Genome-wide screen for heavy alcohol consumption

BACKGROUND: To find specific genes predisposing to heavy alcohol consumption (self-reported consumption of 24 grams or more of alcohol per day among men and 12 grams or more among women), we studied 330 families collected by the Framingham Heart Study made available to participants in the Genetic Analysis Workshop 13 (GAW13). RESULTS: Parametric and nonparametric methods of linkage analysis were used. No significant evidence of linkage was found; however, weak signals were identified in several chromosomal regions, including 1p22, 4q12, 4q25, and 11q24, which are in the vicinity of those reported in other similar studies. CONCLUSION: Our study did not reveal significant evidence of linkage to heavy alcohol use; however, we found weak confirmation of studies carried out in other populations

Genome-wide screen for genes involved in Caenorhabditis elegans developmentally timed sleep

In Caenorhabditis elegans, Notch signaling regulates developmentally timed sleep during the transition from L4 larval stage to adulthood (L4/A) . To identify core sleep pathways and to find genes acting downstream of Notch signaling, we undertook the first genome-wide, classical genetic screen focused on C. elegans developmentally timed sleep. To increase screen efficiency, we first looked for mutations that suppressed inappropriate anachronistic sleep in adult hsp::osm-11 animals overexpressing the Notch coligand OSM-11 after heat shock. We retained suppressor lines that also had defects in L4/A developmentally timed sleep, without heat shock overexpression of the Notch coligand. Sixteen suppressor lines with defects in developmentally timed sleep were identified. One line carried a new allele of goa-1; loss of GOA-1 Gαo decreased C. elegans sleep. Another line carried a new allele of gpb-2, encoding a Gβ5 protein; Gβ5 proteins have not been previously implicated in sleep. In other scenarios, Gβ5 GPB-2 acts with regulators of G protein signaling (RGS proteins) EAT-16 and EGL-10 to terminate either EGL-30 Gαq signaling or GOA-1 Gαo signaling, respectively. We found that loss of Gβ5 GPB-2 or RGS EAT-16 decreased L4/A sleep. By contrast, EGL-10 loss had no impact. Instead, loss of RGS-1 and RGS-2 increased sleep. Combined, our results suggest that, in the context of L4/A sleep, GPB-2 predominantly acts with EAT-16 RGS to inhibit EGL-30 Gαq signaling. These results confirm the importance of G protein signaling in sleep and demonstrate that these core sleep pathways function genetically downstream of the Notch signaling events promoting sleep

A transcriptional network associated with natural variation in Drosophila aggressive behavior

A genome-wide screen of inbred Drosophila lines together with transcriptional network modeling reveals insights into the genetic bases of heritable aggression

A genome-wide screen for resilient responses in growing pigs

Background There is a growing interest to decipher the genetic background of resilience and its possible improvement through selective breeding. The objective of the present study was to provide new insights into the genetic make-up of resilience in growing pigs by identifying genomic regions and candidate genes associated with resilience indicators. Commercial Duroc pigs were challenged with an attenuated Aujeszky vaccine at 12 weeks of age. Two resilience indicators were used: deviation from the expected body weight at 16 weeks of age given the growth curve of non-vaccinated pigs (∆BW) and the increase in acute-phase protein haptoglobin at four days post-vaccination (∆HP). Genome-wide association analyses were carried out on 445 pigs, using genotypes at 41,165 single nucleotide polymorphisms (SNPs) and single-marker and Bayesian multiple-marker regression approaches. Results Genomic regions on pig chromosomes 2, 8, 9, 11 (∆BW) and 8, 9, 13 (∆HP) were found to be associated with the resilience indicators and explained high proportions of their genetic variance. The genomic regions that were associated explained 27 and 5% of the genetic variance of ∆BW and ∆HP, respectively. These genomic regions harbour promising candidate genes that are involved in pathways related to immune response, response to stress, or signal transduction ( CD6 , PTGDR2 , IKZF1 , RNASEL and MYD88 ), and growth ( GRB10 and LCORL ). Conclusions Our study identified novel genomic regions that are associated with two resilience indicators (∆BW and ∆HP) in pigs. These associated genomic regions harbour potential candidate genes involved in immune response and growth pathways, which emphasise the strong relationship between resilience and immune response.The research was funded by the Spanish Ministry of Science, Innovation and Universities and the European Union Regional Development Funds (Grant RTI2018-097700-B-I00). HL is a recipient of a PhD scholarship from the Department of Research and Universities of the Government of Catalonia

Identification of New Genes Involved in Meiosis by a Genetic Screen

Budding yeast Saccharomyces cerevisiae contains a group of proteins named ZMM that constitutes a link between recombination and Synaptonemal Complex (SC) assembly. Yeast mutants that lack ZMM proteins have defects in recombination, SC formation and nuclear division progression. Meiotic cell cycle progression in zmm mutants is modulated by temperature. This conditional behavior is different at high and low temperatures. In my work so far, I have tried to identify new zmm-like genes involved in meiosis. To that end, I have carried out a genome-wide screen in the budding yeast S. cerevisiae. I have identified sporulation temperature sensitive zmm-like truncation mutants by using mini-transposon mediated random insertional mutagenesis approach. To confirm that the observed sporulation-temperature sensitive phenotype is caused by the transposon, a genetic outcross assay was carried out, and to determine the exact position of transposon integration in the yeast genome, direct genome sequencing was performed, followed by Southern hybridization. The defects that can potentially be detected by this genome wide screen approach are growth defects, defects in meiotic divisions and spore viability defect. Different classes of mutants have been identified, suggesting that insertional mutagenesis mediated genome wide screen is an appropriate genetic approach for identifying new genes involved in meiosi

PDGF/VEGF signaling controls cell size in Drosophila

Pvr and its ligands, Pvf 2 and 3, which are upstream of Ras and PI3kinase, are identified from a genome-wide screen in Drosophila cells, as regulators of cell growth

Genome-Wide Screen for Mycobacterium tuberculosis Genes That Regulate Host Immunity

In spite of its highly immunogenic properties, Mycobacterium tuberculosis (Mtb) establishes persistent infection in otherwise healthy individuals, making it one of the most widespread and deadly human pathogens. Mtb's prolonged survival may reflect production of microbial factors that prevent even more vigorous immunity (quantitative effect) or that divert the immune response to a non-sterilizing mode (qualitative effect). Disruption of Mtb genes has produced a list of several dozen candidate immunomodulatory factors. Here we used robotic fluorescence microscopy to screen 10,100 loss-of-function transposon mutants of Mtb for their impact on the expression of promoter-reporter constructs for 12 host immune response genes in a mouse macrophage cell line. The screen identified 364 candidate immunoregulatory genes. To illustrate the utility of the candidate list, we confirmed the impact of 35 Mtb mutant strains on expression of endogenous immune response genes in primary macrophages. Detailed analysis focused on a strain of Mtb in which a transposon disrupts Rv0431, a gene encoding a conserved protein of unknown function. This mutant elicited much more macrophage TNFα, IL-12p40 and IL-6 in vitro than wild type Mtb, and was attenuated in the mouse. The mutant list provides a platform for exploring the immunobiology of tuberculosis, for example, by combining immunoregulatory mutations in a candidate vaccine strain

A genome-wide screen for noncoding elements important in primate evolution

<p>Abstract</p> <p>Background</p> <p>A major goal in the study of human evolution is to identify key genetic changes which occurred over the course of primate evolution. According to one school of thought, many such changes are likely to be found in noncoding sequence. An approach to identifying these involves comparing multiple genomes to identify conserved regions with an accelerated substitution rate in a particular lineage. Such acceleration could be the result of positive selection.</p> <p>Results</p> <p>Here we develop a likelihood ratio test method to identify such regions. We apply it not only to the human terminal lineage, as has been done in previous studies, but also to a number of other branches in the primate tree. We present the top scoring elements, and compare our results with previous studies. We also present resequencing data from one particular element accelerated on the human lineage. These data indicate that the element lies in a region of low polymorphism in humans, consistent with the possibility of a recent selective sweep. They also show that the AT to GC bias for polymorphism in this region differs dramatically from that for substitutions.</p> <p>Conclusion</p> <p>Our results suggest that screens of this type will be helpful in unraveling the complex set of changes which occurred during primate evolution.</p

Genome-wide screen for modifiers of Parkinson's disease genes in Drosophila

<p>Abstract</p> <p>Background</p> <p>Mutations in <it>parkin </it>and <it>PTEN-induced kinase 1 </it>(<it>Pink1) </it>lead to autosomal recessive forms of Parkinson's disease (PD). <it>parkin </it>and <it>Pink1 </it>encode a ubiquitin-protein ligase and a mitochondrially localized serine/threonine kinase, respectively. Recent studies have implicated Parkin and Pink1 in a common and evolutionarily conserved pathway for protecting mitochondrial integrity.</p> <p>Results</p> <p>To systematically identify novel components of the PD pathways, we generated a genetic background that allowed us to perform a genome-wide F1 screen for modifiers of <it>Drosophila parkin </it>(<it>park</it>) and <it>Pink1 </it>mutant phenotype. From screening ~80% of the fly genome, we identified a number of cytological regions that interact with <it>park </it>and/or <it>Pink1</it>. Among them, four cytological regions were selected for identifying corresponding PD-interacting genes. By analyzing smaller <it>deficiency </it>chromosomes, available transgenic RNAi lines, and P-element insertions, we identified five PD-interacting genes. Among them, <it>opa1 </it>and <it>drp1 </it>have been previously implicated in the PD pathways, whereas <it>debra (dbr), Pi3K21B </it>and <it>β4GalNAcTA </it>are novel PD-interacting genes.</p> <p>Conclusions</p> <p>We took an unbiased genetic approach to systematically isolate modifiers of PD genes in <it>Drosophila</it>. Further study of novel PD-interacting genes will shed new light on the function of PD genes and help in the development of new therapeutic strategies for treating Parkinson's disease.</p