, African, and European peoples. While previous studies provide genetic perspectives on the general Puerto Rican population, less is known about the islands sub-populations, specifically Afro-Puerto Ricans. Materials and MethodsIn this study, the genetic ancestry of Afro-Puerto Ricans is characterized and compared to other Caribbean populations. Thirty DNA samples collected among self-identified Puerto Ricans of African descent in Loiza (n=2), Pinones (n=13), San Juan (n=2), Mayaguez (n=9), and Ponce (n=4), were genotyped at 750,000 loci on the National Geographic Genochip. We then applied unsupervised clustering and dimensionality-reduction methods to detect continental and subcontinental African and European genetic ancestry patterns. ResultsAdmixture analyses reveal that on average, the largest genetic ancestry component for Afro-Puerto Ricans is African in origin, followed by European and Indigenous American genetic ancestry components. African biogeographic origins of Afro-Puerto Ricans align most closely with contemporary peoples of Lower Guinea and the Bight of Biafra, while the European genetic ancestry component is most similar to contemporary Iberian, Italian, and Basque populations. These findings contrast with the biogeographic origins of comparative Barbadian and Puerto Rican populations. DiscussionOur results suggest that while there are similarities in general patterns of genetic ancestry among African descendants in the Caribbean, there is previously unrecognized regional heterogeneity, including among Puerto Rican sub-populations. These results are also consistent with available historical sources, while providing depth absent from the documentary record, particularly with regard to African ancestry.

genomics↗

bioRxiv2024

Genotype inference from aggregated chromatin accessibility data reveals genetic regulatory mechanisms

BackgroundUnderstanding the genetic causes for variability in chromatin accessibility can shed light on the molecular mechanisms through which genetic variants may affect complex traits. Thousands of ATAC-seq samples have been collected that hold information about chromatin accessibility across diverse cell types and contexts, but most of these are not paired with genetic information and come from diverse distinct projects and laboratories. ResultsWe report here joint genotyping, chromatin accessibility peak calling, and discovery of quantitative trait loci which influence chromatin accessibility (caQTLs), demonstrating the capability of performing caQTL analysis on a large scale in a diverse sample set without pre-existing genotype information. Using 10,293 profiling samples representing 1,454 unique donor individuals across 653 studies from public databases, we catalog 23,381 caQTLs in total. After joint discovery analysis, we cluster samples based on accessible chromatin profiles to identify context-specific caQTLs. We find that caQTLs are strongly enriched for annotations of gene regulatory elements across diverse cell types and tissues and are often strongly linked with genetic variation associated with changes in expression (eQTLs), indicating that caQTLs can mediate genetic effects on gene expression. We demonstrate sharing of causal variants for chromatin accessibility and diverse complex human traits, enabling a more complete picture of the genetic mechanisms underlying complex human phenotypes. ConclusionsOur work provides a proof of principle for caQTL calling from previously ungenotyped samples, and represents one of the largest, most diverse caQTL resources currently available, informing mechanisms of genetic regulation of gene expression and contribution to disease.

genomics↗

bioRxiv2024

Neural-symbolic hybrid model for myosin complex in cardiac ventriculum decodes structural bases for inheritable heart disease from its genetic encoding

BackgroundHuman ventriculum myosin ({beta}mys) powers contraction sometimes in complex with myosin binding protein C (MYBPC3). The latter regulates {beta}mys activity and impacts overall cardiac function. Nonsynonymous single nucleotide variants (SNVs) change protein sequence in {beta}mys or MYBPC3 causing inheritable heart diseases by affecting the {beta}mys/MYBPC3 complex. Muscle genetics encode instructions for contraction informing native protein construction, functional integration, and inheritable disease impairment. A digital model decodes these instructions and evolves by continuously processing new information content from diverse data modalities in partnership with the human agent. MethodsA general neural-network contraction model characterizes SNV impacts on human health. It rationalizes phenotype and pathogenicity assignment given the SNVs genetic characteristics and in this sense decodes {beta}mys/MYBPC3 complex genetics and implicitly captures ventricular muscle functionality. When a SNV modified domain locates to an inter-protein contact in {beta}mys/MYBPC3 it affects complex coordination. Domains involved, one in {beta}mys and the other in MYBPC3, form coordinated domains (co-domains). Co-domains are bilateral implying potential for their SNV modification probabilities to respond jointly to a common perturbation to reveal their location. Human genetic diversity from the serial founder effect is the common systemic perturbation coupling co-domains that are mapped by a methodology called 2-dimensional correlation genetics (2D-CG). ResultsInterpreting the general neural-network contraction model output involves 2D-CG co-domain mapping that provides natural language expressed structural insights. It aligns machine-learned intelligence from the neural network model with human provided structural insight from the 2D-CG map, and other data from the literature, to form a neural-symbolic hybrid model integrating genetic and protein interaction data into a nascent digital twin. This process is the template for combining new information content from diverse data modalities into a digital model that can evolve. The nascent digital twin interprets SNV implications to discover disease mechanism, can evaluate potential remedies for efficacy, and does so without animal models. HighlightsNeural-symbolic hybrid model decodes muscle genetics into contraction mechanisms And evolves in virtuous cycle Optimize-Interpret-Revise-Repeat aided by human partner Nascent digital twin unravels inheritable disease mechanism without animal models And estimates cardiac phenotype coupling strength to myosin thick-filament structures

bioinformatics↗

bioRxiv2024

Paternal genome elimination, monogenic reproduction, and the evolutionary genetics of atypical sex chromosome systems

Sex chromosomes differ from autosomes in both their ploidy and transmission genetics. Consequently, selection, mutation, and drift may act differently upon them, driving distinct patterns in genetic divergence, diversity, and gene content. Recently, researchers have begun to consider a wider set of organisms with non-standard inheritance and sex-determination systems, however in many cases we lack theory which extends to such cases. One such example is paternal genome elimination (PGE), an unusual reproductive system which has independently evolved in two fly families, the fungus gnats (Sciaridae) and gall midges (Cecidomyiidae), and one order of springtails (Symphypleona). Under PGE, males receive but do not transmit a paternal genome, such that the autosomes and X chromosomes exhibit the same transmission genetics, but with different somatic ploidy. This makes them uniquely suited to test hypotheses about the role of haploid selection in males. Additionally, repeatedly throughout these groups a novel sex determination system - monogeny - has evolved, whereby females produce broods of exclusively one sex. The genetic basis of monogeny partitions the X chromosome into three segments, all displaying distinct inheritance patterns. Here we develop a series of theoretical models adapted to the genetics of these groups, generating testable predictions as to the relative genetic diversity within populations, and divergence between populations. Our results suggest that these species are excellent systems with which to test many fundamental principles in evolutionary genetics.

evolutionary biology↗

bioRxiv2024

Long-term hybridization in a karst window reveals the genetic basis of eye loss in cavefish

Eye loss is a hallmark trait of animals inhabiting perpetual darkness, yet the precise genetic variants underlying this evolutionary change remain largely unknown. The Mexican tetra (Astyanax mexicanus) provides a powerful model for dissecting the genetic basis of eye degeneration, as sighted surface fish and multiple independently evolved blind cave populations remain interfertile; yet despite decades of research and numerous QTL studies, the genetic basis of eye loss has remained unresolved at the level of specific variants. Here, we exploit a rare natural experiment in the Caballo Moro cave, where the collapse of a karst window created a partially illuminated pool inhabited by both fully eyed and completely eyeless cavefish of closely related genetic background. Whole-genome sequencing reveals a long-standing hybrid population between cave and surface lineages, enabling a dramatic refinement of the genetic architecture of eye degeneration to 203 candidate SNPs across 41 genes. Among these, we identified a nonsynonymous mutation in the lens gap-junction protein Connexin-50 (Cx50). CRISPR-based disruption of cx50 induces early eye loss in surface fish, and F2 laboratory crosses confirm genetic linkage between cx50 variants and eye size. Additional Cx50 mutations are present in independent cavefish populations and correlate with reduced eye size. Notably, variants in conserved regions of Cx50 also occur in other cave-dwelling fish and subterranean mammals, suggesting repeated evolutionary targeting of this gene. Introduction of the Caballo Moro mutation into mice causes cataracts and reduced eye and lens size, confirming its functional impact. Together, these findings identify the first SNP directly implicated in cavefish eye loss, demonstrate the power of natural hybrid populations to resolve the genetic basis of complex traits, and reveal Cx50 as a case of molecular convergence in vertebrate eye degeneration.

evolutionary biology↗

bioRxiv2024

An alpine plant shows no decrease in genetic diversity associated with rapid post-glacial range expansion

While range expansion is hypothesized to be a mechanism for species persistence under climate change, many eco-evolutionary models describe demographic and genetic processes during range expansion that may decrease genetic variation and increase genetic load at the leading edge (i.e., expansion load). These predictions are related to dispersal limitation at the leading edge driving colonization dynamics, a scenario common in post-glacial range expansion at the continental scale ([~]20,000 years ago). However, post-glacial range expansion can also occur on contemporary time scales, such as alpine glacier recession following the end of The Little Ice Age ([~]150 years ago) and our understanding of dispersal limitation structuring these instances of rapid range expansion are relatively understudied. Here, we test whether there is evidence supporting the role of dispersal limitation during range expansion following alpine glacier retreat using the native alpine plant Erythranthe (Mimulus) lewisii by examining patterns of neutral genetic diversity (single nucleotide polymorphisms) across the history of glacier recession (i.e., glacier chronosequence) across two glacier forelands in Garibaldi Provincial Park, BC. We find weak support for the prediction of increasing clines in genetic differentiation towards the range edge, and no support for decreasing clines in genetic diversity, suggesting dispersal limitation is not characterizing colonization during range expansion, with the implication that the accumulation of expansion load at the range edge is likely not applicable on these spatiotemporal scales. Together, our results suggest that loss of genetic diversity for range-shifting species in the alpine is likely not a key contributing factor to any decreased fitness over time.

evolutionary biology↗

bioRxiv2024

The AMD-associated genetic polymorphism CFH Y402H confers vulnerability to Hydroquinone-induced stress in iPSC-RPE cells

Age-related macular degeneration (AMD), a degenerative disease of the macula, is caused by an interplay of diverse risk factors (genetic predisposition, age and lifestyle habits). One of the main genetic risks includes the Y402H polymorphism in complement Factor H (FH), an inhibitor of complement system activation. There has been, and continues to be, much discussion around the functional consequences of this Y402H polymorphism, whether the soluble FH protein confers its risk association, or if the cells expressing the protein themselves are affected by the genetic alteration. In our study, we examined the cell characteristics of the retinal pigment epithelium (RPE) cells, which play a major role in retinal homeostasis and stability and which are synonymously linked to AMD. Here, we employ RPE cells derived from induced pluripotent stem cells (iPSC) generated from donors, carrying either homozygous 402Y (low risk) or 402H (high risk) variants of the CFH gene. RPE cells were treated with Hydroquinone (HQ), a component of cigarette smoke, to induce oxidative damage. Intriguingly, RPE cells carrying high genetic risk proved more vulnerable to oxidative insult when exposed to HQ, as demonstrated by increased cytotoxicity, caspase activation, compared to the low-risk RPE cells. The exposure of RPE cells to RPE conditioned medium, normal human serum (NHS) and inactivated NHS (iNHS) had minimal impact on cell cytotoxicity and caspase activation, nor did the presence of purified soluble FH rescue the observed effects. This suggests that the degree of cellular susceptibility to oxidative stress is not conferred by soluble FH protein and other complement sources, but intercellularly because of the corresponding genetic risk predisposition. Considering the known connection of oxidative stress to proteotoxic stress and degrading processes, we investigated the unfolded protein response (UPR) and autophagy. When exposed to HQ, RPE cells showed an increase in autophagy markers, however iPSC-RPE cells carrying high genetic risk showed an overall reduced autophagic flux. Our data support the hypothesis that RPE cells carrying high genetic risk are less resilient to oxidative stress.

cell biology↗

bioRxiv2024

Sparse matrix factorization of GWAS summary statistics robust to sample sharing improves detection and interpretation of factors with diverse genetic architectures

Complex trait-associated genetic variation is highly pleiotropic. This extensive pleiotropy implies that multi-phenotype analyses are informative for characterizing genetic associations, as they facilitate the discovery of trait-shared and trait-specific variants and pathways ("genetic factors"). Previous efforts have estimated genetic factors using matrix factorization (MF) applied to numerous GWAS. However, existing methods are susceptible to spurious factors arising from residual confounding due to sample-sharing in biobank GWAS. Furthermore, MF approaches have historically estimated dense factors, loaded on most traits and variants, that are challenging to map onto interpretable biological pathways. To address these shortcomings, we introduce "GWAS latent embeddings accounting for noise and regularization" (GLEANR), a MF method for detection of sparse genetic factors from summary statistics. GLEANR accounts for sample sharing between studies and uses regularization to estimate a data-driven number of interpretable factors. GLEANR is robust to confounding induced by shared samples and improves the replication of genetic factors derived from distinct biobanks. We used GLEANR to evaluate 137 diverse GWAS from the UK Biobank, identifying 58 factors that decompose the genetic architecture of input traits and have distinct signatures of negative selection and degrees of polygenicity. These sparse factors can be interpreted with respect to disease, cell-type, and pathway enrichment. We highlight three such factors capturing platelet measure phenotypes and enriched for disease-relevant markers corresponding to distinct stages of platelet differentiation. Overall, GLEANR is a powerful tool for discovering both trait-specific and trait-shared pathways underlying complex traits from GWAS summary statistics.

genomics↗