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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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Admix-kit: An Integrated Toolkit and Pipeline for Genetic Analyses of Admixed Populations

SummaryAdmixed populations, with their unique and diverse genetic backgrounds, are often underrepresented in genetic studies. This oversight not only limits our understanding but also exacerbates existing health disparities. One major barrier has been the lack of efficient tools tailored for the special challenges of genetic study of admixed populations. Here, we present admix-kit, an integrated toolkit and pipeline for genetic analyses of admixed populations. Admix-kit implements a suite of methods to facilitate genotype and phenotype simulation, association testing, genetic architecture inference, and polygenic scoring in admixed populations. Availability and implementationAdmix-kit package is open-source and available at https://github.com/KangchengHou/admix-kit. Additionally, users can use the pipeline designed for admixed genotype simulation available at https://github.com/UW-GAC/admix-kit_workflow.

genetics↗

Linking the genetic structure of neuroanatomical phenotypes with psychiatric disorders

There is increasing evidence of shared genetic factors between psychiatric disorders and brain magnetic resonance imaging (MRI) phenotypes. However, deciphering the joint genetic architecture of these outcomes has proven challenging, and new approaches are needed to infer potential genetic structure underlying those phenotypes. Here, we demonstrate how multivariate analyses can help reveal links between MRI phenotypes and psychiatric disorders missed by univariate approaches. We first conducted univariate and multivariate genome-wide association studies (GWAS) for eight MRI-derived brain volume phenotypes in 20K UK Biobank participants. We performed various enrichment analyses to assess whether and how univariate and multitrait approaches can distinguish disorder-associated and non-disorder-associated variants from six psychiatric disorders: bipolarity, attention-deficit/hyperactivity disorder (ADHD), autism, schizophrenia, obsessive-compulsive disorder, and major depressive disorder. Univariate MRI GWAS displayed only negligible genetic correlation with psychiatric disorders at all the levels we investigated. Multitrait GWAS identified multiple new associations and showed significant enrichment for variants related to both ADHD and schizophrenia. We further clustered top associated variants based on their MRI multitrait association using an optimized k-medoids approach and detected two clusters displaying not only enrichment for association with ADHD and schizophrenia, but also consistent direction of effects. Functional annotation analyses pointed to multiple potential mechanisms, suggesting in particular a role of neurotrophin pathways on both MRI and schizophrenia. Altogether our results show that multitrait association signature can be used to infer genetically-driven latent MRI variables associated with psychiatric disorders, opening paths for future biomarker development.

genetics↗

Genetic Discovery Enabled by A Large Language Model

Artificial intelligence (AI) has been used in many areas of medicine, and recently large language models (LLMs) have shown potential utility for clinical applications. However, since we do not know if the use of LLMs can accelerate the pace of genetic discovery, we used data generated from mouse genetic models to investigate this possibility. We examined whether a recently developed specialized LLM (Med-PaLM 2) could analyze sets of candidate genes generated from analysis of murine models of biomedical traits. In response to free-text input, Med-PaLM 2 correctly identified the murine genes that contained experimentally verified causative genetic factors for six biomedical traits, which included susceptibility to diabetes and cataracts. Med-PaLM 2 was also able to analyze a list of genes with high impact alleles, which were identified by comparative analysis of murine genomic sequence data, and it identified a causative murine genetic factor for spontaneous hearing loss. Based upon this Med-PaLM 2 finding, a novel bigenic model for susceptibility to spontaneous hearing loss was developed. These results demonstrate Med-PaLM 2 can analyze gene-phenotype relationships and generate novel hypotheses, which can facilitate genetic discovery.

genetics↗

Cell morphology QTL reveal gene by environment interactions in a genetically diverse cell population

Genetically heterogenous cell lines from laboratory mice are promising tools for population-based screening as they offer power for genetic mapping, and potentially, predictive value for in vivo experimentation in genetically matched individuals. To explore this further, we derived a panel of fibroblast lines from a genetic reference population of laboratory mice (the Diversity Outbred, DO). We then used high-content imaging to capture hundreds of cell morphology traits in cells exposed to the oxidative stress-inducing arsenic metabolite monomethylarsonous acid (MMAIII). We employed dose-response modeling to capture latent parameters of response and we then used these parameters to identify several hundred cell morphology quantitative trait loci (cmQTL). Response cmQTL encompass genes with established associations with cellular responses to arsenic exposure, including Abcc4 and Txnrd1, as well as novel gene candidates like Xrcc2. Moreover, baseline trait cmQTL highlight the influence of natural variation on fundamental aspects of nuclear morphology. We show that the natural variants influencing response include both coding and non-coding variation, and that cmQTL haplotypes can be used to predict response in orthogonal cell lines. Our study sheds light on the major molecular initiating events of oxidative stress that are under genetic regulation, including the NRF2-mediated antioxidant response, cellular detoxification pathways, DNA damage repair response, and cell death trajectories.

genetics↗

Associations between common genetic variants and income provide insights about the socioeconomic health gradient

We conducted a genome-wide association study (GWAS) on income among individuals of European descent and leveraged the results to investigate the socio-economic health gradient (N=668,288). We found 162 genomic loci associated with a common genetic factor underlying various income measures, all with small effect sizes. Our GWAS-derived polygenic index captures 1 - 4% of income variance, with only one-fourth attributed to direct genetic effects. A phenome-wide association study using this polygenic index showed reduced risks for a broad spectrum of diseases, including hypertension, obesity, type 2 diabetes, coronary atherosclerosis, depression, asthma, and back pain. The income factor showed a substantial genetic correlation (0.92, s.e. = .006) with educational attainment (EA). Accounting for EAs genetic overlap with income revealed that the remaining genetic signal for higher income related to better mental health but reduced physical health benefits and increased participation in risky behaviours such as drinking and smoking.

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Quantitative genetics of natural S. cerevisiae strains upon sexual mating reveals heritable determinants of cellular fitness

Quantitative genetics requires large datasets of diverse phenotyped-genotyped strains from the same species. A special need is for such archived biological material and computerized data in sexually reproducing individuals from a species. Here we leverage sexual mating among close to 100 diverse natural isolates of the yeast S. cerevisiae that form about 4,000 hybrids combinations in several ecologically relevant growth conditions. In a first genetic study of this new resource we focus on fitness measurements and its modes of inheritance as a quantitative trait from parents to offspring hybrids. We employ genomic barcoding of all strains and a barcode recombination technique to follow hybrids of each successful mate combination. For all parents, and separately for all offspring hybrids we measure fitness under each condition. We focus on the inheritance of fitness, the ultimate evolutionary trait, and its inheritance as a quantitative trait upon sexual mating. Predicting hybrid fitness given parental parameters is a major challenge as it is likely multi-factorial. We find that hybrids fitness in fermentable carbon source correlates positively, yet modestly, with parental fitness, while on non-fermentable carbon, hybrid fitness shows no detectable correlation with parental fitness. Instead, the non-fermentable condition, hybrid fitness increases sharply with genetic distance between their parents, suggesting that outbreeding maximizes fitness irrespective of parental fitness at that condition. The number of minor alleles in the genome of each hybrid, analogous to polygenic risk score in classical genetics, negatively correlates with fitness in both conditions. Fitness inheritance can be explained by either a dominance or a co-dominance modes of inheritance, in the non-fermentable and fermentable conditions respectively. Our newly suggested biological resource and data provide new foundations for a quantitative research in genetics and evolution upon sexual mating. Furthermore, our barcoded strains and mating tracking method provide an important research resource for the yeast community.

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Genetic diversity within a tree and alternative indexes for different evolutionary effects

Trees, living for centuries, accumulate somatic mutations in their growing trunks and branches, causing genetic divergence within a single tree. Stem cell lineages in a shoot apical meristem accumulate mutations independently and diverge from each other. In plants, somatic mutations can alter the genetic composition of reproductive organs and gametes, impacting future generations. To evaluate the genetic variation among a trees reproductive organs, we consider three indexes: mean pairwise phylogenetic distance [Formula], phylogenetic diversity (PD; sum of branch lengths in molecular phylogeny), and parent-offspring phylogenetic distance (DPO). The tissue architecture of trees facilitated the accumulation of somatic mutations, which have various evolutionary effects, including enhancing fitness under strong sib competition and intense host-pathogen interactions, efficiently eliminating deleterious mutations through epistasis, and increasing genetic variance in the population. Choosing appropriate indexes for the genetic diversity of somatic mutations depends on the specific aspect of evolutionary influence being assessed.

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Complex genetic architecture underlying the plasticity of tobacco leaf width provides insight into across-environment genomic prediction

Phenotypic plasticity refers to the ability of a given genotype to produce multiple phenotypes in response to changing environmental conditions. Understanding the genetic basis of phenotypic plasticity and developing predictive models for agronomic traits are crucial for future agricultural adaptation to climate change. In this study, we investigated the genetic basis of leaf width mean (LWm) and plasticity (LWp) in a tobacco multiparent advanced generation inter-cross (MAGIC) population which consisting of 594 individuals. We identified 14 quantitative trait loci (QTLs) significantly associated with LWm, 43 with LWp. Our findings suggest that dynamic changes in QTL effects across environments, along with polygenic effects, may underlie the genetic basis of leaf width plasticity. Among them, qLW14 was narrowed down to a 3 Mb structural variation region. When this fragment was deleted in tobacco, plants exhibited increased leaf width, but only under specific environmental conditions. This finding suggests that the key gene within qLW14 may act as a negative regulator of leaf width through interactions with specific environmental factors. By integrating genetic diversity, environments variation, and their interactions into a GEAI model, we were able to build a framework for cross-environment prediction, improving prediction accuracy by 8.7% when compared to traditional model. Overall, this study highlights the complex genetic basis underlying LWp, involving multiple alleles and genotype-environment interactions. These findings provide valuable insights into the role of phenotypic plasticity in plant adaptation to environmental changes.

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Confounding of indirect genetic and epigenetic effects

An individuals phenotype reflects a complex interplay of the direct effects of their DNA, epigenetic modifications of their DNA induced by their parents, and indirect effects of their parents DNA. Here, we derive how the genetic variance within a population is changed under the influence of indirect maternal, paternal and parent-of-origin effects under random mating. We also consider indirect effects of a sibling, in particular how the genetic variance is altered when looking at the phenotypic difference between two siblings. The calculations are then extended to include assortative mating (AM), which alters the variance by inducing increased homozygosity and correlations within and across loci. AM likely leads to covariance of parental genetic effects, a measure of the similarity of parents in the indirect effects they have on their children. We propose that this assortment for parental characteristics, where biological parents create similar environments for their children, can create shared parental effects across traits and the appearance of cross-trait AM. Interestingly, the genetic variances is increased under AM for the childmother-father design, while it is decreased for the sibling difference. Our results demonstrate that it is not possible to get unbiased estimates of direct genetic effects without controlling for parental and parent-of-origin effects.

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Chromosome X Dosage Modulates Development of Aneuploidy in Genetically Diverse Mouse Embryonic Stem Cells

The genetic integrity of pluripotent stem cells (PSC) is critical to their applications in research and therapy, but it is compromised by frequent development of structural chromosome variants associated with malignancy. Many cell lines exhibit remarkable genetic stability, but little is known about the basis of the known variation in genomic integrity amongst different PSC isolates. Here we identify aneuploidies using RNA-seq and proteomics data from a panel of mouse embryonic stem cell (mESC) lines derived from 170 Diversity Outbred mice. We found 62 lines with detectable aneuploid subpopulations and a subset of originally XX lines that lost one Chromosome X (XO). Strikingly, a much lower proportion of XX lines were aneuploid, compared to XY or XO lines. Two single-cell RNA-seq data sets demonstrated that aneuploid XY DO mESC also show lower Chromosome X gene expression, and a prospective study confirmed that XY mESC accumulate higher aneuploid proportions in culture than isogenic XX lines. We identify potential mechanisms for this protective effect of X chromosome dosage, including our findings that the lines with two active X Chromosomes have a higher proportion of 2-cell-like cells, a state associated with maintenance of genetic integrity of mESC, and that they show differential expression of X-linked tumor suppressor genes associated with the DNA damage response. HighlightsO_LIFirst genetic analysis of predisposition to aneuploidy in pluripotent stem cell cultures C_LIO_LIChromosomal regions duplicated in aneuploid mouse embryonic stem cells are syntenic with regions overrepresented in human pluripotent stem cell lines bearing recurrent genetic abnormalities C_LIO_LIX-Chromosome dosage strongly influences susceptibility to aneuploidy in mouse embryonic stem cells and to a lesser degree in human pluripotent stem cells C_LIO_LIXX mouse embryonic stem cell lines show a higher proportion of cells in 2 cell-like state and higher expression of tumor suppressor genes associated with DNA damage response C_LI

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Hierarchical population genetic structure and signatures of adaptation in Lates calcarifer

ContextLates calcarifer is a widespread Indo-Pacific fish that is important in aquaculture, recreational and commercial fisheries. Genetic divergences from different data sources and sampling schemes have been reported. AimsTo conduct phylogenetic and population genetic analyses from a geographically and phylogenetically representative data set to identify hierarchical divisions within L. calcarifer. We further test the evolutionary significance of genetic units in terms of signatures of adaptation. MethodsUsing a whole-genome sequence data set of 61 fish including an outgroup, we conducted phylogenetic and population genetic analyes. We also generated measures of Fst, nucleotide diversity ({pi}) and Tajimas D (D). Key ResultsWe identify three main lineages of L. calcarifer corresponding to the Indian subcontinent, Southeast Asia and Australasia. Subdivision within each of the three main lineages is also identified and characterized. Adaptively significant differences are indicated within and between the three main lineages. ConclusionsL. calcarifer exhibits genetic divergences at different levels that originate before and during the Pleistocene. These divergences are associated with adaptive divergence but unclear phenotypic changes. ImplicationsThis study highlights the need for comprehensive sampling and integrative study of genotypes and phenotypes across the range of L. calcarifer.

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Not like other conifers: evaluation of phenotypic diversity in British common juniper, Juniperus communis, indicates genetic isolation and local adaptations among remnant populations

Habitat fragmentation and genetic isolation pose threats to the genetic diversity and resilience of natural populations. Protecting the genetic diversity of populations, and the processes that sustain it, optimises their ability to adapt to changing conditions and new threats: conservation efforts with this specific goal are known as "dynamic conservation." The common juniper, Juniperus communis, is a keystone species that provides habitat and resources for many plants and animals. It is a highly polymorphic species, and across its natural range it grows in a variety of habitats and growth forms. Juniper populations have been shrinking and becoming increasingly fragmented for over a century in the UK and elsewhere in Europe, raising concerns about the genetic diversity present in juniper populations and their ability to adapt to changing conditions, or their adaptive potential. This paper presents an analysis of the partitioning of phenotypic diversity among regions, populations and families from 16 UK populations assessed in a common garden trial. Our findings suggest high phenotypic variation among populations compared to the variation among families within populations, indicating barriers to gene flow between juniper populations, relatively homogenous populations and, consequently, potentially reduced adaptive potential. This information is a useful baseline for conservation managers and can also help to infer the genetic diversity and adaptive potential of populations.

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Understanding genetic diversity and phylogeography of Common Teal and its phylogenetic relationship with other water bird species in the wetlands of Kashmir Himalayas.

Understanding the genetic diversity and phylogeography of migratory species is critical for biodiversity conservation and the effective management of wetland ecosystems. The Kashmir Himalayas, an integral part of the Central Asian Flyway, host several key wetlands that provide critical wintering grounds for a variety of migratory birds. This study focuses on assessing the genetic characteristics and phylogenetic relationships of the Common Teal (Anas crecca) in comparison to other species within the families Anatidae and Rallidae. We analysed 149 blood samples, including 71 from A. crecca and 78 from other species in the two families, collected from wetlands in the Kashmir region. Using four mitochondrial markers--cytochrome oxidase subunit I (COI), cytochrome b (Cyt b), 16S rRNA, and the control region--we evaluated the genetic diversity and lineage connectivity of these species. Our findings reveal that the mitochondrial DNA haplotypes of A. crecca in the Kashmir Himalayas are shared with European populations, indicating strong maternal gene flow and connectivity between distant populations. A minimum spanning haplotype network analysis showed minimal nucleotide differences among haplotypes, particularly in the Cyt b and control regions, suggesting low genetic differentiation and a high degree of similarity among individuals. Notably, we identified at least four distinct maternal lineages of A. crecca in the Kashmir wetlands, reflecting diverse migratory sources. Our results also highlight that DNA barcoding using COI exhibited both high and low species resolution, with significant intraspecific variation, making it a valuable tool for further phylogeographic studies. The observed genetic diversity and haplotype sharing with distant populations underscore the ecological importance of Kashmirs wetlands as crucial habitats for migratory species. Our study emphasizes the need for targeted conservation and management strategies to preserve these vital ecosystems and the biodiversity they support.

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Multidimensional variable dose analysis (mVDA) is a novel method for high-throughput mapping of genetic interactions

The mapping of genetic interactions is a powerful tool to determine gene functions, assemble the structures of biological pathways and to identify therapeutic targets for disease. However, while there have been significant advances in the screening techniques used to identify genetic interactions over the past decade, methods that are sufficiently scalable to test genetic interactions on a genome level are still far from our current capabilities. Here, we describe an approach to genetic interaction screening in Drosophila cells that overcomes the scaling issues associated with most other methods. This method, called multidimensional Variable Dose Analysis (mVDA), allows multiple, random genes to be inhibited within each cell of a mixed population and the relative phenotypes caused by each gene or pair of genes to be deconvoluted. This means that reagent library size and cell population size do not scale exponentially with the number of genes to be tested, unlike previous methods. This method therefore has the potential to allow genome wide mapping of genetic interactions in Drosophila cells for the first time.

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Genetic Diversity of Hippophae rhamnoides Varieties with Different Fruit Characteristics

Hippophae rhamnoides is a valuable crop whose fruits are rich in bioactive compounds with health benefits. To date, there is a lack of genetic data for varieties of sea buckthorn. This fact hinders the identification of genetic determinants of valuable traits and limits the efficiency of breeding. In the present study, we analyzed a representative set of 55 valuable H. rhamnoides varieties of Russian breeding with different fruit characteristics and diverse lineages. Whole-genome sequencing was performed on the Illumina platform and at least 25x genome coverage was obtained for each accession. Based on the sequencing data, DNA polymorphisms were identified in genome regions corresponding to genes. These polymorphisms were used to evaluate the genetic relationships of the studied sea buckthorn varieties. We revealed genetically distinct groups of accessions that mostly corresponded to the lineages of the genotypes. Our data are important for assessing the effect of selection on sea buckthorn diversity and for evaluating the genetic relationship of different varieties, which is useful for breeders when selecting parental forms for crosses. The obtained information on DNA polymorphisms is also necessary to study the diversity of genes, including those that may determine valuable sea buckthorn traits, including fruit characteristics. Thus, our data can benefit both basic and applied research on sea buckthorn.

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Robustness of Selection and Timing Inference under Model Variation in Population Genetics

1In population genetics, accurately inferring the selection coefficient and the time of onset of advantageous mutations from genetic data is fundamental for understanding evolutionary processes. Here, we investigate how mismatches between the true evolutionary process and the inference model--specifically in the reproductive variance ({sigma}2) and the number of generations (L)--affect the posterior distributions of the selection coefficient and the time of onset. Using the Kolmogorov forward and backward equations, we model the stochastic dynamics of gene frequencies under selection and drift. We show that while the posterior distribution of the selection coefficient remains unaffected by changes in{sigma} 2 and L, this invariance does not apply to the time of onset. By framing the problem as a first passage time issue, we derive explicit expressions for the offsets in the posterior mean and variance of the time of onset that result from incorrect assumptions about{sigma} 2 and L. Our analysis reveals that these offsets are related to the mean and variance of the first passage time required for the allele frequency to reach a certain threshold, starting from an initial frequency determined by the model parameters. Under the assumption of a uniform prior for the time of onset, we find that the offset in the inferred mean is given by the difference in the effective generation duration ({Delta} = 1/{sigma}2) between the true process and the inference model. We validate our theoretical findings through simulations, demonstrating that the empirical offsets closely match our predictions. Furthermore, we generalize our results to accommodate non-uniform prior distributions, such as exponential priors, and provide numerical methods for calculating offsets under arbitrary priors. Stochastic fluctuations due to genetic drift, which are influenced by the reproductive variance and generational structure, can introduce significant biases in the posterior distribution of time of onset of advantageous mutations. By quantifying these biases, our framework enables more accurate adjustments to inferences drawn from genetic data, thereby enhancing our understanding of evolutionary dynamics and improving the reliability of population genetic analyses.

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The Role of Genetic Variation in Shaping Phenotypic Responses to Diet in Aging Drosophila melanogaster

Nutrition plays a central role in healthy living, however, extensive variability in individual responses to dietary interventions complicates our understanding of its effects. Here we present a comprehensive study utilizing the Drosophila Genetic Reference Panel (DGRP), investigating how genetic variation influences responses to diet and aging. Quantitative genetic analyses of the impact of dietary restriction on lifespan, locomotor activity, dry weight, and heat knockdown time were performed. Locomotor activity, dry weight and heat knockdown time were measured on the same individual flies. We found significant genotype-by-diet interaction (GDI) and genotype-by-age interaction (GAI) for all traits. Therefore, environmental factors play a crucial role in shaping trait variation at different ages and diets, and/or distinct genetic variation influences these traits at different ages and diets. Our genome wide association study also identified a quantitative trait locus for age-dependent dietary response. The observed GDI and GAI indicates that susceptibility to environmental influences changes as organisms age, which could have significant implications for dietary recommendations and interventions aimed at promoting healthy aging in humans. The identification of associations between DNA sequence variation and age-dependent dietary responses opens new avenues for research into the genetic mechanisms underlying these interactions.

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A Murine Database of Structural Variants Enables the Genetic Architecture of a Spontaneous Murine Lymphoma to be Characterized

A more complete map of the pattern of genetic variation among inbred mouse strains is essential for characterizing the genetic architecture of the many available mouse genetic models of important biomedical traits. Although structural variants (SVs) are a major component of genetic variation, they have not been adequately characterized among inbred strains due to methodological limitations. To address this, we generated high-quality long-read sequencing data for 40 inbred strains; and designed a pipeline to optimally identify and validate different types of SVs. This generated a database for 40 inbred strains with 573,191SVs, which included 10,815 duplications and 2,115 inversions, which also has 70 million SNPs and 7.5 million insertions/deletions. Analysis of this SV database identified an SV that is one component of a bi-genic model for lymphoma susceptibility in SJL mice, which provides mechanistic insight into the genetic basis for susceptibility to murine (and potentially human) lymphomas.

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