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bioRxiv2017

Genetic Architecture of Subcortical Brain Structures in Over 40,000 Individuals Worldwide

Subcortical brain structures are integral to motion, consciousness, emotions, and learning. We identified common genetic variation related to the volumes of nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen, and thalamus, using genome-wide association analyses in over 40,000 individuals from CHARGE, ENIGMA and the UK-Biobank. We show that variability in subcortical volumes is heritable, and identify 25 significantly associated loci (20 novel). Annotation of these loci utilizing gene expression, methylation, and neuropathological data identified 62 candidate genes implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

genetics↗

bioRxiv2017

Quantification of frequency-dependent genetic architectures and action of negative selection in 25 UK Biobank traits

Understanding the role of rare variants is important in elucidating the genetic basis of human diseases and complex traits. It is widely believed that negative selection can cause rare variants to have larger per-allele effect sizes than common variants. Here, we develop a method to estimate the minor allele frequency (MAF) dependence of SNP effect sizes. We use a model in which per-allele effect sizes have variance proportional to [p(1-p)], where p is the MAF and negative values of imply larger effect sizes for rare variants. We estimate by maximizing its profile likelihood in a linear mixed model framework using imputed genotypes, including rare variants (MAF >0.07%). We applied this method to 25 UK Biobank diseases and complex traits (N = 113,851). All traits produced negative estimates with 20 significantly negative, implying larger rare variant effect sizes. The inferred best-fit distribution of true values across traits had mean -0.38 (s.e. 0.02) and standard deviation 0.08 (s.e. 0.03), with statistically significant heterogeneity across traits (P = 0.0014). Despite larger rare variant effect sizes, we show that for most traits analyzed, rare variants (MAF <1%) explain less than 10% of total SNP-heritability. Using evolutionary modeling and forward simulations, we validated the model of MAF-dependent trait effects and estimated the level of coupling between fitness effects and trait effects. Based on this analysis an average genome-wide negative selection coefficient on the order of 10-4 or stronger is necessary to explain the values that we inferred.

genetics↗

bioRxiv2017

Genetic Diversity Turns a New PAGE in Our Understanding of Complex Traits

Summary/AbstractGenome-wide association studies (GWAS) have laid the foundation for investigations into the biology of complex traits, drug development, and clinical guidelines. However, the dominance of European-ancestry populations in GWAS creates a biased view of the role of human variation in disease, and hinders the equitable translation of genetic associations into clinical and public health applications. The Population Architecture using Genomics and Epidemiology (PAGE) study conducted a GWAS of 26 clinical and behavioral phenotypes in 49,839 non-European individuals. Using strategies designed for analysis of multi-ethnic and admixed populations, we confirm 574 GWAS catalog variants across these traits, and find 38 secondary signals in known loci and 27 novel loci. Our data shows strong evidence of effect-size heterogeneity across ancestries for published GWAS associations, substantial benefits for fine-mapping using diverse cohorts, and insights into clinical implications. We strongly advocate for continued, large genome-wide efforts in diverse populations to reduce health disparities.

genetics↗

bioRxiv2017

Comparison of GWAS models to identify non-additive genetic control of flowering time in sunflower hybrids

Genome-wide association studies are a powerful and widely used tool to decipher the genetic control of complex traits. One of the main challenges for hybrid crops, such as maize or sunflower, is to model the hybrid vigor in the linear mixed models, considering the relatedness between individuals. Here, we compared two additive and three non-additive association models for their ability to identify genomic regions associated with flowering time in sunflower hybrids. A panel of 452 sunflower hybrids, corresponding to incomplete crossing between 36 male lines and 36 female lines, was phenotyped in five environments and genotyped for 2,204,423 SNPs. Intra-locus effects were estimated in multi-locus models to detect genomic regions associated with flowering time using the different models. Thirteen quantitative trait loci were identified in total, two with both model categories and one with only non-additive models. A quantitative trait loci on LG09, detected by both the additive and non-additive models, is located near a GAI homolog and is presented in detail. Overall, this study shows the added value of non-additive modeling of allelic effects for identifying genomic regions that control traits of interest and that could participate in the heterosis observed in hybrids.

genetics↗

bioRxiv2017

Pleiotropy in enhancer function is encoded through diverse genetic architectures

Developmental genes can have complex c/s-regulatory regions, with multiple enhancers scattered across stretches of DNA spanning tens or hundreds of kilobases. Early work revealed remarkable modularity of enhancers, where distinct regions of DNA, bound by combinations of transcription factors, drive gene expression in defined spatio-temporal domains. Nevertheless, a few reports have shown that enhancer function may be required in multiple developmental stages, implying that regulatory elements can be pleiotropic. In these cases, it is not clear whether the pleiotropic enhancers employ the same transcription factor binding sites to drive expression at multiple developmental stages or whether enhancers function as chromatin scaffolds, where independent sets of transcription factor binding sites act at different stages. In this work we have studied the activity of the enhancers of the shavenbaby gene throughout D. melanogaster development. We found that all seven shavenbaby enhancers drive gene expression in multiple tissues and developmental stages at varying levels of redundancy. We have explored how this pleiotropy is encoded in two of these enhancers. In one enhancer, the same transcription factor binding sites contribute to embryonic and pupal expression, whereas for a second enhancer, these roles are largely encoded by distinct transcription factor binding sites. Our data suggest that enhancer pleiotropy might be a common feature of c/s-regulatory regions of developmental genes and that this pleiotropy can be encoded through multiple genetic architectures.

genetics↗

bioRxiv2017

Genetic analysis of over one million people identifies 535 novel loci for blood pressure.

High blood pressure is the foremost heritable global risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits to date (systolic, diastolic, pulse pressure) in over one million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also reveal shared loci influencing lifestyle exposures. Our findings offer the potential for a precision medicine strategy for future cardiovascular disease prevention.

genetics↗

bioRxiv2017

A parametric interpretation of Bayesian Nonparametric Inference from Gene Genealogies: linking ecological, population genetics and evolutionary processes

Using a nonparametric Bayesian approach Palacios and Minin [1] dramatically improved the accuracy, precision of Bayesian inference of population size trajectories from gene genealogies. These authors proposed an extension of a Gaussian Process (GP) nonparametric inferential method for the intensity function of non-homogeneous Poisson processes. They found that not only the statistical properties of the estimators were improved with their method, but also, that key aspects of the demographic histories were recovered. The authors work represents the first Bayesian nonparametric solution to this inferential problem because they specify a convenient prior belief without a particular functional form on the population trajectory. Their approach works so well and provides such a profound understanding of the biological process, that the question arises as to how truly \"biology-free\" their approach really is. Using well-known concepts of stochastic population dynamics, here I demonstrate that in fact, Palacios and Minins GP model can be cast as a parametric population growth model with density dependence and environmental stochasticity. Making this link between population genetics and stochastic population dynamics modeling provides novel insights into eliciting biologically meaningful priors for the trajectory of the effective population size. The results presented here also bring novel understanding of GP as models for the evolution of a trait. Thus, the ecological principles foundation of Palacios and Minin [1]s prior adds to the conceptual and scientific value of these authorsinferential approach. I conclude this note by listing a series of insights brought about by this connection with Ecology.

genetics↗

bioRxiv2017

An atlas of genetic variation for linking pathogen-induced cellular traits to human disease

Genome-wide association studies (GWAS) have identified thousands of genetic variants associated with disease. To facilitate moving from associations to disease mechanisms, we leveraged the role of pathogens in shaping human evolution with the Hi-HOST Phenome Project (H2P2): a catalog of cellular GWAS comprised of 79 phenotypes in response to 8 pathogens in 528 lymphoblastoid cell lines. Seventeen loci surpass genome-wide significance (p<5x10-8) for phenotypes ranging from pathogen replication to cytokine production. Combining H2P2 with clinical association data from the eMERGE Network and experimental validation revealed evidence for mechanisms of action and connections with diseases. We identified a SNP near CXCL10 as a cis-cytokine-QTL and a new risk factor for inflammatory bowel disease. A SNP in ZBTB20 demonstrated pleiotropy, partially mediated through NF{kappa}B signaling, and was associated with viral hepatitis. Data are available in an H2P2 web portal to facilitate further interpreting human genome variation through the lens of cell biology.

genetics↗

bioRxiv2017

Paleo-Eskimo genetic legacy across North America

Paleo-Eskimos were the first people to settle vast regions of the American Arctic around 5,000 years ago, and were subsequently joined and largely displaced around 1,000 years ago by ancestors of the present-day Inuit and Yupik. The genetic relationship between Paleo-Eskimos and Native American populations remains uncertain. We analyze ancient and present-day genome-wide data from the Americas and Siberia, including new data from Alaskan Inupiat and West Siberian populations, and the first genome-wide DNA from ancient Aleutian Islanders, ancient northern Athabaskans, and a 4,250-year-old individual of the Chukotkan Ust'-Belaya culture. Employing new methods based on rare allele and haplotype sharing as well as established methods based on allele frequency correlations, we show that Paleo-Eskimo ancestry is widespread among populations who speak Na-Dene and Eskimo-Aleut languages. Using phylogenetic modelling with allele frequency correlations and rare variation, we present a comprehensive model for the complex peopling of North America.

genetics↗

bioRxiv2017

Leveraging molecular QTL to understand the genetic architecture of diseases and complex traits

There is increasing evidence that many GWAS risk loci are molecular QTL for gene ex-pression (eQTL), histone modification (hQTL), splicing (sQTL), and/or DNA methylation (meQTL). Here, we introduce a new set of functional annotations based on causal posterior prob-abilities (CPP) of fine-mapped molecular cis-QTL, using data from the GTEx and BLUEPRINT consortia. We show that these annotations are very strongly enriched for disease heritability across 41 independent diseases and complex traits (average N = 320K): 5.84x for GTEx eQTL, and 5.44x for eQTL, 4.27-4.28x for hQTL (H3K27ac and H3K4me1), 3.61x for sQTL and 2.81x for meQTL in BLUEPRINT (all P [≤] 1.39e-10), far higher than enrichments obtained using stan-dard functional annotations that include all significant molecular cis-QTL (1.17-1.80x). eQTL annotations that were obtained by meta-analyzing all 44 GTEx tissues generally performed best, but tissue-specific blood eQTL annotations produced stronger enrichments for autoimmune dis-eases and blood cell traits and tissue-specific brain eQTL annotations produced stronger enrich-ments for brain-related diseases and traits, despite high cis-genetic correlations of eQTL effect sizes across tissues. Notably, eQTL annotations restricted to loss-of-function intolerant genes from ExAC were even more strongly enriched for disease heritability (17.09x; vs. 5.84x for all genes; P = 4.90e-17 for difference). All molecular QTL except sQTL remained significantly enriched for disease heritability in a joint analysis conditioned on each other and on a broad set of functional annotations from previous studies, implying that each of these annotations is uniquely informative for disease and complex trait architectures.

genetics↗

bioRxiv2017

Pathways-wide genetic risks in Chlamydial infections overlap between tissue tropisms: A genome-wide association scan

Chlamydia trachomatis is the most commonly diagnosed bacterial sexually transmitted infection and can lead to tubal factor infertility, a disease characterised by fibrosis of the fallopian tubes. Genetic polymorphisms in molecular pathways involving G protein coupled receptor signalling, the Akt/PI3K cascade, the mitotic cell cycle and immune response have been identified in association with the development of trachomatous scarring, an ocular form of chlamydia-related fibrotic pathology. In this case control study, we performed genome-wide association and pathways based analysis in a sample of 71 Dutch women who attended an STI clinic who were seropositive for Chlamydia trachomatis antibodies and 169 high risk Dutch women who sought similar health services but who were seronegative. We identified two regions of within-gene SNP association with Chlamydia trachomatis serological response and found that GPCR signalling and cell cycle pathways were also associated with the trait. These pathway level associations appear to be common to immunological sequelae of Chlamydial infections in both ocular and urogenital tropisms. These pathways may be central mediators of human refractoriness to chlamydial diseases.

genetics↗

bioRxiv2017

A non-genetic meiotic repair program inferred from spore survival values in fission yeast wild isolates: a clue for an epigenetic ratchet-like model of ageing?

What is the nature of the ageing process? What is the spore survival, that one would expect upon analysing a self-cross, in a wild fission yeast strain? Could this two research questions be, somehow, related? In this manuscript, I am describing some interesting observations obtained while studying fission yeast spore survival values upon genetic crosses. Early findings brought my attention into mainly studying self-crosses (intra-strain crosses in which any cell can be involved in by mating with a sibling cell). This study, yield some interesting findings. As a summary: 1) most fission yeast self-crosses do show low spore survival values; 2) clonally related strains show a high phenotypic variability in self-cross spore survival values; 3) differences in self-cross spore survival values can be detected when comparing zygotic and azygotic matings; 4) self-cross spore survival values are highly affected by environmental factors, mainly producing a reduction in the spore survival values; 5) self-cross spore survival values are "recovered" when cells are subjected to several rounds of meiotic divisions; 6) signs of correlation between spore survival and vegetative cell survival (prior to the entry into meiosis) have been observed in this study. All those observations, among others, are discussed as part of an epigenetic variability that exist in fission yeast populations. A cyclical behaviour, of this epigenetic variability it is proposed, defining an underlying ratchet-like epigenetic mechanisms acting in all cells. In this manuscript, I propose that this mechanism, is, indeed, the main cause of the ageing process.

genetics↗

bioRxiv2018

Mitochondrial D-loop DNA analyses of Norway Lobster (Nephrops norvegicus) reveals genetic isolation between Atlantic and Mediterranean populations

Nephrops norvegicus is a commercially valuable demersal fisheries species. Relatively little is understood about this species population dynamics across its distribution with previous mitochondrial and microsatellite studies failing to identify significant population-level differentiation. In this study, sequence variation in the mitochondrial (mtDNA) D-loop was analysed from samples across the distribution range. Analysis of a 375bp fragment of the D-loop revealed significant genetic differentiation between samples from the northeast Atlantic and the East Mediterranean (FST = 0.107, P<0.001). Tau ({tau}), theta ({theta}0 and {theta}1) and Fus Fs values suggest the species spread between 10,500 to 19,000 ybp and subsequently expanded rapidly across the Atlantic.

genetics↗

bioRxiv2018

Divergent genetic mechanisms lead to spiny hair in mammals

Spines, or modified hairs, have evolved multiple times in mammals, particularly in rodents. In this study, we investigated the evolution of spines in six rodent families. We first measured and compared the morphology and physical properties of hairs between paired spiny and non-spiny sister lineages. We found two distinct hair morphologies had repeatedly evolved in spiny rodents: hairs with a grooved cross-section and a second near cylindrical form. Compared to the ancestral elliptical-shaped hairs, spiny hairs had higher tension and stiffness, and overall, hairs with similar morphology had similar functional properties. To examine the genetic basis of this convergent evolution, we tested whether a single amino acid change (V370A) in the Ecdysoplasin A receptor (Edar) gene is associated with spiny hair, as this substitution causes thicker and straighter hair in East Asian human populations. We found that most mammals have the common amino acid valine at position 370, but two species, the kangaroo rat (non-spiny) and spiny pocket mouse (spiny), have an isoleucine. Importantly, none of the variants we identified are associated with differences in rodent hair morphology. Thus, the specific Edar mutation associated with variation in human hair does not seem to play a role in modifying hairs in wild rodents, suggesting that different mutations in Edar and/or other genes are responsible for variation in the spiny hair phenotypes we observed within rodents.

genetics↗

bioRxiv2018

Quantitative Genetic Analysis of the Maize Leaf Microbiome

The degree to which an organism can affect its associated microbial communities (\"microbiome\") varies by organism and habitat, and in many cases is unknown. We address this question by analyzing the metabolically active bacteria of the maize phyllosphere across 300 diverse maize lines growing in a common environment. We performed comprehensive heritability analysis for 49 community diversity metrics, 380 bacterial clades (individual operational taxonomic units and higher-level groupings), and 9042 predicted metagenomic functions. We find that only a few few bacterial clades (5) and diversity metrics (2) are significantly heritable, while a much larger number of metabolic functions (200) are. Many of these associations appear to be driven by the amount of Methylobacteria present in each sample, and we find significant enrichment for traits relating to short-chain carbon metabolism, secretion, and nitrotoluene degradation. Genome-wide association analysis identifies a small number of associated loci for these heritable traits, including two loci (on maize chromosomes 7 and 10) that affect a large number of traits even after correcting for correlations among traits. This work is among the most comprehensive analyses of the maize phyllosphere to date. Our results indicate that while most of the maize phyllosphere composition is driven by environmental factors and/or stochastic founder events, a subset of bacterial taxa and metabolic functions is nonetheless significantly impacted by host plant genetics. Additional work will be needed to identify the exact nature of these interactions and what effects they may have on the phenotype of host plants.

genetics↗

bioRxiv2018

Rapid preimplantation genetic screening (PGS) using a handheld, nanopore-based, DNA sequencer

ObjectiveTo determine if a handheld, nanopore-based DNA sequencer can be used for rapid preimplantation genetic screening (PGS).\n\nDesignRetrospective study.\n\nSettingAcademic medical center.\n\nPatient(s)Amplified genomic DNA from euploid and aneuploid trophectoderm biopsy samples (n=9) that was also tested using traditional next generation sequencing (NGS).\n\nIntervention(s)Short-read DNA library preparation and nanopore-based sequencing using a hand-held MinION sequencer.\n\nMain outcome measure(s)Comparison of cytogenetic testing result from NGS and nanopore-based sequencing and the time required for library preparation and sequencing.\n\nResult(s)Multiplexed short-read DNA library preparation was completed in 45 minutes. Sequencing times varied from 1 to 2 hours. These times compare favorably with NGS library preparation (>3.5 hours) and sequencing (>12 hours) times. Whole-chromosome aneuploidy screening results obtained from nanopore-based sequencing were identical to those obtained using NGS.\n\nConclusion(s)Methods for PGS of embryos have evolved from FISH to microarrays and most recently to NGS. Here we report the first application of nanopore-based sequencing for PGS on trophecoderm biopsy samples using a rapid multiplex short-read nanopore sequencing library preparation. Aneuploidy screening could be performed on 5 samples in one nanopore flowcell with 1 to 2 hour sequencing times. Overall, nanopore sequencing is a promising tool to perform rapid PGS assay onsite with a rapid turnover time, enabling same day testing and embryo transfer thus obviating the need for complex, large and expensive DNA sequencers or frozen embryos.

genetics↗

bioRxiv2018

Molecular Genetic Analysis of Rbm45/Drbp1: Genomic Structure, Expression, and Evolution

RNA recognition motif-type RNA-binding domain containing proteins (RBDPs) participate in RNA metabolism including regulating mRNA stability, nuclear-cytoplasmic shuttling, and splicing. Rbm45 is an RBDP first cloned from rat brain and expressed spatiotemporally during rat neural development. More recently, RBM45 has been associated with pathological aggregates in the human neurological disorders amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and Alzheimers. Rbm45 and the neural developmental protein musashi-1 are in the same family of RDBPs and have similar expression patterns. In contrast to Musashi-1, which is upregulated during colorectal carcinogenesis, we found no association of RBM45 overexpression in human colon cancer tissue. In order to begin characterizing RNA-binding partners of Rbm45, we have successfully cloned and expressed human RBM45 in an Intein fusion-protein expression system. Furthermore, to gain a better understanding of the molecular genetics and evolution of Rbm45, we used an in silico approach to analyze the gene structure of the human and mouse Rbm45 homologues and explored the evolutionary conservation of Rbm45 in metazoans. Human RBM45 and mouse Rbm45 span {bsim}17 kb and 13 kb, respectively, and contain 10 exons, one of which is non-coding. Both genes have TATA-less promoters with an initiator and a GC-rich element. Downstream of exon 10, both homologues have canonical polyadenylation signals and an embryonic cytoplasmic polyadenylation element. Moreover, our data indicate Rbm45 is conserved across all metazoan taxa from sponges (phylum Porifera) to humans (phylum Chordata), portending a fundamental role in metazoan development.

genetics↗

bioRxiv2018

Construction of a Genetic Sexing Strain for Aedes albopictus: a promising tool for the development of sterilizing insect control strategies targeting the tiger mosquito

BackgroundAedes albopictus is an invasive mosquito species of global medical concern as its distribution has recently expanded to Africa, the Americas and Europe. In the absence of prophylaxis protecting human populations from emerging arboviruses transmitted by this mosquito species, the most straightforward control measures rely on the suppression or manipulation of vector natural populations. A number of environmental-friendly methods using innundative releases of sterilizing males are currently under development. However, these strategies are still lacking an efficient sexing method required for mass production of males.\n\nResultsWe present the first Genetic Sexing Strain (GSS) in Ae. albopictus, hereafter referred as TiCoq, obtained by sex linkage of rdl gene conferring dieldrin resistance. Hatching rate, larval survival and sex ratio were followed during twelve generations. The use of dieldrin at third larval stage allowed selecting 98% of males on average.\n\nConclusionA good production rate of TiCoq males makes this GSS suitable for any control method based on mass production of Ae. albopictus sterilizing males. Despite limitations resulting from affected egg hatch as well as the nature of the used insecticide, the construction of this GSS paves the way for industrial sex separation of Ae. albopictus.

genetics↗