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bioRxiv2022

Invasive genetic rescue: Dispersal following repeated culling reinforces the genetic diversity of an invasive mammal

Since its introduction from the United States in 1876 the invasive North American Eastern grey squirrel (Sciurus carolinensis) has contributed to the decline of the native Eurasian red squirrel (Sciurus vulgaris) in Britain. Consequently, grey squirrel populations are often subjected to extensive control efforts in order to reduce local abundance and prevent spread, particularly within habitats containing red squirrels. Grey squirrel removal from the island of Anglesey off the coast of north Wales began in 1998 and was completed in 2013. A parallel successful red squirrel reinforcement translocation project also took place. The narrow sea-channel, road and rail bridge connection has meant that the adjacent mainland grey squirrel population has been controlled in subsequent years to reduce the probability of re-invasion. The aim of this study was to assess the overall impact of repeated culling efforts carried out between 2011 and 2020 on the genetic diversity of the grey squirrel population in north Wales to inform future adaptive management plans. Using a combination of mitochondrial DNA (mtDNA) and microsatellite DNA analysis, we found high genetic diversity in both marker types, with six diverse mtDNA haplotypes found and relatively high levels of nuclear genetic diversity, even after repeated culling efforts. Our results suggest that ongoing culling efforts may not adequately reduce genetic diversity to a level where it contributes to a long-term population decline.

ecology↗

bioRxiv2022

Genetic architecture of acute hyperthermia resistance in juvenile rainbow trout (Oncorhynchus mykiss) and genetic correlations with production traits

BackgroundSelective breeding is a promising solution to reduce fish farms vulnerability to heat peaks which intensity and frequency are predicted to increase due to climate change. However, limited information about the genetic architecture of acute hyperthermia resistance in fish is available. Two batches of sibs from a rainbow trout commercial line were produced. The first batch (N=1,382) was phenotyped for acute hyperthermia resistance at nine months, and the second batch (N=1,506) was phenotyped for main production traits (growth, body length, muscle fat content and carcass yield) at twenty months. Fish were genotyped on a 57K SNP array, and their genotypes were imputed at high-density thanks to their parents being genotyped on a 665K SNP array. ResultsThe heritability estimate of resistance to acute hyperthermia in juveniles was 0.29 {+/-} 0.05, confirming the potential of selective breeding for this trait. Genetic correlations between acute hyperthermia resistance and main production traits at near harvest age were all close to zero. Hence, selecting for acute hyperthermia resistance should not impact the main production traits, and reversely. The genome-wide association study revealed that resistance to acute hyperthermia is highly polygenic; altogether, the six detected QTL explained less than 5% of the genetic variance. Two of these QTL, including the most significant one, might explain acute hyperthermia resistance differences across INRAE isogenic lines of rainbow trout. The phenotypic mean differences between homozygotes at peak SNP were up to 69% of the phenotypic standard deviation, showing promising potential for marker-assisted selection. We identified 89 candidate genes within the six QTL regions, among which the most convincing functional candidate genes were dnajc7, hsp70b, nkiras2, cdk12, phb, fkbp10, ddx5, cygb1, enpp7, pdhx and acly. ConclusionsThis study provides valuable insight on the genetic architecture of acute hyperthermia resistance in juvenile rainbow trout. The potential for the selective breeding of this trait was shown to be substantial and should not interfere with selection for main production traits. Identified functional candidate genes give a new insight on physiological mechanisms involved in acute hyperthermia resistance, such as protein chaperoning, oxidative stress response, homeostasis maintenance and cell survival.

genomics↗

bioRxiv2023

A diverse panel of 755 bread wheat accessions harbors untapped genetic diversity in landraces and reveals novel genetic regions conferring powdery mildew resistance

Wheat breeding for disease resistance relies on the availability and use of diverse genetic resources. More than 800,000 wheat accessions are globally conserved in gene banks, but they are mostly uncharacterized for the presence of resistance genes and their potential for agriculture. Based on the selective reduction of previously assembled collections for allele mining for disease resistance, we assembled a trait-customized panel of 755 geographically diverse bread wheat accessions with a focus on landraces, called the LandracePLUS panel. Population structure analysis of this panel based on the TaBW35K SNP array revealed an increased genetic diversity compared to 632 landraces genotyped in an earlier study and 17 high-quality sequenced wheat accessions. The additional genetic diversity found here mostly originated from Turkish, Iranian and Pakistani landraces. We characterized the LandracePLUS panel for resistance to ten diverse isolates of the fungal pathogen powdery mildew. Performing genome-wide association studies and dividing the panel further by a targeted subsetting approach for accessions of distinct geographical origin, we detected several known and already cloned genes, including the Pm2a gene. In addition, we identified 22 putatively novel powdery mildew resistance loci that represent useful sources for resistance breeding and for research on the mildew-wheat pathosystem. Our study shows the value of assembling trait-customized collections and utilizing a diverse range of pathogen races to detect novel loci. It further highlights the importance of integrating landraces of different geographical origins into future diversity studies. Key MessageA bread wheat panel reveals rich genetic diversity in Turkish, Pakistani, and Iranian landraces and novel resistance loci to diverse powdery mildew isolates via subsetting approaches in association studies.

plant biology↗

bioRxiv2024

Genetic and phenotypic characterization of global Lupinus albus genetic resources for the development of a CORE collection

Lupinus albus is a food grain legume recognized for its high levels of seed protein (30-40%) and oil (6-13%), and its adaptability to different climatic and soil conditions. To develop the next generation of L. albus cultivars, we need access to well-characterized, genetically and phenotypically diverse germplasm. Here we evaluated more than 2000 L. albus accessions with passport data based on 35 agro-morphological traits to develop Intelligent CORE Collections. The reference CORE (R-CORE), representing global diversity, exemplified the genotypic variation of cultivars, breeding/research materials, landraces and wild relatives. A subset of 300 R-CORE accessions was selected as a training CORE (T-CORE), representing the diversity in the entire collection. We divided the L. albus R-CORE into four phenotypic groups (A1, A2, A3 and B) based on principal component analysis, with groups A3 and B distinguished by pod shattering and seed ornamentation, respectively. The coefficient of additive genetic variation differed across morphological traits, phenotypic groups, geographic regions, and according to biological status. These CORE collections will facilitate agricultural research by identifying the genes responsible for desirable traits in crop improvement programs, and by shedding light on the use of orphan genetic resources for origin and domestication studies in L. albus. Understanding the variation in these genetic resources will allow us to develop sustainable tools and technologies that address global challenges such as providing healthy and sustainable diets for all, and contrasting the current climate change crisis.

plant biology↗

bioRxiv2025

Museum genomics reveals temporal genetic stasis and global genetic diversity in Arabidopsis thaliana

Global patterns of population genetic variation through time offer a window into evolutionary processes that maintain diversity. Over time, lineages may expand or contract their distribution, causing turnover in population genetic composition. At individual loci, migration, drift, and selection (among other processes) may affect allele frequencies. Museum specimens of widely distributed species offer a unique window into the genetics of understudied populations and changes over time. Here, we sequenced genomes of 130 herbarium specimens and 91 new field collections of Arabidopsis thaliana and combined these with published genomes. We sought a broader view of genomic diversity across the species, and to test if population genomic composition is changing through time. We documented extensive and previously uncharacterized diversity in a range of populations in Africa, populations that are under threat from anthropogenic climate change. Through time, we did not find dramatic changes in genomic composition of populations. Instead, we found a pattern of genetic change every 100 years of the same magnitude seen when comparing Eurasian populations that are 185 km apart, potentially due to a combination of drift and changing selection. We found only mixed signals of polygenic adaptation at phenology and physiology QTL. We did find that genes conserved across eudicots show altered levels of directional allele frequency change, potentially due to variable purifying and background selection. Our study highlights how museum specimens can reveal new dimensions of population diversity and show how wild populations are evolving in recent history.

evolutionary biology↗

bioRxiv2025

Genetic architecture of the red blood cell proteome in genetically diverse mice reveals central role of hemoglobin beta cysteine redox status in maintaining circulating glutathione pools

Red blood cells (RBCs) transport oxygen but accumulate oxidative damage over time, reducing function in vivo and during storage--critical for transfusions. To explore genetic influences on RBC resilience, we profiled proteins, metabolites, and lipids from fresh and stored RBCs obtained from 350 genetically diverse mice. Our analysis identified over 6,000 quantitative trait loci (QTL). Compared to other tissues, prevalence of trans genetic effects over cis reflects the absence of de novo protein synthesis in anucleated RBCs. QTL hotspots at Hbb, Hba, Mon1a, and storage-specific Steap3 linked ferroptosis to hemolysis. Proteasome components clustered at multiple loci, underscoring the importance of degrading oxidized proteins. Post-translational modifications (PTMs) mapped predominantly to hemoglobins, particularly cysteine residues. Loss of reactive C93 in humanized mice (HBB C93A) disrupted redox balance, affecting glutathione pools, protein glutathionylation, and redox PTMs. These findings highlight genetic regulation of RBC oxidation, with implications for transfusion biology and oxidative stress-dependent hemolytic disorders. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/640676v1_ufig1.gif" ALT="Figure 1"> View larger version (98K): org.highwire.dtl.DTLVardef@14a3cc2org.highwire.dtl.DTLVardef@daf8b4org.highwire.dtl.DTLVardef@1fe306forg.highwire.dtl.DTLVardef@11de734_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2025

Fighting to persist: Genetic rescue increases long-term fitness despite elevated genetic load

Genetic rescue (GR) can restore fitness in small genetically depauperate populations, however, long-term effectiveness, impact of rescuer quality and introduced deleterious load on population persistence remains uncertain. Using a male-dimorphic mite we tested whether a condition-dependent sexually selected trait influences GR. Genome-wide diversity and genetic load increased similarly for both morphs, while population fitness trajectories differed, suggesting that genetic quality is associated with the trait. Overall, GR sustained fitness benefits over 20 generations. The benefits persisted under thermal stress lowering extinction risk regardless of the rescuers morph and introduced load indicating their minimal importance. These results provide experimental evidence that maximising genome-wide variation via GR can yield lasting benefits, even when many deleterious mutations are introduced to populations facing environmental change.

evolutionary biology↗

bioRxiv2018

Master regulators of genetic interaction networks mediating statin drug response in Saccharomyces cerevisiae vary with genetic background

Determination of genetic interaction networks (GINs) surrounding drug targets identifies buffering genes and provides molecular insight into drug response in individuals. Here we used backcross methodology to create Saccharomyces cerevisiae deletion libraries in three genetic backgrounds resistant to statins, which are additional to the statin-sensitive S288C deletion library that has provided much of what is known about GINs in eukaryotes. Whole genome sequencing and linkage group analysis confirmed the genomic authenticity of the new deletion libraries. Statin response was probed by drug-gene interactions with atorvastatin and cerivastatin treatments, as well as gene-gene interactions with the statin target HMG1 and HMG2 genes or the sterol homeostatic ARV1 gene. The 20 GINs generated from these interactions were not conserved by function or topology across the four genetic backgrounds. Centrality measures and hierarchical agglomerative clustering identified master regulators that if removed collapsed the networks. Community structure distinguished a characteristic early secretory pathway pattern of gene usage in each genetic background. ER stress in statin-resistant backgrounds was buffered by protein folding genes, which was confirmed by reduced activation of the unfolded protein response in statin-resistant backgrounds relative to the statin-sensitive S288C background. These network analyses of new gene deletion libraries provide insight into the complexity of GINs underlying individual drug response.

systems biology↗

bioRxiv2019

Estimating genetic and non-genetic effects for host susceptibility, infectivity and recoverability using temporal epidemic data

Individuals differ widely in their contribution to the spread of infection within and across populations. Three key epidemiological host traits affect infectious disease spread: susceptibility (propensity to acquire infection), infectivity (propensity to transmit infection to others) and recoverability (propensity to recover quickly). Interventions aiming to reduce disease spread may target improvement in any one of these traits, but the necessary statistical methods for obtaining risk estimates are lacking. In this paper we introduce a novel software tool called SIRE (standing for "Susceptibility, Infectivity and Recoverability Estimation"), which allows simultaneous estimation of the genetic effect of a single nucleotide polymorphism (SNP), as well as non-genetic influences on these three unobservable host traits. SIRE implements a flexible Bayesian algorithm which accommodates a wide range of disease surveillance data comprising any combination of recorded individual infection and/or recovery times, or disease status measurements. Different genetic and non-genetic regulations and data scenarios (representing realistic recording schemes) were simulated to validate SIRE and to assess their impact on the precision, accuracy and bias of parameter estimates. This analysis revealed that with few exceptions, SIRE provides unbiased, accurate parameter estimates associated with all three host traits. For most scenarios, SNP effects associated with recoverability can be estimated with highest precision, followed by susceptibility. For infectivity, many epidemics with few individuals give substantially more statistical power to identify SNP effects than the reverse. Importantly, precise estimates of SNP and other effects could be obtained even in the case of incomplete, censored and relatively infrequent measurements of individuals infection or survival status, albeit requiring more individuals to yield equivalent precision. SIRE represents a new tool for analysing a wide range of experimental and field disease data with the aim of discovering and validating SNPs and other factors controlling infectious disease transmission.

epidemiology↗

bioRxiv2026

A Chemical-Genetic Interaction Matrix Reveals Drug Mechanism and Genetic Architecture

To probe drug mechanism of action (MOA) and interrogate the genetic architecture of human cells, we carried out isogenic genome-wide CRISPR/Cas9 knockout screens against 310 diverse drugs, bioactive compounds, and stress conditions. Stringent statistical correction for gene knockout fitness defects yielded a large-scale matrix of >12,000 high confidence chemical-genetic interactions (CGIs). This dataset revealed many previously unappreciated off-target effects for well-characterized compounds and novel MOAs for uncharacterized compounds. The CGI matrix uncovered dense genetic modules that yielded new biological insights into phospholipidosis, mitotic regulation, metabolism, the DNA damage response, and mTOR signaling. The dataset allowed identification of multi-drug sensitization and resistance mechanisms, inference of gene function, elaboration of cross-process connectivity, evaluation of the cell type specificity of CGIs, prediction of chemical synergism, and extensive annotation of understudied genes. This resource provides a map of the genetic landscape in human cells and a framework to help guide drug discovery.

systems biology↗

bioRxiv2020

Levels of genetic diversity of SARS-CoV-2 virus: reducing speculations about the genetic variability of the virus in South America

In this work, we evaluated the levels of genetic diversity in 38 complete Genomes of SARS-CoV-2 from six countries in South America, using specific methodologies for paired FST, AMOVA, mismatch, demographic and spatial expansions, molecular diversity and for the time of evolutionary divergence. The analyses showed non-significant evolutionary divergences within and between the six countries, as well as a significant similarity to the time of genetic evolutionary divergence between all populations. Thus, it seems safe to affirm that we will find similar results for the other Countries of South America, reducing speculation about the existence of rapid and silent mutations that, although there are as we have shown in this work, do not increase, until this moment, the genetic variability of the Virus, a fact that would hinder the work with molecular targets for vaccines and drugs in general.

genetics↗

bioRxiv2021

High-resolution genetic mapping of the mucosa-associated gut microbiome in hybrid mice provides novel insight on the impact of host genetics

Determining the forces that shape diversity in host-associated bacterial communities is critical to understanding the evolution and maintenance of metaorganisms. To gain deeper understanding of the role of host genetics in shaping gut microbial traits, we employed a powerful genetic mapping approach using inbred lines derived from the hybrid zone of two incipient house mouse species. Further, we uniquely performed our analysis on microbial traits measured at the gut mucosal interface, which is in more direct contact with host cells and the immune system. A high number of mucosa-associated bacterial taxa have significant heritability estimates; heritabilities are greater for 16S rRNA transcript-compared to gene copy-based traits, and interestingly, are positively correlated with cospeciation rate estimates. Genomewide association mapping identifies 443 loci influencing 123 taxa, with narrow genomic intervals pinpointing promising candidate genes and pathways. Importantly, we identified an enrichment of candidate genes associated with several human diseases, including inflammatory bowel disease, and functional categories including innate immunity and G-protein-coupled receptors. These results highlight key features of the genetic architecture of mammalian host-microbe interactions and how they diverge as new species form.

genetics↗

bioRxiv2022

Genetics of Fertility Restoration in A1 Cytoplasmic Genetic Male Sterility (CGMS) Systems in Sorghum (Sorghum bicolor L. Moench)

The cause of Cytoplasmic Genetic Male Sterility (CGMS) is specific nuclear and mitochondrial interactions. Almost all commercial sorghum hybrids were developed using the A1 cytoplasmic genetic male sterility system. Understanding the inheritance of fertility restoration in sorghum for A1 cytoplasm, for example, can improve the selection efficiency of restorer lines for increased seed production. In a cross of male sterile line 296A with A1 cytoplasm and restorer lines comprised of a set of Recombinant Inbred Lines (RILs), the inheritance pattern of fertility restoration of sorghum was studied. The F1 hybrid was completely fertile, revealing the dominant nature of fertility restoration, which is controlled by one or two major genes with modifiers. In this study, the genetics of fertility restoration of the A1 cytoplasmic nuclear male sterility system (CGMS) in sorghum were investigated in segregating F2 and BC1 populations of A1 cytoplasm crosses. Fertility restoration was governed by a monogenic inheritance (3F:1S) mechanism represented by a single dominant gene responsible for fertility restoration in all of the crosses studied.

genetics↗

bioRxiv2022

Quantifying portable genetic effects and improving cross-ancestry genetic prediction with GWAS summary statistics

Polygenic risk scores (PRS) calculated from genome-wide association studies (GWAS) of Europeans are known to have substantially reduced predictive accuracy in non-European populations, limiting its clinical utility and raising concerns about health disparities across ancestral populations. Here, we introduce a novel statistical framework named X-Wing to improve predictive performance in ancestrally diverse populations. X-Wing quantifies local genetic correlations for complex traits between populations, employs a novel annotation-dependent estimation procedure to amplify correlated genetic effects between populations, and combines multiple population-specific PRS into a unified score with GWAS summary statistics alone as input. Through extensive benchmarking, we demonstrate that X-Wing pinpoints portable genetic effects and substantially improves PRS performance in non-European populations, showing 18.7%-122.1% gain in predictive R2 compared to state-of-the-art methods based on GWAS summary statistics. Overall, X-Wing addresses critical limitations in existing approaches and may have broad applications in cross-population polygenic prediction.

genetics↗

bioRxiv2022

Ts66Yah, a refined Ts65Dn DS mouse model, unravels genetic interaction between regions homologous to Human chromosome 21 and the Scaf8-Pde10a genetic interval.

Down syndrome is caused by trisomy of human chromosome 21 (Hsa21). The understanding of phenotype-genotype relationships, the identification of driver genes and various proof-of-concepts for therapeutics have benefited from mouse models. The premier model, named Ts(1716)65Dn/J (Ts65Dn), displayed phenotypes related to the human DS features. It carries an additional minichromosome with the Mir155 to Zbtb21 region of mouse chromosome 16 (Mmu16), homologous to Hsa21, encompassing around 90 genes, fused to the centromeric part of mouse chromosome 17 (Mmu17) fromPisd-ps2/Scaf8 to Pde10a, containing 46 genes, not related to Hsa21. Here, we report the investigation of a new model, Ts66Yah, generated by CrispR/Cas9 without the genomic region unrelated to Hsa21 on the minichromosome. As expected, Ts66Yah replicated DS cognitive features. However, certain phenotypes related to increased activity, spatial learning and molecular signatures, were changed suggesting genetic interactions between the Mir155-Zbtb21 and the Scaf8-Pde10a interval. Thus, Ts66Yah mice have a stronger construct and face validity for mimicking consequences of DS genetic overdosage. Furthermore, this report is the first to demonstrate genetic interactions between triplicated regions homologous to Hsa21 and others unrelated to Hsa21.

genetics↗

bioRxiv2023

A reduced SNP panel optimised for non-invasive genetic assessment of a genetically impoverished conservation icon, the European bison

The European bison was saved from the brink of extinction due to considerable conservation efforts since the early 20th century. The current global population of > 9,500 individuals is the result of successful ex situ breeding based on a stock of only 12 founders, resulting in an extremely low level of genetic variability. Due to the low allelic diversity, traditional molecular tools, such as microsatellites, fail to provide sufficient resolution for accurate genetic assessments in European bison, let alone from non-invasive samples. Here, we present a SNP panel for accurate high-resolution genotyping of European bison, which is suitable for a wide variety of sample types. The panel accommodates 96 markers allowing for individual and parental assignment, sex determination, breeding line discrimination, and cross-species detection. Two applications were shown to be utilisable in further Bos species with potential conservation significance. The new SNP panel will allow to tackle crucial tasks in European bison conservation, including the genetic monitoring of reintroduced populations, and a molecular assessment of pedigree data documented in the worlds first studbook of a threatened species.

genetics↗

bioRxiv2018

Long term context dependent genetic adaptation of the viral genetic cloud

RNA viruses generate a cloud of genetic variants within each host. This cloud contains high frequency genotypes, and a very large number of rare variants. While the dynamics of frequent variants are affected by the fitness of each variant, the rare variants cloud is affected by more complex genetic factors, including context dependent mutations. It serves as a spearhead for the viral populations movement within the adaptive landscape. We here use an experimental evolution system to show that the genetic cloud surrounding the Coxsackie virus master sequence slowly, but steadily, evolves over hundreds of generations. The evolution of the rare variants cloud often precedes the appearance of high frequency variants. The rare variants clouds evolution is driven by a combination of a context-dependent mutation pattern and selection for and against specific nucleotide compositions.This combination affects the mutated dinucleotide distribution, and eventually leads to a non-uniform dinucleotide distribution in the main viral sequence. We then tested these conclusions on other RNA viruses with similar conclusions.

genetics↗

bioRxiv2018

Powerful and Efficient Strategies for Genetic Association Testing of Symptom and Questionnaire Data in Psychiatric Genetic Studies

Genetic studies of psychiatric disorders often deal with phenotypes that are not directly measurable. Instead, researchers rely on multivariate symptom data from questionnaires and surveys like the PTSD Symptom Scale (PSS) and Beck Depression Inventory (BDI) to indirectly assess a latent phenotype of interest. Researchers subsequently collapse such multivariate questionnaire data into a univariate outcome to represent a surrogate for the latent phenotype. However, when a causal variant is only associated with a subset of collapsed symptoms, the effect will be challenging to detect using the univariate outcome. We describe a more powerful strategy for genetic association testing in this situation that jointly analyzes the original multivariate symptom data collectively using a statistical framework that compares similarity in multivariate symptom-scale data from questionnaires to similarity in common genetic variants across a gene. We use simulated data to demonstrate this strategy provides substantially increased power over standard approaches that collapse questionnaire data into a single surrogate outcome. We also illustrate our approach using GWAS data from the Grady Trauma Project and identify genes associated with BDI not identified using standard univariate techniques. The approach is computationally efficient, scales to genome-wide studies, and is applicable to correlated symptom data of arbitrary dimension (thereby aligning with National Institute of Mental Healths Research Domain Criteria).

genetics↗