SEARCH · Search bioRxiv

Results for “Genetics”

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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,621 records · Page 90Linked to original sources

bioRxiv2018

Genetic dissection of the different roles of hypothalamic kisspeptin neurons in regulating female reproduction

The brain regulates fertility through gonadotropin-releasing hormone (GnRH) neurons. Estradiol induces negative feedback on pulsatile GnRH/luteinizing hormone (LH) release and positive feedback generating preovulatory GnRH/LH surges. Negative and positive feedback are postulated to be mediated by kisspeptin neurons in arcuate and anteroventral periventricular (AVPV) nuclei, respectively. Kisspeptin-specific ER knockout mice exhibit disrupted LH pulses and surges. This knockout approach is neither location-specific nor temporally-controlled. We utilized CRISPR-Cas9 to disrupt ER in adulthood. Mice with ER disruption in AVPV kisspeptin neurons have typical reproductive cycles but blunted LH surges, associated with decreased excitability of these neurons. Mice with ER knocked down in arcuate kisspeptin neurons showed disrupted cyclicity, associated with increased glutamatergic transmission to these neurons. These observations suggest activational effects of estradiol regulate surge generation and maintain cyclicity through AVPV and arcuate kisspeptin neurons, respectively, independent from its role in the development of hypothalamic kisspeptin neurons or puberty onset.\n\nSignificant StatementThe brain regulates fertility through gonadotropin-releasing hormone (GnRH) neurons. Ovarian estradiol regulates GnRH pulses (negative feedback) and the GnRH surge release that ultimately triggers ovulation (positive feedback). Kisspeptin neurons in the arcuate and anteroventral periventricular nuclei are postulated to convey negative and positive feedback to GnRH neurons, respectively. Kisspeptin-specific ER knockout mice exhibited disrupted negative and positive feedback. However, it is not clear what roles each kisspeptin population plays, and not possible to separate their roles during development vs adulthood in this model. Here we utilized CRISPR-Cas9 to disrupt ER in each population in adulthood. We found activational effects of estradiol regulate surge generation and maintain cyclicity through AVPV and arcuate kisspeptin neurons, respectively, independent from estradiol action during development.

neuroscience↗

bioRxiv2018

Genetic dissection of Nodal and Bmp signalling requirements during primordial germ cell development

The essential roles played by Nodal and Bmp signalling during early mouse development have been extensively documented. Here we used conditional deletion strategies to investigate functional contributions made by Nodal, Bmp and Smad downstream effectors during primordial germ cell (PGC) development. We demonstrate that Nodal and its target gene Eomes provide early instructions during formation of the PGC lineage. We discovered that Smad2 inactivation in the visceral endoderm results in increased numbers of PGCs due to an expansion of the PGC niche. Smad1 is required for specification, whereas in contrast Smad4 controls the maintenance and migration of PGCs. Importantly we found that beside Blimp1, down-regulated phosphoSmad159 levels also distinguishes PGCs from their somatic neighbours so that emerging PGCs become refractory to Bmp signalling that otherwise promotes mesodermal development in the posterior epiblast. Thus balanced Nodal/Bmp signalling cues regulate germ cell versus somatic cell fate decisions in the early posterior epiblast.

developmental biology↗

bioRxiv2018

VCF/Plotein: A web application to facilitate the clinical interpretation of genetic and genomic variants from exome sequencing projects

PurposeTo create a user-friendly web application that allows researchers, medical professionals and patients to easily and securely view, filter and interact with human exome sequencing data in the Variant Call Format (VCF).\n\nMethodsWe have created VCF/Plotein, a web application written entirely in JavaScript using the Vue.js framework, available at http://vcfplotein.liigh.unam.mx. After a VCF is loaded, gene and variant information is extracted from Ensembl, and cross-referencing with external databases is performed via the Elasticsearch search engine. Support for application-based gene and variant filtering has also been implemented. Interactive graphs are created using the D3.js library. All data processing is done locally in the users CPU to ensure the security of patient data.\n\nResultsVCF/Plotein allows users to interactively view and filter VCF files without needing any bioinformatics knowledge. A number of features make it especially suited for the medical community, such as its speed, security, the ability to filter by disease or gene function, and the ease with which information may be shared with collaborators/co-workers.\n\nConclusionVCF/Plotein is a novel web application that allows users to easily and interactively filter and display exome sequencing information, and that is especially suited for bench researchers, medical professionals and patients.

bioinformatics↗

bioRxiv2018

Genetic selection for small molecule production in competitive microfluidic droplets

Biosensors can be used to screen or select for small molecule production in engineered microbes. However, mutations to the biosensor that interfere with accurate signal transduction are common, producing an excess of false positives. Strategies have been developed to avoid this limitation by physically separating the production pathway and biosensor, but these approaches have only been applied to screens, not selections. We have developed a novel biosensor-mediated selection strategy using competition between co-cultured bacteria. When applied to biosynthesis of cis,cis-muconate, we show that this strategy yields a selective advantage to producer strains that outweighs the costs of production. By encapsulating the competitive co-cultures into microfluidic droplets, we successfully enriched for muconate-producing strains from a large population of control non-producers. Facile selections for small molecule production will increase testing throughput for engineered microbes and allow for the rapid optimization of novel metabolic pathways.

synthetic biology↗

bioRxiv2018

Genetic loss of the ubiquitin ligase RNF126, an AID interacting partner and modifier, affects strand targeting during somatic hypermutation of antibody genes

Activation-induced cytidine deaminase (AID) initiates somatic hypermutation (SHM) and class switch recombination (CSR) in B lymphocytes by catalyzing the introduction of deoxyuracil: deoxyguanine mismatches into the DNA of the transcribed Ig locus. Repair pathways then process these mismatches to produce point mutations in the Ig variable region or double-stranded DNA breaks in the switch region followed by deletional recombination. It has been suggested that post-translational modifications on AID mediate a number of these different decisions, ranging from global targeting (Ig vs the genome), local targeting (variable vs switch region; transcribed vs non-transcribed strand) as well as process-appropriate DNA repair. Here we demonstrate that absence of RNF126, an E3 ligase shown to mono-ubiquitylate AID, results in a specific strand targeting defect in SHM, producing substantial G>C bias; strickingly, loss of RNF126 was also associated with tandem indels within the variable region (JH4 intron) but only a slight increase in the types of chromosomal translocations that are characteristic of deregulated AID. Conversely, these findings suggest that mono-ubiquitination of AID, likely in situ, is necessary for the proper removal of the protein from the non-transcribed strand, thus producing both optimal patterns of SHM and also limiting the number of indels within the target locus.

immunology↗

bioRxiv2018

DNA microscopy: Optics-free spatio-genetic imaging by a stand-alone chemical reaction

Analyzing the spatial organization of molecules in cells and tissues is a cornerstone of biological research and clinical practice. However, despite enormous progress in profiling the molecular constituents of cells, spatially mapping these constituents remains a disjointed and machinery-intensive process, relying on either light microscopy or direct physical registration and capture. Here, we demonstrate DNA microscopy, a new imaging modality for scalable, optics-free mapping of relative biomolecule positions. In DNA microscopy of transcripts, transcript molecules are tagged in situ with randomized nucleotides, labeling each molecule uniquely. A second in situ reaction then amplifies the tagged molecules, concatenates the resulting copies, and adds new randomized nucleotides to uniquely label each concatenation event. An algorithm decodes molecular proximities from these concatenated sequences, and infers physical images of the original transcripts at cellular resolution. Because its imaging power derives entirely from diffusive molecular dynamics, DNA microscopy constitutes a chemically encoded microscopy system.

bioengineering↗

bioRxiv2018

Genetic resistance to DEHP-induced transgenerational endocrine disruption

Di(2-ethylhexyl)phthalate (DEHP) interferes with sex hormones signaling pathways (SHP). C57BL/6J mice prenatally exposed to DEHP develop a testicular dysgenesis syndrome (TDS) at adulthood, but similarly-exposed FVB/N mice are not affected. Here we aim to understand the reasons behind this drastic difference that should depend on the genome of the strain. In both backgrounds, pregnant female mice received per os either DEHP or corn oil vehicle and the male filiations were examined. Computer-assisted sperm analysis showed a DEHP-induced decreased sperm count and velocities in C57BL/6J. Sperm RNA sequencing experiments resulted in the identification of the 62 most differentially expressed RNAs. These RNAs, mainly regulated by hormones, produced strain-specific transcriptional responses to prenatal exposure to DEHP; a pool of RNAs was increased in FVB, another pool of RNAs was decreased in C57BL/6J. In FVB/N, analysis of non-synonymous SNP impacting SHP identified rs387782768 and rs387782768 respectively associated with absence of the Forkhead Box A3 (Foxa3) RNA and increased expression of estrogen receptor 1 variant 4 (NM_001302533) RNA. Analysis of the role of SNPs modifying SHP binding sites in function of strain-specific responses to DEHP revealed a DEHP-resistance allele in FVB/N containing an additional FOXA1-3 binding site at rs30973633 and four DEHP-induced beta-defensins (Defb42, Defb30, Defb47 and Defb48). A DEHP-susceptibility allele in C57BL/6J contained five SNPs (rs28279710, rs32977910, rs46648903, rs46677594 and rs48287999) affecting SHP and six genes (Svs2, Svs3b, Svs4, Svs3a, Svs6 and Svs5) epigenetically silenced by DEHP. Finally, targeted experiments confirmed increased methylation in the Svs3ab promoter with decreased SEMG2 persisting across generations, providing a molecular explanation for the transgenerational sperm velocity decrease found in C57BL/6J after DEHP exposure. We conclude that the existence of SNP-dependent mechanisms in inbred mice may confer resistance to transgenerational endocrine disruption.

genomics↗

bioRxiv2018

Genetic dissection of a Leishmania flagellar proteome demonstrates requirement for directional motility in sand fly infections

The protozoan parasite Leishmania possesses a single flagellum, which is remodelled during the parasites life cycle from a long motile flagellum in promastigote forms in the sand fly to a short immotile flagellum in amastigotes residing in mammalian phagocytes. This study examined the protein composition and in vivo function of the promastigote flagellum. Protein mass spectrometry and label free protein enrichment testing of isolated flagella and deflagellated cell bodies defined a flagellar proteome for L. mexicana promastigote forms (available via ProteomeXchange with identifier PXD011057). This information was used to generate a CRISPR-Cas9 knockout library of 100 mutants to screen for flagellar defects. This first large-scale knockout screen in a Leishmania sp. identified 56 mutants with altered swimming speed (52 reduced and 4 increased) and defined distinct mutant categories (faster swimmers, slower swimmers, slow uncoordinated swimmers and paralysed cells, including aflagellate promastigotes and cells with curled flagella and disruptions of the paraflagellar rod). Each mutant was tagged with a unique 17-nt barcode, providing a simple barcode sequencing (bar-seq) method for measuring the relative fitness of L. mexicana mutants in vivo. In mixed infections of the permissive sand fly vector Lutzomyia longipalpis, paralysed promastigotes and uncoordinated swimmers were severely diminished in the fly after defecation of the bloodmeal. Subsequent examination of flies infected with a single mutant lacking the central pair protein PF16 showed that these paralysed promastigotes did not reach anterior regions of the fly alimentary tract. These data show that L. mexicana need directional motility for successful colonisation of sand flies.\n\nAuthor SummaryLeishmania are protozoan parasites, transmitted between mammals by the bite of phlebotomine sand flies. Promastigote forms in the sand fly have a long flagellum, which is motile and used for anchoring the parasites to prevent clearance with the digested blood meal remnants. To dissect flagellar functions and their importance in life cycle progression, we generated here a comprehensive list of >300 flagellar proteins and produced a CRISPR-Cas9 gene knockout library of 100 mutant Leishmania. We studied their behaviour in vitro before examining their fate in the sand fly Lutzomyia longipalpis. Measuring mutant swimming speeds showed that about half behaved differently compared to the wild type: a few swam faster, many slower and some were completely paralysed. We also found a group of uncoordinated swimmers. To test whether flagellar motility is required for parasite migration from the fly midgut to the foregut from where they reach the next host, we infected sand flies with a mixed mutant population. Each mutant carried a unique tag and tracking these tags up to nine days after infection showed that paralysed and uncoordinated Leishmania were rapidly lost from flies. These data indicate that directional swimming is important for successful colonisation of sand flies.

cell biology↗

bioRxiv2018

Network-based genetic profiling, and therapeutic target identification of Thyroid Cancer

Pathogenic mechanisms that underlie malignant follicular thyroid carcinoma (FTC) development are poorly understood. To identify key genes and pathways driving malignant behaviour we employed a system biology-based integrative analyses comparing FTC transcriptomes with a similar but benign lesion, follicular thyroid adenoma (FTA). We identified differentially expressed genes (DEGs) in microarray gene expression datasets (n=52) of FTCs and FTA tissues. Pathway analyses of DEGs using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) resources revealed significant pathways, and pathway hub genes using protein-protein interactions (PPI). We identified 598 DEGs (relative to FTAs) in FTCs and 12 significant pathways with altered expression in FTC. 10 GO groups were significantly connected with FTC-high expression DEGs and 80 with low-FTC expression. PPI analysis identified 12 potential hub genes based on degree and betweenness centrality. Moreover, 10 transcription factors (TFs) were identified that may underlie DEG expression as well as a number of microRNA (miRNAs). Thus, we identified DEGs, pathways, TFs and miRNAs that reflect molecular mechanisms differing between FTC and benign FTA. These may constitute biomarkers that distinguish these lesions and, given the similarities and common origin of the lesions, they may also be indicators of malignant progression potential.

bioinformatics↗

bioRxiv2018

Flexible, fast and selective genetic manipulation of the vertebrate CNS with misPiggy

In utero electroporation is increasingly used for manipulation of gene expression in the mammalian central nervous system. Here we created a transposon-based single plasmid system, that allows long-term conditional loss- and gain-of-function experiments across major CNS cell types. The system is widely applicable across species, allowing fast, flexible and cheap cell manipulation in previously non-transgenic species.

neuroscience↗

bioRxiv2018

Genetic, structural, and functional analysis of mutations causing methylmalonyl-CoA epimerase deficiency

Human methylmalonyl-CoA epimerase (MCEE) catalyzes the interconversion of D-methylmalonyl-CoA and L-methylmalonyl-CoA in propionate catabolism. Autosomal recessive mutations in MCEE reportedly cause methylmalonic aciduria (MMAuria) in eleven patients. We investigated a cohort of 150 individuals suffering from MMAuria of unknown origin, identifying ten new patients with mutations in MCEE. Nine patients were homozygous for the known nonsense mutation p.Arg47* (c.139C>T), and one for the novel missense mutation p.Ile53Arg (c.158T>G). To understand better the molecular basis of MCEE deficiency, we mapped p.Ile53Arg, and two previously described patient mutations p.Lys60Gln and p.Arg143Cys, onto our 1.8 [A] structure of wild-type (wt) human MCEE. This revealed potential dimeric assembly disruption by p.Ile53Arg, but no clear defects from p.Lys60Gln or p.Arg143Cys. Functional analysis of MCEE-Ile53Arg expressed in a bacterial recombinant system as well as patient-derived fibroblasts revealed nearly undetectable soluble protein levels, defective globular protein behavior, and using a newly developed assay, lack of enzymatic activity - consistent with misfolded protein. By contrast, soluble protein levels, unfolding characteristics and activity of MCEE-Lys60Gln were comparable to wt, leaving unclear how this mutation may cause disease. MCEE-Arg143Cys was detectable at comparable levels to wt MCEE, but had slightly altered unfolding kinetics and greatly reduced activity. We solved the structure of MCEE-Arg143Cys to 1.9 [A] and found significant disruption of two important loop structures, potentially impacting surface features as well as the active-site pocket. These studies reveal ten new patients with MCEE deficiency and rationalize misfolding and loss of activity as molecular defects in MCEE-type MMAuria.

biochemistry↗

bioRxiv2018

Suicidal Red Queen: Population dynamics and genetic drift accelerate diversity loss

BackgroundRed Queen dynamics are defined as long term co-evolutionary dynamics, often with oscillations of genotype abundances driven by fluctuating selection in host-parasite systems. Much of our current understanding of these dynamics is based on theoretical concepts explored in mathematical models that are mostly (i) deterministic, inferring an infinite population size and (ii) evolutionary, thus ecological interactions that change population sizes are excluded. Here, we recall the different mathematical approaches used in the current literature on Red Queen dynamics. We then compare models from game theory (evo) and classical theoretical ecology models (eco-evo), that are all derived from individual interactions and are thus intrinsically stochastic. We assess the influence of this stochasticity through the time to the first loss of a genotype within a host or parasite population. ResultsThe time until the first genotype is lost ("extinction time"), is shorter when ecological dynamics, in the form of a changing population size, is considered. Furthermore, when individuals compete only locally with other individuals extinction is even faster. On the other hand, evolutionary models with a fixed population size and competition on the scale of the whole population prolong extinction and therefore stabilise the oscillations. The stabilising properties of intraspecific competitions become stronger when population size is increased and the deterministic part of the dynamics gain influence. In general, the loss of genotype diversity can be counteracted with mutations (or recombination), which then allow the populations to recurrently undergo negative frequency-dependent selection dynamics and selective sweeps. ConclusionAlthough the models we investigated are equal in their biological motivation and interpretation, they have diverging mathematical properties both in the derived deterministic dynamics and the derived stochastic dynamics. We find that models that do not consider intraspecific competition and that include ecological dynamics by letting the population size vary, lose genotypes - and thus Red Queen oscillations - faster than models with competition and a fixed population size.

evolutionary biology↗

bioRxiv2018

Tracking genetic invasions: genome-wide SNPs reveal the source of pyrethroid-resistant Aedes aegypti (yellow fever mosquito) incursions at international ports

Biological invasions are increasing globally in number and extent despite efforts to restrict their spread. Knowledge of incursion pathways is necessary to prevent new invasions and to design effective biosecurity protocols at source and recipient locations. This study uses genome-wide single-nucleotide polymorphisms (SNPs) to determine the origin of 115 incursive Aedes aegypti (yellow fever mosquito) detected at international ports in Australia and New Zealand. We also genotyped mosquitoes at three point mutations in the voltage-sensitive sodium channel (Vssc) gene: V1016G, F1534C, and S989P. These mutations confer knockdown resistance to synthetic pyrethroid insecticides, widely used for controlling invertebrate pests. We first delineated reference populations using Ae. aegypti sampled from 15 locations in Asia, South America, Australia and the Pacific Islands. Incursives were assigned to these populations using discriminant analysis of principal components (DAPC) and an assignment test with a support vector machine predictive model. Bali, Indonesia, was the most common origin of Ae. aegypti detected in Australia, while Ae. aegypti detected in New Zealand originated from Pacific Islands such as Fiji. Most incursives had the same allelic genotype across the three Vssc gene point mutations, which confers strong resistance to synthetic pyrethroids, the only insecticide class used in current, widely-implemented aircraft disinsection protocols endorsed by the World Health Organisation (WHO). Additionally, all internationally-assigned Ae. aegypti had Vssc point mutations linked to pyrethroid resistance that are not found in Australian populations. These findings demonstrate that protocols for preventing introductions of invertebrates must consider insecticide resistance, and highlights the usefulness of genomic datasets for managing global biosecurity objectives.

genomics↗

bioRxiv2018

A genome-wide haploid genetic screen for essential factors in vaccinia virus infection identifies TMED10 as regulator of macropinocytosis

Vaccinia virus is a promising viral vaccine and gene delivery candidate, and has historically been used as a model to study poxvirus-host cell interactions. We employed a genome-wide insertional mutagenesis approach in human haploid cells to identify host factors crucial for vaccinia virus infection. A library of mutagenized HAP1 cells was exposed to Modified Vaccinia Virus Ankara (MVA). Deep-sequencing analysis of virus-resistant cells identified host factors involved in heparan sulfate synthesis, Golgi organization, and vesicular protein trafficking. We validated EXT1, TM9SF2 and TMED10 (TMP21/p23/p24{delta}) as important host factors for vaccinia virus infection. The critical role of EXT1 in heparan sulfate synthesis and vaccinia virus infection was confirmed. TM9SF2 was validated as a player mediating heparan sulfate expression, explaining its contribution to vaccinia virus infection. In addition, TMED10 was found to be crucial for virus-induced plasma membrane blebbing and phosphatidylserine-induced macropinocytosis, suggesting that TMED10 regulates actin cytoskeleton remodelling necessary for virus infection.\n\nImportancePoxviruses are large DNA viruses that can infect a wide range of host species. A number of these viruses are clinically important to humans, including variola virus (smallpox) and vaccinia virus. Since the eradication of smallpox, zoonotic infections with monkeypox virus and cowpox virus are emerging. Additionally, poxviruses can be engineered to specifically target cancer cells, and are used as vaccine vector against tuberculosis, influenza, and coronaviruses.\n\nPoxviruses rely on host factors for most stages of their life cycle, including attachment to the cell and entry. These host factors are crucial for virus infectivity and host cell tropism. We used a genome-wide knock-out library of host cells to identify host factors necessary for vaccinia virus infection. We confirm a dominant role for heparin sulfate in mediating virus attachment. Additionally, we show that TMED10, previously not implicated in virus infections, modulates the host cell membrane to facilitate virus uptake.

microbiology↗

bioRxiv2018

Rapid evolution of spontaneous mutation increases genetic diversity facilitating plant population survival

Using a mechanistic eco-evolutionary trait-based neighborhood-model, we quantify the impact of mutations on spatial interactions to better understand the potential effect of niche evolution through mutations on the population dynamics of Arabidopsis thaliana. We use 100 twenty-fifth generation mutation accumulation (MA) lines (genotypes) derived from one founder genotype to study mutational effects on neighbor responses in a field experiment. We created individual-based maps (15,000 individuals), including phenotypic variation, to quantify mutational effects within genotypes versus between genotypes on reproduction and survival. At small-scale, survival is enhanced but reproduction is decreased when a genotype is surrounded by different genotypes. At large-scale, seed set is facilitated by different genotypes while the same genotype has either no effect or negative effects. Mutations may provide a mechanism for plants to quickly evolve niches and may drive competition, facilitation and selection with profound consequences for future population and community dynamics.

ecology↗

bioRxiv2016

Polygenic analysis of schizophrenia and 19 immune diseases reveals modest pleiotropy

Epidemiological studies indicate that many immune diseases occur at different rates among people with schizophrenia compared to the general population. Here, we evaluated whether this phenotypic correlation between immune diseases and schizophrenia might be explained by shared genetic risk factors (genetic correlation). We used data from a large genome-wide association study (GWAS) of schizophrenia (N=35,476 cases and 46,839 controls) to compare the genetic architecture of schizophrenia to 19 immune diseases. First, we evaluated the association with schizophrenia of 581 variants previously reported to be associated with immune diseases at genome-wide significance. We identified three variants with pleiotropic effects, located in regions associated with both schizophrenia and immune disease. Our analyses provided the strongest evidence of pleiotropy at rs1734907 ([~]85kb upstream of EPHB4), a variant which was associated with increased risk of both Crohns disease (OR = 1.16, P = 1.67x10-13) and schizophrenia (OR = 1.07, P = 7.55x10-6). Next, we investigated genome-wide sharing of common variants between schizophrenia and immune diseases using polygenic risk scores (PRS) and cross-trait LD Score regression (LDSC). PRS revealed significant genetic overlap with schizophrenia for narcolepsy (p=4.1x10-4), primary biliary cirrhosis (p=1.4x10-8), psoriasis (p=3.6x10-5), systemic lupus erythematosus (p=2.2x10-8), and ulcerative colitis (p=4.3x10-4). Genetic correlations between these immune diseases and schizophrenia, estimated using LDSC, ranged from 0.10 to 0.18 and were consistent with the expected phenotypic correlation based on epidemiological data. We also observed suggestive evidence of sex-dependent genetic correlation between schizophrenia and multiple sclerosis (interaction p=0.02), with genetic risk scores for multiple sclerosis associated with greater risk of schizophrenia among males but not females. Our findings suggest that shared genetic risk factors contribute to the epidemiological co-occurrence of schizophrenia and certain immune diseases, and suggest that in some cases this genetic correlation is sex-dependent. Author SummaryImmune diseases occur at different rates among patients with schizophrenia compared to the general population. While the reasons for this phenotypic correlation are unclear, shared genetic risk (genetic correlation) has been proposed as a contributing factor. Prior studies have estimated the genetic correlation between schizophrenia and a handful of immune diseases, with conflicting results. Here, we performed a comprehensive cross-disorder investigation of schizophrenia and 19 immune diseases. We identified three individual genetic variants associated with both schizophrenia and immune diseases, including a variant near EPHB4 - a gene whose protein product guides the migration of lymphocytes towards infected cells in the immune system and the migration of neuronal axons in the brain. We demonstrated significant genome-wide genetic correlation between schizophrenia and narcolepsy, primary biliary cirrhosis, psoriasis, systemic lupus erythematosus, and ulcerative colitis. Finally, we identified a potential sex-dependent pleiotropic effect between schizophrenia and multiple sclerosis. Our findings point to shared genetic risk for schizophrenia and at least a subset of immune diseases, which likely contributes to their epidemiological co-occurrence. These results raise the possibility that the same genetic variants may exert their effects on neurons or immune cells to influence the development of psychiatric and immune disorders, respectively.

Genetics↗

bioRxiv2017

Is the sky the limit? On the expansion threshold of a species’ range

More than a hundred years after Griggs influential analysis of species borders, the causes of limits to species ranges still represent a puzzle that has never been understood with clarity. The topic has become especially important recently as many scientists have become interested in the potential for species ranges to shift in response to climate change - and yet, nearly all of those studies fail to recognise or incorporate evolutionary genetics in a way that relates to theoretical developments. I show that range margins can be understood based on just two measurable parameters: i) the fitness cost of dispersal - a measure of environmental heterogeneity - and ii) the strength of genetic drift, which reduces genetic diversity. Together, these two parameters define an expansion threshold: adaptation fails when genetic drift reduces genetic diversity below that required for adaptation to environmental heterogeneity. When the key parameters drop below this expansion threshold locally, a sharp range margin forms. When they drop below this threshold throughout the species range, adaptation collapses everywhere, resulting in either extinction, or formation of a fragmented meta-population. Because the effects of dispersal differ fundamentally with dimension, the second parameter - the strength of genetic drift - is qualitatively different compared to a linear habitat. In two-dimensional habitats, genetic drift becomes effectively independent of selection. It decreases with neighbourhood size - the number of individuals accessible by dispersal within one generation. Moreover, in contrast to earlier predictions, which neglected evolution of genetic variance and/or stochasticity in two dimensions, dispersal into small marginal populations aids adaptation. This is because the reduction of both genetic and demographic stochasticity has a stronger effect than the cost of dispersal through increased maladaptation. The expansion threshold thus provides a novel, theoretically justified and testable prediction for formation of the range margin and collapse of the species range.\n\nAuthor summaryGene flow across environments has conflicting effects: while it increases the genetic variation necessary for adaptation and counters the loss of genetic diversity due to genetic drift, it may also swamp adaptation to local conditions. This interplay is crucial for the dynamics of a species range expansion, which can thus be understood based on two dimensionless parameters: i) the fitness cost of dispersal - a measure of environmental heterogeneity - and ii) the strength of genetic drift - a measure of reduction of genetic diversity. Together, these two parameters define an expansion threshold: adaptation fails when the number of individuals accessible by dispersal within one generation is so small that genetic drift reduces genetic diversity below the level required for adaptation to environmental heterogeneity. This threshold provides a novel, theoretically justified and testable prediction for formation of a range margin and a collapse of a species range in two-dimensional habitats.

evolutionary biology↗

bioRxiv2016

A model of compound heterozygous, loss-of-function alleles is broadly consistent with observations from complex-disease GWAS datasets

The genetic component of complex disease risk in humans remains largely unexplained. A corollary is that the allelic spectrum of genetic variants contributing to complex disease risk is unknown. Theoretical models that relate population genetic processes to the maintenance of genetic variation for quantitative traits may suggest profitable avenues for future experimental design. Here we use forward simulation to model a genomic region evolving under a balance between recurrent deleterious mutation and Gaussian stabilizing selection. We consider multiple genetic and demographic models, and several different methods for identifying genomic regions harboring variants associated with complex disease risk. We demonstrate that the model of gene action, relating genotype to phenotype, has a qualitative effect on several relevant aspects of the population genetic architecture of a complex trait. In particular, the genetic model impacts genetic variance component partitioning across the allele frequency spectrum and the power of statistical tests. Models with partial recessivity closely match the minor allele frequency distribution of significant hits from empirical genome-wide association studies without requiring homozygous effect-sizes to be small. We highlight a particular gene-based model of incomplete recessivity that is appealing from first principles. Under that model, deleterious mutations in a genomic region partially fail to complement one another. This model of gene-based recessivity predicts the empirically observed inconsistency between twin and SNP based estimated of dominance heritability. Furthermore, this model predicts considerable levels of unexplained variance associated with intralocus epistasis. Our results suggest a need for improved statistical tools for region based genetic association and heritability estimation.\n\nAuthor SummaryGene action determines how mutations affect phenotype. When placed in an evolutionary context, the details of the genotype-to-phenotype model can impact the maintenance of genetic variation for complex traits. Likewise, non-equilibrium demographic history may affect patterns of genetic variation. Here, we explore the impact of genetic model and population growth on distribution of genetic variance across the allele frequency spectrum underlying risk for a complex disease. Using forward-in-time population genetic simulations, we show that the genetic model has important impacts on the composition of variation for complex disease risk in a population. We explicitly simulate genome-wide association studies (GWAS) and perform heritability estimation on population samples. A particular model of gene-based partial recessivity, based on allelic non-complementation, aligns well with empirical results. This model is congruent with the dominance variance estimates from both SNPs and twins, and the minor allele frequency distribution of GWAS hits.

Genetics↗