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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2022

Genetic architecture of creativity and extensive genetic overlap with psychiatric disorders revealed from genome-wide association analyses of 241,736 individuals

Creativity is heritable and exhibits familial aggregation with psychiatric disorders, but its genomic basis and genetic relationship with psychiatric disorders remain largely unknown. Here, we conducted a genome-wide association study (GWAS) using an expanded, machine learning-based definition of creativity in individuals of European ancestry from the UK Biobank (n = 241,736) and identified 25 creativity-associated loci. Extensive genetic overlap with psychiatric disorders, including schizophrenia, major depression, bipolar I disorder, attention deficit/hyperactivity disorder, and anorexia nervosa, was demonstrated by the genetic correlation, polygenic risk score, and MiXeR analyses. The condFDR and conjFDR analyses identified additional loci for creativity and psychiatric disorders, as well as shared genetic loci between creativity and psychiatric disorders. This GWAS showed significant correlations with GWASs using traditional definitions of creativity and GWASs adjusted for educational attainment. Our findings contribute to the understanding of the genetic architecture of creativity and reveal its polygenic relationships with psychiatric disorders.

genomics↗

bioRxiv2023

Genetic and dietary modulators of the inflammatory response in the gastro-intestinal tract of the BXD mouse genetic reference population

Inflammatory gut disorders, including inflammatory bowel disease (IBD), can be impacted by dietary, environmental and genetic factors. While the incidence of IBD is increasing worldwide, we still lack a complete understanding of the gene-by-environment interactions underlying inflammation and IBD. Here, we profiled the colon transcriptome of 52 BXD mouse strains fed with a chow or high-fat diet (HFD) and identified a subset of BXD strains that exhibit an IBD-like transcriptome signature on HFD, indicating that an interplay of genetics and diet can significantly affect intestinal inflammation. Using gene co-expression analyses, we identified modules that are enriched for IBD-dysregulated genes and found that these IBD-related modules share cis-regulatory elements that are responsive to the STAT2, SMAD3, and REL transcription factors. We used module quantitative trait locus (ModQTL) analyses to identify genetic loci associated with the expression of these modules. Through a prioritization scheme involving systems genetics in the mouse and integration with external human datasets, we identified Muc4 and Epha6 as the top candidates mediating differences in HFD-driven intestinal inflammation. This work provides insights into the contribution of genetics and diet to IBD risk and identifies two candidate genes, MUC4 and EPHA6, that may mediate IBD susceptibility in humans.

systems biology↗

bioRxiv2024

SIMHYB 2: a software tool to explore and illustrate evolutionary forces in Population Genetics teaching and research. Application to Conservation Genetics

Practical approaches have become a standard in many scientific disciplines, including population genetics. By analyzing properly selected datasets, the students can calculate parameters and draw conclusions about genetic diversity, differentiation and evolution of populations with higher efficiency than if based exclusively on theoretical lessons. However, preparing the appropriate datasets is a hard task and a wrong selection can spoil a well-aimed practice. Here we present SO_SCPLOWIMC_SCPLOWHO_SCPLOWYBC_SCPLOW 2, a software tool specifically intended to ease the full understanding of evolutionary forces by the students and to help the teacher to prepare adequate datasets and examples for the practices. It simulates the course of a mixed population under user-defined reproductive and evolutionary conditions. Outputs can be easily adapted for downstream analysis with other popular tools as GO_SCPLOWENC_SCPLOWAO_SCPLOWLC_SCPLOWEO_SCPLOWXC_SCPLOW or SO_SCPLOWTRUCTUREC_SCPLOW. Thus, SO_SCPLOWIMC_SCPLOWHO_SCPLOWYBC_SCPLOW 2 is very suitable for project-based-learning approaches: students can produce their own datasets in different scenarios of genetic drift, migration, selective advantage, reproductive success... Additionally, SO_SCPLOWIMC_SCPLOWHO_SCPLOWYBC_SCPLOW 2 is the only simulation software available to date providing traceable pedigrees of individuals, being therefore very convenient for preparing datasets for parentage analysis, spatial genetic structure or conservation genetics study cases. Satisfactory results from its ongoing utilization in higher education and research are reported.

scientific communication and education↗

bioRxiv2024

Species-specific loss of genetic diversity and accumulation of genetic load following agricultural intensification

Land-use change from agricultural intensification is a major driver of global insect declines. We investigated the genetic consequences of grassland decline in Sweden by sequencing museum and modern specimens of three focal and five additional Polyommatinae butterfly species. From 59 historical and 90 contemporary genomes, we find a 6% decline in genetic diversity and increased isolation and inbreeding in the grassland specialist Cyaniris semiargus over the past 70 years. In contrast, generalist Polyommatus icarus and heathland specialist Plebejus argus maintained genetic diversity and connectivity. Although currently genomic erosion is mild, we infer it lags considerably larger declines in effective population sizes. Using simulations, we demonstrate that only a small portion of genetic diversity is lost in early stages of decline, creating a genetic extinction debt. Two of five additional species show similar reductions, underscoring that restoration of grassland habitat is necessary to restore gene flow and halt further genomic erosion in grassland insects.

genomics↗

bioRxiv2025

GENETIC ENGINEERING THROUGH QUANTUM CIRCUITS: CONSTRUCTION OF CODES AND ANALYSIS OF GENETIC ELEMENTS BIOBLOQU

Quantum biology is an emergent field that investigates quantum-mechanical phenomena, such as superposition, tunneling, and entanglement, in the context of data manipulation from living systems. The exploration and engineering of nucleotide sequences rely on quantum mechanical principles, particularly the use of qubit states for the development of quantum codes. Biological sequencing data is produced at about 1 Gb/h, but analysis lags due to complexity and the limitations of classical computing. Despite these challenges, quantum computing offers a potential tool for analyzing and assembling biological data. Here, we developed quantum codes for genetic engineering. The developed quantum computational framework identifies sequences of interest within a genomic database. It locates the left and right boundaries of the scar region in the JCVI-Syn3B genome and detects 20 nucleotides flanking each boundary. After confirming the left and right ends of the scar, a secondary computational routine performs the targeted insertion of the BioBloQu structure, composed of genetic elements, into the previously characterized scar region. Our algorithms constitute a unique starting point for advanced genetic data manipulation. This tool could accelerate the exploration of large volumes of genetic data and enable the developmental design and assembly of synthetic genomes enhanced by quantum computing. Further improvements in algorithms and codes, along with the expanded availability of devices, will accelerate the search for data for applied genetic research.

bioinformatics↗

bioRxiv2018

High-dimensional Bayesian network inference from systems genetics data using genetic node ordering

Studying the impact of genetic variation on gene regulatory networks is essential to understand the biological mechanisms by which genetic variation causes variation in phenotypes. Bayesian networks provide an elegant statistical approach for multi-trait genetic mapping and modelling causal trait relationships. However, inferring Bayesian gene networks from high-dimensional genetics and genomics data is challenging, because the number of possible networks scales super-exponentially with the number of nodes, and the computational cost of conventional Bayesian network inference methods quickly becomes prohibitive. We propose an alternative method to infer high-quality Bayesian gene networks that easily scales to thousands of genes. Our method first reconstructs a node ordering by conducting pairwise causal inference tests between genes, which then allows to infer a Bayesian network via a series of independent variable selection problems, one for each gene. We demonstrate using simulated and real systems genetics data that this results in a Bayesian network with equal, and sometimes better, likelihood than the conventional methods, while having a significantly higher over-lap with groundtruth networks and being orders of magnitude faster. Moreover our method allows for a unified false discovery rate control across genes and individual edges, and thus a rigorous and easily interpretable way for tuning the sparsity level of the inferred network. Bayesian network inference using pairwise node ordering is a highly efficient approach for reconstructing gene regulatory networks when prior information for the inclusion of edges exists or can be inferred from the available data.

systems biology↗

bioRxiv2019

Genetic dominance governs the evolution and spread of mobile genetic elements in bacteria

Mobile genetic elements (MGEs), such as plasmids, promote bacterial evolution through horizontal gene transfer (HGT). However, the rules governing the repertoire of traits encoded on MGEs remain unclear. In this study, we uncovered the central role of genetic dominance shaping genetic cargo in MGEs, using antibiotic resistance as a model system. MGEs are typically present in more than one copy per host bacterium and, as a consequence, genetic dominance favors the fixation of dominant mutations over recessive ones. Moreover, genetic dominance also determines the phenotypic effects of horizontally acquired MGE-encoded genes, silencing recessive alleles if the recipient bacterium already carries a wild-type copy of the gene. The combination of these two effects governs the catalogue of genes encoded on MGEs, dictating bacterial evolution through HGT.

microbiology↗

bioRxiv2026

Widespread decoupling between abundance and genetic diversity, and strong local genetic structuring in marine unicellular eukaryotes

How abundance, connectivity, and genetic diversity covary across space remains a central question in evolutionary biology. Using a global environmental DNA metabarcoding dataset targeting mitochondrial cytochrome c oxidase subunit I (COI), we examined relationships among metabarcoding-derived abundance, nucleotide diversity, and spatial genetic connectivity across marine eukaryotes. We found a widespread but incomplete decoupling between abundance and genetic diversity, particularly in unicellular lineages. By contrast, distance-decay patterns in abundance, diversity, and connectivity were broadly similar across eukaryotes and more strongly associated with cellularity. Focusing on the Iberian Peninsula, we reconstructed locality-centred haplotype networks to quantify the spatial organization of intraspecific genetic variation. Unicellular lineages showed stronger local genetic structuring, whereas multicellular organisms exhibited clearer large-scale biogeographic partitioning. Overall, our results reveal shared biogeographic organization across eukaryotes while demonstrating that abundance-based biodiversity metrics alone cannot fully capture evolutionary and demographic processes, especially in microbial organisms.

ecology↗

bioRxiv2026

Factors underlying creativity show distinct genetic architecture and genetic correlations with psychiatric disorders

While creativity is widely recognized as multifaceted, genome-wide association studies have largely focused on individual measures. Here, we used genomic structural equation modeling of six creativity-related GWASs and identified two latent genetic factors: a general factor and an artistic factor, with 22 and 13 genome-wide significant loci, respectively, nine of which are novel. The general factor was almost perfectly genetically correlated with educational attainment (rg = 0.96), suggesting that it primarily captured genetic influences shared with cognitive and educational processes rather than creativity-specific variation. In contrast, the artistic factor showed only a weak genetic correlation with educational attainment (rg = 0.11) and consistent positive genetic correlations with psychiatric disorders, whereas associations for the general factor were largely null or negative. Biological annotation analyses further identified distinct enrichment patterns unique to the artistic factor, providing initial evidence that different dimensions of creativity may be characterized by partially distinct neurobiological pathways.

genomics↗

bioRxiv2020

Evolution of the genetic architecture of local adaptations under genetic rescue is determined by mutational load and polygenicity

Inbred populations often suffer from heightened mutational load and decreased fitness due to lower efficiency of purifying selection at small effective population size. Genetic rescue (GR) is a tool that is studied and deployed with the aim of increasing fitness of such inbred populations. The success of GR is known to depend on certain factors that may vary between different populations, such as their demographic history and distribution of dominance effects of mutations. While we understand the effects of these factors on the evolution of overall ancestry in the inbred population after GR, it is less clear what the effect is on local adaptations and their genetic architecture. To this end, we conduct a population genetic simulation study evaluating the effect of several different factors on the efficacy of GR including trait complexity (Mendelian vs. polygenic), dominance effects, and demographic history. We find that the effect on local adaptations depends highly on the mutational load at the time of GR, which is shaped dynamically by interactions between demographic history and dominance effects of deleterious variation. While local adaptations are generally restored post-GR in the long run, in the short term they are often compromised in the process of purging deleterious variation. We also show that while local adaptations are almost always fully restored, the degree to which ancestral genetic variation comprising the trait is replaced by donor variation can vary drastically, and is especially high for complex traits. Our results provide considerations for practical GR and its effects on trait evolution.

genetics↗

bioRxiv2021

Genetic lineage of the Amami islanders inferred from classical genetic markers

The genetic structure of the people of mainland Japan and Okinawa has been gradually unveiled in recent years. However, previous anthropological studies dealing with people in the Amami islands, located between mainland Japan and Okinawa, were less informative because of the lack of genetic data. In this study, we collected DNAs from 104 subjects in two of the Amami islands, Amami-Oshima island and Kikai island. We analyzed the D-loop region of mtDNA, four Y-STRs, and four autosomal nonsynonymous SNPs to clarify the Amami islanders genetic structure compared with peoples in Okinawa, mainland Japan, and other regions of East Asia. We found that the Amami islanders showed a genetically intermediate position between mainland Japan and Okinawa in mtDNA and Y-STR. However, the frequencies of several autosomal SNPs in the Amami islanders indicated a significant difference from mainland Japanese, which may be because of the gene flow from Okinawa but not natural selection. Moreover, extremely high or low frequencies of several alleles implied a founder effect in Kikai islanders. Note that there is room for the interpretation of the results because of the small sample size and number of alleles in the present study. Geographically broad and detailed samplings and genome-wide analyses are awaited.

genetics↗

bioRxiv2023

The big (genetic) sort? Reassessing migration patterns and their genetic imprint in the UK

This study reassesses Abdel Abdellaoui et al.s findings that genetically selective migration may lead to persistent and accumulating socioeconomic and health inequalities between "types" (rich or poor) of places in the UK. Their work categorized migrants who moved to the same "type" of place (rich-to-rich or poor-to-poor) as non-migrants. We re-investigate the question of genetically selective migration by examining migration patterns between places rather than "place-types" and find genetic selectively in whether people migrate rather than where. For example, we find evidence of positive selection of people with genetic variants correlated better education moving from rich to poor places with our measure of migration that was obscured in the earlier work that used a non-standard measure of migration.

genetics↗

bioRxiv2025

Identification of genetic and non-genetic modifiers of genomic imprinting through whole genome screening in humans

Genomic imprinting is required for normal development, and abnormal methylation of differentially methylated regions (iDMRs) controlling the parent of origin-dependent expression of the imprinted genes has been found in constitutional disorders affecting growth, metabolism, neurobehavior, and in cancer. In most of these cases the cause of the imprinting abnormalities is unknown. Also, these studies have generally been performed on a limited number of CpGs, and a systematic investigation of iDMR methylation in the general population is lacking. By analysing the iDMRs in a large number of peripheral blood DNA methylation array datasets of unaffected individuals and patients with rare disorders, we determined the most common iDMR methylation profiles and identified many genetic and non-genetic factors contributing to their variability. We found that methylation variability is not homogeneous within the iDMRs and that the CpGs closer to the ZFP57 binding sites are less susceptible to methylation changes. We demonstrated the methylation polymorphism of three iDMRs and the atypical behaviour of several others, and reported the association of 25 disease- and 47 non-disease-complex traits, including blood cell type composition, as well as 15 mendelian or chromosomal disorders, with iDMR methylation changes in blood DNA. These findings identify several genetic and non-genetic factors associated with genomic imprinting maintenance in humans, which may have a role in the aetiology of the diseases associated with imprinting abnormalities and have clear implications in molecular diagnostics.

genetics↗

bioRxiv2019

GWAS of 19,629 individuals identifies novel genetic variants for regional brain volumes and refines their genetic co-architecture with cognitive and mental health traits

Volumetric variations of human brain are heritable and are associated with many brain-related complex traits. Here we performed genome-wide association studies (GWAS) and post-GWAS analyses of 101 brain volumetric phenotypes using the UK Biobank (UKB) sample including 19,629 participants. GWAS identified 287 independent SNPs exceeding genome-wide significance threshold of 4.9*10-10, adjusted for testing multiple phenotypes. Gene-based association study found 142 associated genes (113 new) and functional gene mapping analysis linked 122 more genes. Many of the discovered genetic variants have previously been implicated with cognitive and mental health traits (such as cognitive performance, education, mental disease/disorders), and significant genetic correlations were detected for 29 pairs of traits. The significant SNPs discovered in the UKB sample were supported by a joint analysis with other four independent studies (total sample size 2,192), and we performed a meta-analysis of five samples to provide GWAS summary statistics with sample size larger than 20,000. Using genome-wide polygenic risk scores prediction, up to 4.36% of phenotypic variance (p-value=2.97*10-22) in the four independent studies can be explained by the UKB GWAS results. In conclusion, our study identifies many new genetic variants at SNP, locus and gene levels and advances our understanding of the pleiotropy and genetic co-architecture between brain volumes and other traits.

genetics↗

bioRxiv2019

Pan-Cancer Study Detects Novel Genetic Risk Variants and Shared Genetic Basis in Two Large Cohorts

Deciphering the shared genetic basis of distinct cancers has the potential to elucidate carcinogenic mechanisms and inform broadly applicable risk assessment efforts. However, no studies have investigated pan-cancer pleiotropy within single, well-defined populations unselected for phenotype. We undertook novel genome-wide association studies (GWAS) and comprehensive evaluations of heritability and pleiotropy across 18 cancer types in two large, population-based cohorts: the UK Biobank (413,870 European ancestry individuals; 48,961 cancer cases) and the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohorts (66,526 European ancestry individuals; 16,001 cancer cases). The GWAS detected 21 novel genome-wide significant risk variants. In addition, numerous cancer sites exhibited clear heritability. Investigations of pleiotropy identified 12 cancer pairs exhibiting either positive or negative genetic correlations and 43 pleiotropic loci. We identified 158 pleiotropic variants, many of which were enriched for regulatory elements and influenced cross-tissue gene expression. Our findings demonstrate widespread pleiotropy and offer further insight into the complex genetic architecture of cross-cancer susceptibility.

genetics↗

bioRxiv2020

Genetic variation for tolerance to the downy mildew pathogen Peronospora variabilis in genetic resources of quinoa (Chenopodium quinoa)

BackgroundQuinoa (Chenopodium quinoa Willd.) is an ancient grain crop that is tolerant to abiotic stress and has favorable nutritional properties. Downy mildew is the main disease of quinoa and is caused by infections of the biotrophic oomycete Peronospora variabilis Gaum. Since the disease causes major yield losses, identifying sources of downy mildew tolerance in genetic resources and understanding its genetic basis are important goals in quinoa breeding. ResultsWe infected 132 South American genotypes, three Danish cultivars and the weedy relative C. album with a single isolate of P. variabilis under greenhouse conditions and observed a large variation in disease traits like severity of infection, which ranged from 5% to 83%. Linear mixed models revealed a significant effect of genotypes on disease traits with high heritabilities (0.72 to 0.81). Factors like altitude at site of origin or seed saponin content did not correlate with mildew tolerance, but stomatal width was weakly correlated with severity of infection. Despite the strong genotypic effects on mildew tolerance, genome-wide association mapping with 88 genotypes failed to identify significant marker-trait associations indicating a polygenic architecture of mildew tolerance. ConclusionsThe strong genetic effects on mildew tolerance allow to identify genetic resources, which are valuable sources of resistance in future quinoa breeding.

plant biology↗

bioRxiv2021

Molecular population genetics of Sex-lethal (Sxl) in the D. melanogaster species group - a locus that genetically interacts with Wolbachia pipientis in Drosophila melanogaster

Sex-lethal (Sxl) is the sex determination switch in Drosophila, and also plays a critical role in germ-line stem cell (GSC) daughter differentiation in Drosophila melanogaster. Three female-sterile alleles at Sxl in Drosophila melanogaster were previously shown to genetically interact to varying degrees with the maternally inherited endosymbiont Wolbachia pipientis. Given this genetic interaction and W. pipientis ability to manipulate reproduction in Drosophila, we carried out a careful study of both the population genetics (within four Drosophila species) and molecular evolutionary analysis (across 20 Drosophila species) of Sxl. Consistent with earlier studies, we find that selective constraint has played a prominent role in Sxls molecular evolution within Drosophila, but we also observe patterns that suggest both episodic bursts of protein evolution and recent positive selection at Sxl. The episodic nature of Sxls protein evolution is discussed in light of its genetic interaction with W. pipientis.

evolutionary biology↗

bioRxiv2021

Kernel-based genetic association analysis for microbiome phenotypes identifies host genetic drivers of beta-diversity

Understanding human genetic influences on the gut microbiota helps elucidate the mechanisms by which genetics affects health outcomes. We propose a novel approach, the covariate-adjusted kernel RV (KRV) framework, to map genetic variants associated with microbiome beta-diversity, which focuses on overall shifts in the microbiota. The proposed KRV framework improves statistical power by capturing intrinsic structure within the genetic and microbiome data while reducing the multiple-testing burden. We apply the covariate-adjusted KRV test to the Hispanic Community Health Study/Study of Latinos in a genome-wide association analysis (first gene-level, then variant-level) for microbiome beta-diversity. We have identified an immunity-related gene, IL23R, reported in previous association studies and discovered 3 other novel genes, 2 of which are involved in immune functions or autoimmune disorders. Our findings highlight the value of the KRV as a powerful microbiome GWAS approach and support an important role of immunity-related genes in shaping the gut microbiome composition.

genomics↗