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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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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At least 163 records · Page 9Linked to original sources

bioRxiv2022

Robust identification of extrachromosomal DNA and genetic variants using multiple genetic abnormality sequencing (MGA-Seq)

Genomic abnormalities, including structural variation (SV), copy number variation (CNV), single-nucleotide polymorphism (SNP), homogenously staining regions (HSR) and extrachromosomal DNA (ecDNA), are strongly associated with cancer, rare diseases and infertility. A robust technology to simultaneously detect these genomic abnormalities is highly desired for clinical diagnosis and basic research. In this study, we developed a simple and cost-effective method - multiple genetic abnormality sequencing (MGA-Seq) - to simultaneously detect SNPs, CNVs, SVs, ecDNA and HSRs in a single tube. This method has been successfully applied in both cancer cell lines and clinical tumour samples and revealed that focal amplification in tumour tissue is substantially heterogeneous. Notably, we delineated the architecture of focal amplification and the ecDNA network by MGA-Seq, which facilitated the exploration of the regulation of gene expression in ecDNA. This method could be extensively applied for diagnosis and may greatly facilitate the investigation of the genomic mechanism for genetic diseases.

genomics↗

bioRxiv2023

Using inbreeding to test the contribution of non-additive genetic effects to additive genetic variance: a case study in Drosophila serrata

Additive genetic variance, VA, is the key parameter for predicting adaptive and neutral phenotypic evolution. Changes in demography (e.g., increased close-relative inbreeding) can alter VA, but how depends on the, typically unknown, gene action and allele frequencies across many loci. For example, VA increases proportionally with the inbreeding coefficient when allelic effects are additive, but larger (or smaller) increases can occur when allele frequencies are unequal at causal loci with dominance effects. Here, we describe an experimental approach to assess the potential for rare, recessive alleles to inflate VA under inbreeding. Applying a powerful paired pedigree design in Drosophila serrata, we measured 11 wing traits on half-sibling families bred via either random or sibling mating, differing only in homozygosity (not allele frequency). Despite close inbreeding and substantial power to detect small VA, we detected no deviation from the expected additive effect of inbreeding on genetic (co)variances. Our results suggest the average dominance coefficient is very small relative to the additive effect, or that allele frequencies are relatively equal at loci affecting wing traits. We outline the further opportunities for this paired pedigree approach to reveal the characteristics of VA, providing insight into historical selection and future evolutionary potential.

evolutionary biology↗

bioRxiv2024

Genetic-Dependent Brain Signatures of Resilience: Interactions among Childhood Abuse, Genetic Risks and Brain Function

Resilience to emotional disorders is critical for adolescent mental health, especially following childhood abuse. Yet, brain signatures of resilience remain undetermined due to the differential susceptibility of the brains emotion processing system to environmental stresses. Analyzing brains responses to angry faces in a longitudinally large-scale adolescent cohort (IMAGEN), we identified two functional networks related to the orbitofrontal and occipital regions as candidate brain signatures of resilience. In girls, but not boys, higher activation in the orbitofrontal-related network was associated with fewer emotional symptoms following childhood abuse, but only when the polygenic burden for depression was high. This finding defined a genetic-dependent brain (GDB) signature of resilience. Notably, this GDB signature predicted subsequent emotional disorders in late adolescence, extending into early adulthood and generalizable to another independent prospective cohort (ABCD). Our findings underscore the genetic modulation of resilience-brain connections, laying the foundation for enhancing adolescent mental health through resilience promotion.

neuroscience↗

bioRxiv2025

A gene-based model of fitness and its implications for genetic variation: Genetic and inbreeding loads

In the companion paper to this, we examined the consequences for patterns of linkage disequilibrium of the "gene" model of fitness, which postulates that the effects of recessive or partially recessive deleterious mutations located at different sites within a gene fail to complement each other. Here, we examine the consequences of the gene model for the genetic and inbreeding loads, using both analytical and simulation methods, and contrast it with the frequently used "sites" model that allows allelic complementation. We show that the gene model results in a slightly lower genetic load, but a much smaller inbreeding load, than the sites model, implying that standard predictions of mutational contributions to inbreeding depression may be overestimates. Synergistic epistasis between pairs of mutations was also modeled, and shown to considerably reduce the inbreeding load for both the gene and sites models. The theoretical results are discussed in relation to data on inbreeding load in Drosophila melanogaster. The widespread assumption that inbreeding depression is largely due to deleterious mutations should be re-examined in the light of our findings.

evolutionary biology↗

bioRxiv2025

Genetic Mapping in Diversity Outbred Mice Identifies Novel Loci and Candidate Genes for Anxiety-Like Behavior and Genetic Subgroups Predictive of Ethanol Consumption

Anxiety disorders are the most common class of psychiatric disorder. Risk for anxiety disorders is thought to be influenced by many genes, each contributing a small effect. The light-dark box behavioral assay was designed to measure anxiety-like behavior in rodents. Diversity Outbred (DO) mice were designed for high-resolution quantitative trait loci (QTL) mapping on a genetically-diverse background. Here, we studied a population of 518 male DO mice for anxiety-like and locomotor behaviors from a light-dark box assay. Multivariate analysis of behavioral data identified two major subgroups of animals differing in basal anxiety behavior and subsequent ethanol consumption patterns. Behavioral QTL analysis identified a significant locus on Chromosome 14 associated with 3 anxiety-like behavioral phenotypes. Haplotype analysis revealed an effect of C57BL/6J alleles at this locus, with mice carrying those alleles exhibiting more anxiety-like behavior. An additional 9 suggestive loci were identified. Genes located within the confidence intervals for the Chromosome 14 locus were analyzed for coding sequence polymorphisms, prefrontal cortex expression QTLs, human GWAS data, and additional data sets related to psychiatric conditions including substance use. Results prioritized two candidate genes, Tbc1d4 and Lmo7, for further study. These results represent the highest-resolution genetic mapping of light-dark box behaviors in mice to date, revealing insights into the complex biology of anxiety disorders. Additionally the studies identify striking subgroups of animals where basal anxiety-like behavior predicts eventual ethanol consumption phenotypes.

animal behavior and cognition↗

bioRxiv2025

Application of the CPER reverse genetics system for genetic engineering of rabies virus

Reverse genetics (RG) systems are essential tools for basic virological studies and applied studies using engineered recombinant viruses in various research fields. While the circular polymerase extension reaction (CPER) has been widely applied to prepare a full-length infectious complementary DNA (cDNA) of positive-sense RNA viruses, its use for negative-sense RNA viruses (mononegaviruses) remains limited. Here, we report the first CPER-based RG system for rabies virus (RABV), a member of mononegaviruses. Infectious RABV was successfully rescued from cells transfected with helper plasmids and the CPER product, the assembled overlapping DNA fragments encoding the full-length viral genome cDNA and regulatory elements. Using this system, we generated wild-type, point-mutant, reporter-expressing, and chimeric RABVs, all of which retained their expected biological properties. Deep sequencing revealed that CPER-derived viruses occasionally harbor low-frequency mutations undetectable by Sanger sequencing, highlighting PCR-related artifacts as a limitation. In addition, CPER products with a pUC19 backbone could be directly applied for E. coli transformation and cloning of RABV full genome cDNA plasmids, offering a flexible, ligase-free cloning strategy for conventional RG. Our work establishes CPER as a versatile platform for engineering recombinant RABVs, facilitating rapid generation and genetic manipulation of RABV with potential applications for research on other mononegaviruses.

microbiology↗

bioRxiv2018

Host range expansion and genetic plasticity drive the trade-off between integrative and extrachromosomal mobile genetic elements

Self-transmissible mobile genetic elements drive horizontal gene transfer between prokaryotes. Some of these elements integrate in the chromosome, whereas others replicate autonomously as plasmids. Recent works showed the existence of few differences, and occasional interconversion, between the two types of elements. Here, we enquired on why evolutionary processes have maintained the two types of mobile genetic elements by comparing integrative and conjugative elements (ICE) with extrachromosomal ones (conjugative plasmids) of the highly abundant MPFT conjugative type. We observed that plasmids encode more replicases, partition systems, and antibiotic resistance genes, whereas ICEs encode more integrases and metabolism-associated genes. ICEs and plasmids have similar average sizes, but plasmids are much more variable, have more DNA repeats, and exchange genes more frequently. On the other hand, we found that ICEs are more frequently transferred between distant taxa. We propose a model where differential plasticity and transmissibility range explain the co-occurrence of integrative and extra-chromosomal elements in microbial populations. In particular, the conversion from ICE to plasmid allows ICE to be more plastic, while the conversion from plasmid to ICE allows the expansion of the element s host range.

evolutionary biology↗

bioRxiv2018

Garcinia cambogia extract removes calcium oxalate kidney stones in both genetic and non-genetic Drosophila models of nephrolithiasis

Kidney stone formers with family history have a high rate of stone recurrence after kidney stone removal surgery and there is no effective medication available for treatment. Here, we show that Garcinia cambogia extract (GCE) efficiently removes calcium oxalate kidney stones from Malpighian tubules in both genetic and non-genetic Drosophila models of nephrolithiasis, and hydroxycitrate -a major component of GCE, directly dissolves calcium oxalate stones in Drosophila Malpighian tubules ex vivo. Our study discovers a potential novel therapeutic strategy for the clinical treatment of nephrolithiasis and suggests that clinical-grade Garcinia cambogia extract could be used to treat patients with nephrolithiasis in the future.

pharmacology and toxicology↗

bioRxiv2019

Population genetic simulation study of power in association testing across genetic architectures and study designs

While it is well established that genetics can be a major contributor to population variation of complex traits, the relative contributions of rare and common variants to phenotypic variation remains a matter of considerable debate. Here, we simulate rare variant association studies across different case/control panel sampling strategies, sequencing methods, and genetic architecture models based on evolutionary forces to determine the statistical performance of RVATs widely in use. We find that the highest statistical power of RVATs is achieved by sampling case/control individuals from the extremes of an underlying quantitative trait distribution. We also demonstrate that the use of genotyping arrays, in conjunction with imputation from a whole genome sequenced (WGS) reference panel, recovers the vast majority (90%) of the power that could be achieved by sequencing the case/control panel using current tools. Finally, we show that for dichotomous traits, the statistical performance of RVATs decreases as rare variants become more important in the trait architecture. Our results extend previous work to show that RVATs are insufficiently powered to make generalizable conclusions about the role of rare variants in dichotomous complex traits.

genomics↗

bioRxiv2026

A Genetically Engineered Human Organoid Model Reveals Distinct Genetic and Epigenetic Barriers of Lineage Plasticity in Early PDAC Transformation

The lack of accurate, human-based models recapitulating early-stage pancreatic ductal adenocarcinoma (PDAC) has hindered therapeutic development. Using pluripotent stem cell-derived pancreatic progenitor organoids, we established a human PDAC model that faithfully reproduces the genetic, epigenetic, and transcriptomic trajectory of tumor initiation and progression in vitro, validated against clinical datasets and histopathology. We demonstrate that CDKN2A loss, nearly universal in patients but dispensable in mouse models, is essential for neoplastic transformation when combined with KRAS and TP53 mutations, while SMAD4 loss promotes tumor progression. Multi-omics profiling reveals epigenetic repression of pancreatic lineage program during PDAC initiation, alongside oncogenic AP-1-driven chromatin remodeling. Notably, we identify TET1 suppression as a mechanistic link between oncogenic ERK signaling and the hypermethylation and silencing of essential pancreatic transcription factors. This model captures the genetic and epigenetic determinants of human PDAC, reveals antagonism between oncogenic and lineage restriction programs, and supports TET-based lineage restoration as a promising early intervention strategy for high-risk individuals.

cancer biology↗

bioRxiv2026

Condition manipulation reveals an increase in sex-specific additive genetic variance, and reduced intersex genetic covariances in Drosophila prolongata, a species with sexual trait exaggeration

The between sex genetic correlation for traits has long been hypothesized as a constraint to the evolution of sexual dimorphism. Both empirical and theoretical work has suggested that this constraint is influenced by genotype-sex-environment interactions. We examine genotype-sex-environment interactions in both sexually exaggerated and non-exaggerated legs of Drosophila prolongata, to examine the role of organismal condition on evolvability of an extreme trait. We employed a nested full-sib half-sib crossing design, providing food either ad libitum, or restricting food during larval growth, to each brood. When provided food ad libitum, inter-sex genetic correlations between traits is high and positive, whereas under food restriction this correlation substantially weakens, with a modest negative sign. Similarly, comparisons of the G matrix across sexes becomes less associated under food restriction. We discuss these results in the context of the growing appreciation of the factors that facilitate sex-specific evolutionary change.

evolutionary biology↗

bioRxiv2026

Genetic mapping of trait plasticity in a plant pathogenic fungus reveals genetic architecture and candidate genes for plasticity

Understanding how plant pathogens respond to environmental change is needed to better manage plant diseases. Phenotypic plasticity, the ability of a single genotype to produce different phenotypes across different environments, can influence pathogen adaptation and host-pathogen dynamics. Few studies have investigated the mechanisms underlying phenotypic plasticity in plant pathogens. Here we used phenotypic and genotypic data collected over >15 years and across multiple environments to perform genetic mapping of plasticity traits in the wheat pathogen Zymoseptoria tritici. Most (75%) of the QTL for plasticity (plQTL) overlapped with their corresponding mean QTL (mnQTL), suggesting that plasticity is controlled mainly by pleiotropic genes or tightly linked genes. 25% of the plQTL mapped to genomic locations separate from the mnQTL, suggesting that plasticity in these cases results from epistasis between unlinked loci. In several cases plasticity measured across different environmental gradients mapped to the same genomic positions, suggesting a shared control of plasticity for unrelated factors. These cases of shared control could be due to master regulators of plasticity or gene clusters. This mapping study provide unprecedented insights into the genetic architecture of plasticity in fungal plant pathogens.

evolutionary biology↗

bioRxiv2020

The genetic architecture of fruit colour in strawberry (Fragaria x ananassa) uncovers the predominant contribution of the F. vesca subgenome to anthocyanins and reveals underlying genetic variations

Fruit colour, which is central to the sensorial and nutritional quality of the fruit, is a major breeding target in cultivated strawberry (Fragaria x ananassa). Red fruit colour is caused by the accumulation of anthocyanins, which are water-soluble flavonoids. Here, using pseudo F1 progeny derived from the cv. Capitola and the advanced line CF1116 and taking advantage of the available high density SNP array, we delineated fruit flavonoids mQTLs (13 compounds: anthocyanin, flavonols and flavan-3-ols) and colour-related QTLs (total anthocyanins and fruit colour) to narrow genomic regions corresponding to specific subgenomes of the cultivated strawberry. Findings showed that the overwhelming majority of the anthocyanin mQTLs and other colour-related QTLs are specific to F. vesca subgenome but that other subgenomes also contribute to colour variations. We then focused on two major homoeo-mQTLs for pelargonidin-3-glucoside (PgGs) localized on both male and female maps on linkage group LG3a (F. vesca subgenome). Combined high-resolution mapping of PgGs mQTLs and colour QTLs, transcriptome analysis of selected progeny individuals and whole genome sequencing of the parents led to the identification of several INDELS in the cis-regulatory region of a MYB102-like ODORANT gene and of the deletion of a putative MADS box binding motif in the 5UTR upstream region of an anthocyanidin reductase (ANR) gene, which likely underlie significant colour variations in strawberry fruit. The implications of these findings are important for the functional analysis and genetic engineering of colour-related genes and for the breeding by Marker-Assisted-Selection of new strawberry varieties with improved colour and health-benefits.

genetics↗

bioRxiv2024

The Genetic History of the South Caucasus from the Bronze to the Early Middle Ages: 5000 years of genetic continuity despite high mobility

Archaeological and archaeogenetic studies have highlighted the pivotal role of the Caucasus region throughout prehistory, serving as a central hub for cultural, technological, and linguistic innovations. However, despite its dynamic history, the critical area between the Greater and Lesser Caucasus mountain ranges, mainly corresponding to modern-day Georgia, has received limited attention. Here, we generated an ancient DNA time transect consisting of 219 individuals with genome-wide data from 47 sites in this region, supplemented by 97 new radiocarbon dates. Spanning from the Early Bronze Age 5000 years ago to the so-called Migration Period that followed the fall of the Western Roman Empire, we document a largely persisting local gene pool that continuously assimilated migrants from Anatolia/Levant and the populations of the adjacent Eurasian steppe. More specifically, we observe these admixture events as early as the Middle Bronze Age. Starting with Late Antiquity (late first century AD), we also detect an increasing number of individuals with more southern ancestry, more frequently associated with urban centers - landmarks of the early Christianization in eastern Georgia. Finally, in the Early Medieval Period starting 400 AD, we observe genetic outlier individuals with ancestry from the Central Eurasian steppe, with artificial cranial deformations (ACD) in several cases. At the same time, we reveal that many individuals with ACD descended from native South Caucasus groups, indicating that the local population likely adopted this cultural practice.

genetics↗

bioRxiv2018

Beyond Bonferroni Revisited: Concerns over inflated false positives in conservation genetics, genetics, and neuroscience

In 2006, Narum published a paper in Conservation Genetics that was motivated by the stringent nature of the Bonferroni approach for family wise error correction. That work suggested that the approach of Benjamini and Yekutieli in 2001 provided adequate correction and was more biologically relevant. However, there are crucial differences between the original Benjamini and Yekutieli procedure and that described by Narum. After carefully reviewing both papers, we believe that the Narum procedure is both different than the Benjamini and Yekutieli procedure and does not adequately control for family wise error. We provide an overview of approaches for FWE correction as well as evidence for the faulty implementation of the Benjamini and Yekutieli procedure by Narum using the equations from the respective papers, data from both papers, and the results of simulation.

genetics↗

bioRxiv2026

Genetic Modifiers of Cognitive Function: Novel Genetic Associations with Memory, Executive Function, and Attention in the Long Life Family Study

Cognitive performance is central to health and quality of life. Studying the factors that sustain performance may offer insights into maintaining cognitive function into advanced ages and may inform strategies to promote healthy cognitive aging. To identify single nucleotide polymorphisms (SNPs) underlying cognitive function, we performed genome-wide association studies (GWAS) of nine neuropsychological test scores capturing performance in three cognitive domains in 2,455 participants of the Long Life Family Study (LLFS). We identified 12 variants in seven tests and three domains that reached genome-wide significance (p < 5x10-). Three rare (minor allele frequency, European population MAF<0.01) protective, intronic variants, rs190287985 (CCSER1), rs75730801 (FHOD3), and rs552842447 (LINC00508), were uniquely associated with semantic fluency, phonemic fluency and number span forward, respectively. Two rare deleterious variants, rs556333682 and rs188304645, were associated with performance on the Hopkins Verbal Learning Test-Revised (HVLT-R) learning trials and lie in ischemia-related genes SH3TC1 and RPH3A. Another variant, rs180691759, associated with HVLT-R delayed recall, was proximal to RSPO3 and linked to decreased ECHDC1 expression, implicating ischemic and unexplained Ethylmalonic acid (EMA) pathways. We compared the results with GWASs of a general cognitive factor (GCF) and reaction time (RT) in the UK Biobank and meta-analysis results of the UK Biobank, CHARGE and COGENT by Davies et al. We found that rs535509651 associates with HVLT-R delayed recall in the LLFS and nominally associates (p<0.05) with GCF, and that rs10424537 associates with Immediate Logical Memory in the LLFS and nominally associates with RT. Furthermore, we identified 5 genome-wide significant loci in Davies et al. that reached loci adjusted significance in the LLFS (GCF p<0.05/128 and RT p<0.05/39). Each locus was associated with a single cognitive domain in the LLFS. We annotated the genome-wide significant results with quantitative trait loci (QTL) analyses of whole blood transcriptomic, serum metabolomic data, and gene set enrichment analyses (GSEA) using all nominally significant transcripts (p < 0.05/12). QTL analyses discovered 1 SNP-transcript (ECHDC1, p < 3 x 10-6), no SNP-lipid (p < 2 x 10-4), and no SNP-polar metabolite (p < 2 x 10-4) associations. Gene set enrichment analyses identified three pathways at FDR < 0.05. Our findings provide insight into the domain-specific genetic architecture of cognitive function.

genetics↗

bioRxiv2015

Genome-wide association and prediction reveals the genetic architecture of cassava mosaic disease resistance and prospects for rapid genetic improvement

Cassava (Manihot esculenta) is a crucial, under-researched crop feeding millions worldwide, especially in Africa. Cassava mosaic disease (CMD) has plagued production in Africa for over a century. Bi-parental mapping studies suggest primarily a single major gene mediates resistance. To be certain and to potentially identify new loci we conducted the first genome-wide association mapping study in cassava with 6128 African breeding lines. We also assessed the accuracy of genomic selection to improve CMD resistance. We found a single region on chromosome 8 accounts for most resistance but also identified 13 small effect regions. We found evidence that two epistatic loci and/or alternatively multiple resistance alleles exist at major QTL. We identified two peroxidases and one thioredoxin as candidate genes. Genomic prediction of additive and total genetic merit was accurate for CMD and will be effective both for selecting parents and identifying highly resistant clones as varieties.

Genomics↗

bioRxiv2016

Tissue-specific functional effect prediction of genetic variation and applications to complex trait genetics

AO_SCPCAPBSTRACTC_SCPCAPWe describe here a new method based on a latent Dirichlet allocation model for predicting functional effects of noncoding genetic variants in a cell type and tissue specific way (FUN-LDA) by integrating diverse epigenetic annotations for specific cell types and tissues from large scale epige-nomics projects such as ENCODE and Roadmap Epigenomics. Using this unsupervised approach we predict tissue-specific functional effects for every position in the human genome. We demonstrate the usefulness of our predictions using several validation experiments. Using eQTL data from several sources, including the Genotype-Tissue Expression project, the Geuvadis project and Twin-sUK cohort, we show that eQTLs in specific tissues tend to be most enriched among the predicted functional variants in relevant tissues in Roadmap. We further show how these integrated functional scores can be used to derive the most likely cell/tissue type causally implicated for a complex trait using summary statistics from genome-wide association studies, and estimate a tissue-based correlation matrix of various complex traits. We find large enrichment of heritability in functional components of relevant tissues for various complex traits, with FUN-LDA yielding the highest enrichment estimates relative to existing methods. Finally, using experimentally validated functional variants from the literature and variants possibly implicated in disease by previous studies, we rigorously compare FUN-LDA to state-of-the-art functional annotation methods such as GenoSky-line, ChromHMM, Segway, and IDEAS, and show that FUN-LDA has better prediction accuracy and higher resolution compared to these methods. In summary, we describe a new approach and perform rigorous comparisons with the most commonly used functional annotation methods, providing a valuable resource for the community interested in the functional annotation of noncoding variants. Scores for each position in the human genome and for each ENCODE/Roadmap tissue are available from http://www.columbia.edu/~ii2135/funlda.html.

Bioinformatics↗