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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2017

Gene expression in cord blood links genetic risk for neurodevelopmental disorders with maternal psychological distress and adverse childhood outcomes

Prenatal exposure to maternal stress and depression has been identified as a risk factor for adverse behavioral and neurodevelopmental outcomes in early childhood. However, the molecular mechanisms through which maternal psychopathology shapes offspring development remain poorly understood. We applied transcriptome-wide screens to 149 umbilical cord blood samples from neonates born to mothers with posttraumatic stress disorder (PTSD; n=20), depression (n=31) and PTSD with comorbid depression (n=13), compared to carefully matched trauma exposed controls (n=23) and healthy mothers (n=62). Analyses by maternal diagnoses revealed a clear pattern of gene expression signatures distinguishing neonates born to mothers with a history of psychopathology from those without. Co-expression network analysis identified distinct gene expression perturbations across maternal diagnoses, including two depression-related modules implicated in axon-guidance and mRNA stability, as well as two PTSD-related modules implicated in TNF signaling and cellular response to stress. Notably, these disease-related modules were enriched with brain-expressed genes and genetic risk loci for autism spectrum disorder and schizophrenia, which may imply a causal role for impaired developmental outcomes. These molecular alterations preceded changes in clinical measures at twenty-four months, including reductions in cognitive and socio-emotional outcomes in affected infants. Collectively, these findings indicate that prenatal exposure to maternal psychological distress induces neuronal, immunological and behavioral abnormalities in affected offspring and support the search for early biomarkers of exposures to adverse in utero environments and the classification of children at risk for impaired development.

developmental biology↗

bioRxiv2017

Genetic ablation of RhoA in adult microglia causes synapse and neuronal loss

Nervous tissue homeostasis requires regulation of microglia activity. Using conditional gene targeting in mice, we demonstrate that genetic ablation of the small GTPase Rhoa in adult microglia is sufficient to trigger spontaneous microglia activation producing a neurological phenotype (including synapse and neuron loss, impairment of LTP, formation of {beta}-amyloid plaques and memory deficits). Mechanistically, loss of Rhoa in microglia triggers Src activation and Src-mediated Tnf production, leading to excitotoxic glutamate secretion. Inhibiting Src in microglia Rhoa-deficient mice attenuates microglia dysregulation and the ensuing neurological phenotype. We also found that the Rhoa/Src signaling pathway was disrupted in microglia of the APP/PS1 mouse model of Alzheimers disease and that low doses of A{beta} oligomers triggered microglia neurotoxic polarization through the disruption of Rhoa-to-Src signaling. Overall, our results indicate that disturbing RhoGTPase signaling in microglia can directly cause neurodegeneration.

neuroscience↗

bioRxiv2017

Singleton Variants Dominate the Genetic Architecture of Human Gene Expression

The vast majority of human mutations have minor allele frequencies (MAF) under 1%, with the plurality observed only once (i.e., \"singletons\"). While Mendelian diseases are predominantly caused by rare alleles, their cumulative contribution to complex phenotypes remains largely unknown. We develop and rigorously validate an approach to jointly estimate the contribution of all alleles, including singletons, to phenotypic variation. We apply our approach to transcriptional regulation, an intermediate between genetic variation and complex disease. Using whole genome DNA and lymphoblastoid cell line RNA sequencing data from 360 European individuals, we conservatively estimate that singletons contribute ~25% of cis-heritability across genes (dwarfing the contributions of other frequencies). Strikingly, the majority (~76%) of singleton heritability derives from ultra-rare variants absent from thousands of additional samples. We develop a novel inference procedure to demonstrate that our results are consistent with rampant purifying selection shaping the regulatory architecture of most human genes.

evolutionary biology↗

bioRxiv2017

Fronto-limbic dysconnectivity leads to impaired brain network controllability in young people with bipolar disorder and those at high genetic risk

Recent investigations have used diffusion-weighted imaging to reveal disturbances in the neurocircuitry that underlie cognitive-emotional control in bipolar disorder (BD) and in unaffected siblings or children at high genetic risk (HR). It has been difficult to quantify the mechanism by which structural changes disrupt the superimposed brain dynamics, leading to the emotional lability that is characteristic of BD. Average controllability is a concept from network control theory that extends structural connectivity data to estimate the manner in which local neuronal fluctuations spread from a node or subnetwork to alter the state of the rest of the brain. We used this theory to ask whether structural connectivity deficits previously observed in HR (n=84, mean age 22.4) individuals, patients with BD (n=38, mean age 23.9), and age- and gender-matched controls (n=96, mean age 22.6) translate to differences in the ability of brain systems to be manipulated between states. Localized impairments in network controllability were seen in the left parahippocampal, left middle occipital, left superior frontal, right inferior frontal, and right precentral gyri in BD and HR groups. Subjects with BD had distributed deficits in a subnetwork containing the left superior and inferior frontal gyri, postcentral gyrus, and insula (p=0.004). HR participants had controllability deficits in a right-lateralized subnetwork involving connections between the dorsomedial and ventrolateral prefrontal cortex, the superior temporal pole, putamen, and caudate nucleus (p=0.008). Between-group controllability differences were attenuated after removal of topological factors by network randomization. Some previously reported differences in network connectivity were not associated with controllability-differences, likely reflecting the contribution of more complex brain network properties. These analyses highlight the potential functional consequences of altered brain networks in BD, and may guide future clinical interventions.\n\nHighlightsO_LIControl theory estimates how neuronal fluctuations spread from local networks.\nC_LIO_LIWe compare brain controllability in bipolar disorder and their high-risk relatives.\nC_LIO_LIThese groups have impaired controllability in networks supporting cognitive and emotional control.\nC_LIO_LIWeaker connectivity as well as topological alterations contribute to these changes.\nC_LI

neuroscience↗

bioRxiv2017

On the proportional abundance of species: Integrating population genetics and community ecology

The frequency of genes in interconnected populations and of species in interconnected communities are affected by similar processes, such as birth, death and immigration. The equilibrium distribution of gene frequencies in structured populations is known since the 1930s, under Wrights metapopulation model known as the island model. The equivalent distribution for the species frequency (i.e. the species proportional abundance distribution (SPAD), at the metacommunity level, however, is unknown. In this contribution, we develop a stochastic model to analytically account for this distribution (SPAD). We show that the same as for genes SPAD follows a beta distribution, which provides a good description of empirical data and applies across a continuum of scales. This stochastic model, based upon a diffusion approximation, provides an alternative to neutral models for the species abundance distribution (SAD), which focus on number of individuals instead of proportions, and demonstrate that the relative frequency of genes in local populations and of species within communities follow the same probability law. We hope our contribution will help stimulate the mathematical and conceptual integration of theories in genetics and ecology.

ecology↗

bioRxiv2017

Tracing cellular heterogeneity in pooled genetic screens via multi-level barcoding

While pooled loss- and gain-of-function screening approaches have become increasingly popular to systematically investigate mammalian gene function, they have thus far ignored the fact that cell populations are heterogeneous. Here we introduce multi-level barcoded sgRNA libraries to (i) monitor differences in the behavior of multiplexed clonal cell lines, (ii) trace sub-clonal lineages of cells expressing the same sgRNA, (iii) derive in-sample screen replicates and (iv) reduce the number of cells and sequencing read counts required to reach statistical significance. Using our approach, we illustrate how clonal heterogeneity impairs the results of pooled genetic screens and demonstrate the ability of multi-level barcoding to resolve cellular heterogeneity related issues.

genomics↗

bioRxiv2017

Optimal Vaccination of a General Population Network via Genetic Algorithms

Herein we extend the work from Patel et al. (1) to find the approximate, optimal distribution of vaccinations of a virus spreading on a network with the use of Genetic Algorithms (GAs). We situate our investigation in an online social network, a Facebook graph of ~4000 nodes. Within this framework we investigate the performance of an optimized vaccine distribution scheme against that of a well known heuristic scheme: the vaccination of highly ranked nodes. We include also a baseline scheme of vaccinating random nodes. We show the algorithm is superior to rank scheme in low vaccine coverages, and performs comparably for most other coverage values, lending support to the optimality of this heuristic measure.

epidemiology↗

bioRxiv2017

High resolution genetic mapping of causal regulatory interactions in the human genome

Physical interaction of distal regulatory elements in three-dimensional space poses a significant challenge for studies of common disease, because noncoding risk variants may be substantial distances from the genes they regulate. Experimental methods to capture these interactions, such as chromosome conformation capture (CCC), usually cannot assign causal direction of effect between regulatory elements, an important component of disease fine-mapping. Here, we developed a statistical model that uses Mendelian Randomisation within a Bayesian hierarchical model framework, and applied it to a novel ATAC-seq data from 100 individuals mapping over 15,000 putatively causal interactions between distal regions of open chromatin. Strikingly, the majority (>60%) of interactions we detected were over distances of <20Kb, a range where CCC-based methods perform poorly. Because we can infer the direction of causal interactions, the model also significantly improves our ability to fine-map: when we applied it to an eQTL data set we reduced the number of variants in the 90% credible set size by half. We experimentally validate one of our associations using CRISPR engineering of the BLK/FAM167A locus, which is associated with risk for a range of autoimmune diseases and show that the causal variant is likely to be a non-coding insertion within a CTCF binding motif. Our study suggests that many regulatory variants will be challenging to map to their cognate genes using CCC-based techniques, but association genetics of chromatin state can provide a powerful complement to these approaches.

genomics↗

bioRxiv2017

Systematic genetic interaction studies identify histone demethylase Utx as potential target for ameliorating Huntington’s disease

Huntingtons Disease (HD) is a dominantly inherited neurodegenerative disease caused by alterations in the huntingtin gene (htt). Transcriptional dysregulation is an early event in HD progression. Protein acetylation and methylation particularly on histones regulates chromatin structure thereby preventing or facilitating transcription. Although protein acetylation has been found to affect HD symptoms, little is known about the potential role of protein methylation in HD pathology. In recent years, a series of proteins have been described that are responsible for methylating and demethylating histones as well as other proteins. We carried out systematic genetic interaction studies testing lysine and arginine methylases and demethylases in a Drosophila melanogaster HD model. We found that modulating methylation enzymes that typically affect histone positions H3K4, H3K36 or H3K79 had varying effects on HD pathology while modulating ones that typically affect constitutive heterochromatin marks at H3K9 and H4K20 generally had limited impact on HD pathology. In contrast, modulating enzymes acting on the facultative heterochromatin mark at H3K27 had specific effects on HD pathology, with reduction of the demethylase Utx rescuing HTT induced pathology while reducing PRC2 complex core methylase components led to more aggressive pathology. Further exploration of the mechanism underlying the methylation-specific interactions suggest that these lysine and arginine methylases and demethylases are likely exerting their influence through non-histone targets. These results highlight a novel therapeutic approach for HD in the form of Utx inhibition.

neuroscience↗

bioRxiv2017

Genetic knockdown and knockout approaches in Hydra

Hydra is a member of the Cnidaria, an ancient phylum at the base of metazoan evolution and sister group to all bilaterian animals. The regeneration capacity of Hydra, mediated by its stem cell systems is unparalleled in the animal kingdom. The recent sequencing of the Hydra genome and that of other cnidarians has drawn new attention to this well-known model organism. In spite of this, the establishment of methods to manipulate gene expression in Hydra have remained a major challenge. Here we report a CRISPR-Cas9 based targeted mutation approach as well as an optimized, reproducible strategy for the delivery of siRNAs. Both approaches are based on a refined electroporation protocol for adult Hydra polyps. We demonstrate that these strategies provide reliable genetic interference with target gene expression, facilitating functional studies and genome editing in Hydra.

developmental biology↗

bioRxiv2017

Cell Lysate Microarray for Mapping the Network of Genetic Regulators for Histone Marks

Protein, as the major executer for cell progresses and functions, its abundance and the level of post-translational modifications, are tightly monitored by regulators. Genetic perturbation could help us to understand the relationships between genes and protein functions. Herein, we developed a cell lysate microarray on kilo-conditions (CLICK) from 4,837 yeast knockout (YKO) strains and 322 temperature-sensitive mutant strains to explore the impact of the genome-wide interruption on certain protein. Taking histone marks as examples, a general workflow was established for the global identification of upstream regulators. Through a single CLICK array test, we obtained a series of regulators for H3K4me3 which covers most of the known regulators in Saccharomyces cerevisiae. We also noted that several group of proteins that are linked to negatively regulation of H3K4me3. Further, we discovered that Cab4p and Cab5p, two key enzymes of CoA biosynthesis, play central roles in histone acylation. Because of its general applicability, CLICK array could be easily adopted to rapid and global identification of upstream protein/enzyme(s) that regulate/modify the level of a protein or the posttranslational modification of a non-histone protein.

systems biology↗

bioRxiv2017

The fruitENCODE project sheds light on the genetic and epigenetic basis of convergent evolution of climacteric fruit ripening

Fleshy fruit evolved independently multiple times during angiosperm history. Many climacteric fruits utilize the hormone ethylene to regulate ripening. The fruitENCODE project shows there are multiple evolutionary origins of the regulatory circuits that govern climacteric fruit ripening. Eudicot climacteric fruits with recent whole-genome duplications (WGDs) evolved their ripening regulatory systems using the duplicated floral identity genes, while others without WGD utilised carpel senescence genes. The monocot banana uses both leaf senescence and duplicated floral-identity genes, forming two interconnected regulatory circuits. H3K27me3 plays a conserved role in restricting the expression of key ripening regulators and their direct orthologs in both the ancestral dry fruit and non-climacteric fleshy fruit species. Our findings suggest that evolution of climacteric ripening was constrained by limited availability of signalling molecules and genetic and epigenetic materials, and WGD provided new resources for plants to circumvent this limit. Understanding these different ripening mechanisms makes it possible to design tailor-made ripening traits to improve quality, yield and minimize postharvest losses.\n\nOne Sentence SummaryThe fruitENCODE project discovered three evolutionary origins of the regulatory circuits that govern climacteric fruit ripening.

genomics↗

bioRxiv2017

The genomic ancestry, landscape genetics, and invasion history of introduced mice in New Zealand

1. SummaryThe house mouse (Mus musculus) provides a fascinating system for studying both the genomic basis of reproductive isolation, and the patterns of human-mediated dispersal. New Zealand has a complex history of mouse invasions, and the living descendants of these invaders have genetic ancestry from all three subspecies, although most are primarily descended from M. m. domesticus. We used the GigaMUGA genotyping array (~135,000 loci) to describe the genomic ancestry of 161 mice, sampled from 34 locations from across New Zealand (and one Australian city - Sydney). Of these, two populations, one in the south of the South Island, and one on Chatham Island, showed complete mitochondrial lineage capture, featuring two different lineages of M. m. castaneus mitochondrial DNA but with only M. m. domesticus nuclear ancestry detectable. Mice in the northern and southern parts of the North Island had small traces (~2-3%) of M. m. castaneus nuclear ancestry, and mice in the upper South Island had ~7-8% M. m. musculus nuclear ancestry including some Y-chromosomal ancestry - though no detectable M. m. musculus mitochondrial ancestry. This is the most thorough genomic study of introduced populations of house mice yet conducted, and will have relevance to studies of the isolation mechanisms separating subspecies of mice.

genomics↗

bioRxiv2018

Global genetic diversity of small ruminant lentiviruses, and a hypothesis regarding their pandemic spread.

Small ruminant lentiviruses (SRLVs) cause chronic, persistent infections in populations of domestic sheep and goats throughout the world. In this study, we use genomic data to investigate the origins and history of the SRLV pandemic. To explore the hypothesis that SRLV infection disseminated during Neolithic times, we performed a serology and DNA sequencing-based investigation of SRLVs diversity in the Fertile Crescent region, where domestication of sheep and goats is thought to have originally occurred. While we found an elevated level of viral genetic diversity compared to other regions of the world, we did not find unambiguous evidence that the Fertile Crescent region was the centre of the contemporary SRLV pandemic. We therefore examined historical reports to investigate the relationship between contemporary SRLV distribution and diversity and the emergence of SRLV-associated disease. Historical data suggested that the emergence of SRLV-associated disease might be associated with the long-distance export of exotic small ruminant breeds - in particular, karakul sheep from Central Asia - during the late 19th and early 20th centuries. Phylogeographic analysis could neither confirm nor refute this hypothesis. However, we anticipate that future accumulation of genomic data from SRLV strains found throughout the world may allow for a more definitive assessment. The openly available data and resources assembled in this study will facilitate future investigations in this area.\n\nImportanceViruses that cause chronic, persistent infections have circulated in animals for millions of years. However, many have only emerged as pathogens within the far shorter timeframe of recorded human history. It is important to understand the history of chronic viral infections in domestic animals, so that more effective control and eradication programs can be developed.

evolutionary biology↗

bioRxiv2017

Identification and analysis of mobile genetic elements in Gibbon genome

Recent sequencing of genome of northern white-cheeked gibbon (Nomascus leucogenys) has provided important insight into fast evolution of gibbons and signatures relevant to gibbon biology. It was revealed that mobile genetic elements (MGE) seems to play major role in gibbon evolution. Here we report that most of the gibbon genome is occupied by the MGEs such as ALUs, MIRs, LINE1, LINE 2, LINE 3, ERVL, ERV-class1, ERV-class II and other DNA elements which include hAT Charlie and TcMar tigger. We provide detailed description and genome wide distribution of all the MGEs present in gibbon genome. Previously, it was reported that gibbon-specific retrotransposon (LAVA) tend to insert into chromosome segregation genes and alter transcription by providing a premature termination site, suggesting a possible molecular mechanism for the genome plasticity of the gibbon lineage. We show that insertion sites of LAVA elements present atypical signals/patterns which are different from typical signals present at insertion sites of Alu elements. This suggests possibility of distinct insertion mechanism used by LAVA elements for their insertions. We also find similarity in signals of LAVA elements insertion sites with atypical signals present at Alus /L1s insertion sites disrupting the genes leading to diseases such as cancer and Duchenne muscular dystrophy. This suggest role of LAVA in premature transcription termination.

bioinformatics↗

bioRxiv2017

Glyoxalase (GLO1) inhibition or genetic overexpression does not alter ethanol locomotor effects: implications for GLO1 as a therapeutic target in alcohol use disorders

BackgroundGlyoxalase 1 (GLO1) is an enzyme that metabolizes methylglyoxal (MG), which is a competitive partial agonist at GABAA receptors. Inhibition of GLO1 increases concentrations of MG in the brain and decreases binge-like ethanol drinking. The present study assessed whether inhibition of GLO1, or genetic over expression of Glo1, would also alter the locomotor effects of ethanol, which might explain reduced ethanol consumption following GLO1 inhibition. We used the prototypical GABAA receptor agonist muscimol as a positive control.\n\nMethodsMale C57BL/6J mice were pretreated with aeither the GLO1 inhibitor S-bromobenzylglutathione cyclopentyl diester (pBBG; 7.5 mg/kg; Experiment 1) or muscimol (0.75 mg/kg; Experiment 2), or their corresponding vehicle. We then determined whether locomotor response to a range of ethanol doses (0, 0.5, 1.0, 1.5, 2.0, and 2.5) was altered by either pBBG or muscimol pretreatment. We also examined the locomotor response to a range of ethanol doses in FVB/NJ wild type and transgenic Glo1 over expressing mice (Experiment 3). Anxiety-like behavior (time spent in the center of the open field) was assessed in all three experiments.\n\nResultsThe ethanol dose-response curve was not altered by pretreatment with pBBG or by transgenic overexpression of Glo1. In contrast, muscimol blunted locomotor stimulation at low ethanol doses, and potentiated locomotor sedation at higher ethanol doses. No drug or genotype differences were seen in anxiety-like behavior after ethanol treatment.\n\nConclusionsThe dose of pBBG used in this study is within the effective range shown previously to reduce ethanol drinking. Glo1 overexpression has been previously shown to increase ethanol drinking. However, neither manipulation altered the dose response curve for ethanols locomotor effects, whereas muscimol appeared to enhance the locomotor sedative effects of ethanol. The present data demonstrate that reduced ethanol drinking caused by GLO1 inhibition is not due to potentiation of ethanols stimulant or depressant effects.

neuroscience↗

bioRxiv2017

Was maize domesticated in the Balsas Basin? Complex patterns of genetic divergence, gene flow and ancestral introgressions among Zea subspecies suggest an alternative scenario

The study of maize domestication has overlooked the genetic structure within maizes wild relative teosinte. Prior to investigating the domestication history of maize (Zea mays subspecies mays), one should first understand the population history of teosintes and how they relate to maize. To achieve this, we used 32,739 SNPs obtained from a broad sampling of teosinte populations and 46 maize landraces and a) inferred current and past gene flow among teosinte populations and maize, b) analyzed the degree of introgression among Zea mays subspecies, and c) explored the putative domestication location of maize. We found geographic structure and introgression between Zea mays taxa. Teosinte subspecies have diverged significantly from maize, which indicates that current teosinte populations have evolved mainly independently from maize since the domestication. Our results further suggest that the likely ancestor of maize may maybe have come from Jalisco or the Pacific coast.\n\nOne Sentence SummaryShared polymorphism in teosinte suggests a Jalisco origin of maize domestication.

evolutionary biology↗

bioRxiv2017

SeqsLab: an integrated platform for cohort-based annotation and interpretation of genetic variants on Spark

SummarySeqsLab is a platform that helps researchers to easily annotate and interpret genetic variants derived from a large quantity of personal genomes. It provides an integrated interface to annotate the variants based on curated databases as well as in silico estimation on the effects of the variants. SeqsLab adopts the scalable cluster computing framework, Spark, and incorporates several customized algorithms to speed up the process of variant annotation and interpretation. The key features of SeqsLab include efficient annotation on large structural variations, diverse combinations of variant filters, easy incorporation with a vast amount of public databases, and scalable architecture of analyzing hundreds of human whole genomes simultaneously.\n\nAvailability and ImplementationSeqsLab is implemented with JAVA. The generated annotation will then be stored in Elasticsearch for real-time query and exploratory analysis. SeqsLab can be accessed by web browsers and is freely available at http://portal.seqslab.net/.\n\nContactchungtsai_su@atgenomix.com\n\nSupplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics↗