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Guillaume Martin, Lionel Roques
Various models describe asexual evolution by mutation, selection and drift. Some focus directly on fitness, typically modelling drift but ignoring or simplifying both epistasis and the distribution of mutation effects (travelling wave models). Others follow the dynamics of quantitative traits determining fitness (Fisher's geometrical model), imposing a complex but fixed form of mutation effects and epistasis, and often ignoring drift. In all cases, predictions are typically obtained in high or low mutation rate limits and for long-term stationary regimes, thus loosing information on transient behaviors and the effect of initial conditions...
October 21, 2016: Genetics
Jong Wha J Joo, Eun Yong Kang, Elin Org, Nick Furlotte, Brian Parks, Farhad Hormozdiari, Aldons J Lusis, Eleazar Eskin
A typical GWAS tests correlation between a single phenotype and each genotype one at a time. However, single phenotype analysis might miss unmeasured aspects of complex biological networks. Analyzing many phenotypes simultaneously may increase the power to capture these unmeasured aspects and detect more variants. Several multivariate approaches aim to detect variants related to more than one phenotype, but these current approaches do not consider the effects of population structure. As a result, these approaches may result in a significant amount of false positive identifications...
October 21, 2016: Genetics
Auke B C Otten, Alphons P M Stassen, Michiel Adriaens, Mike Gerards, Richard G J Dohmen, Adriana J Timmer, Sabina J V Vanherle, Rick Kamps, Iris B W Boesten, Jo M Vanoevelen, Marc Muller, Bert Smeets
Of all pathogenic mitochondrial DNA (mtDNA) mutations in humans, ~25% is de novo, although the occurrence in oocytes has never been directly assessed. We used next generation sequencing to detect point mutations directly in the mtDNA of 3-15 individual mature oocytes and three somatic tissues from eight zebrafish females. Various statistical and biological filters allowed reliable detection of de novo variants with heteroplasmy ≥1.5%. In total, we detected 38 de novo base substitutions, but no insertions or deletions...
October 21, 2016: Genetics
Daniel Nichol, Mark Robertson-Tessi, Peter Jeavons, Alexander R A Anderson
Non-genetic variation in phenotypes, or bet-hedging, has been observed as a driver of drug resistance in both bacterial infections and cancers. Here, we study how bet-hedging emerges in the genotype-phenotype mapping through a simple interaction model: a molecular switch. We use simple Chemical Reaction Networks to implement stochastic switches that map gene products to phenotypes and investigate the impact of structurally distinct mappings on the evolution of phenotypic heterogeneity. Bet-hedging naturally emerges within this model and is robust to evolutionary loss through mutations to both the expression of individual genes and to the network itself...
October 21, 2016: Genetics
Akhi Akhter, Emanuel Rosonina
The Saccharomyces cerevisiae transcription factor Gcn4 is expressed during amino acid starvation and its abundance is controlled by ubiquitin-mediated proteolysis. Cdk8, a kinase component of the RNA polymerase II Mediator complex, phosphorylates Gcn4 which triggers its ubiquitination/proteolysis and is thought to link Gcn4 degradation with transcription of target genes. In addition to phosphorylation and ubiquitination, we previously showed that Gcn4 becomes sumoylated in a DNA-binding dependent manner, while a non-sumoylatable form of Gcn4 showed increased chromatin occupancy, but only if Cdk8 was present...
October 21, 2016: Genetics
Jhih-Rong Lin, Ying Cai, Quanwei Zhang, Wen Zhang, Ruben Nogales, Zhengdong Zhang
Schizophrenia is a severe mental disorder with a large genetic component. Recent genome-wide association studies (GWAS) have identified many schizophrenia-associated common variants. For most of the reported associations, however, the underlying biological mechanisms are not clear. The critical first step for their elucidation is to identify the most likely disease genes as the source of the association signals. Here, we describe a general computational framework of post-GWAS analysis for complex disease gene prioritization...
October 17, 2016: Genetics
Brian C Searle, Rachel M Gittelman, Ohad Manor, Joshua M Akey
Gene expression levels are dynamic molecular phenotypes that respond to biological, environmental, and technical perturbations. Here we use a novel replicate classifier approach for discovering transcriptional signatures and apply it to the Genotype-Tissue Expression (GTEx) data set. We identified many factors contributing to expression heterogeneity, such as collection center and ischemia time and our approach of scoring replicate classifiers allows us to statistically stratify these factors by effect strength...
October 11, 2016: Genetics
Maryam Ataeian, Justus Tegha-Dunghu, Donna G Curtis, Ellen M E Sykes, Ashkan Nozohourmehrabad, Megha Bajaj, Karen Cheung, Martin Srayko
In most animals, female meiosis completes only after fertilization. Sperm entry has been implicated in providing a signal for the initiation of the final meiotic processes, however, a maternal component required for this process has not been previously identified. We report the characterization of a novel family of three highly similar paralogs (memi-1, memi-2, memi-3) that encode oocyte-specific proteins. A hypermorphic mutation memi-1(sb41) results in failure to exit female meiosis II properly, however, loss of all three paralogs results in a "skipped meiosis II" phenotype...
October 11, 2016: Genetics
Chin Jian Yang, Lisa E Kursel, Anthony J Studer, Madelaine E Bartlett, Clinton J Whipple, John F Doebley
The effects of an allelic substitution at a gene often depend critically on genetic background, the genotype at other genes in the genome. During the domestication of maize from its wild ancestor (teosinte), an allelic substitution at teosinte branched (tb1) caused changes in both plant and ear architecture. The effects of tb1 on phenotype were shown to depend on multiple background loci including one called enhancer of tb1.2 (etb1.2) We mapped etb1.2 to a YABBY class transcription factor (ZmYAB2.1) and showed that the maize alleles of ZmYAB2...
October 11, 2016: Genetics
Eun Yong Kang, Lisa Martin, Serghei Mangul, Warin Isvilanonda, Jennifer Zou, Eyal Ben-David, Buhm Han, Aldons J Lusis, Sagiv Shifman, Eleazar Eskin
The study of the genetics of gene expression is of considerable importance to understanding the nature of common, complex diseases. The most widely applied approach to identifying relationships between genetic variation and gene expression is the expression quantitative trait loci (eQTL) approach. Here we increase the computational power of eQTL with an alternative and complementary approach based on analyzing allele specific expression (ASE). We design a novel analytical method to identify cis-acting regulatory variants based on genome sequencing and measurements of ASE from RNA-seq data...
October 7, 2016: Genetics
Kate Rockenbach, Justin C Havird, J Grey Monroe, Deborah A Triant, Douglas R Taylor, Daniel B Sloan
Rates of sequence evolution in plastid genomes are generally low, but numerous angiosperm lineages exhibit accelerated evolutionary rates in similar subsets of plastid genes. These genes include clpP1 and accD, which encode components of the caseinolytic protease (CLP) and acetyl-coA carboxylase (ACCase) complexes, respectively. Whether these extreme and repeated accelerations in rates of plastid genome evolution result from adaptive change in proteins (i.e., positive selection) or simply a loss of functional constraint (i...
October 5, 2016: Genetics
Aimee Jaramillo-Lambert, Amy S Fabritius, Tyler J Hansen, Harold E Smith, Andy Golden
Topoisomerase II alleviates DNA entanglements that are generated during mitotic DNA replication, transcription, and sister chromatid separation. In contrast to mitosis, meiosis has two rounds of chromosome segregation following one round of DNA replication. In meiosis II, sister chromatids segregate from each other similar to mitosis. Meiosis I, on the other hand, segregates homologs, which requires pairing, synapsis, and recombination. The exact role that topoisomerase II plays during meiosis is unknown. In a screen re-examining Caenorhabditis elegant legacy mutants isolated thirty years ago, we identified a novel allele of the gene encoding topoisomerase II, top-2(it7) In this study, we demonstrate that top-2(it7) males produce dead embryos, even when fertilizing wild-type oocytes...
October 5, 2016: Genetics
Delphine Albrecht, Johanna Ceschin, Jim Dompierre, Florian Gueniot, Benoît Pinson, Bertrand Daignan-Fornier
Identifying synthetic lethal interactions has emerged as a promising new therapeutic approach aimed at targeting cancer cells directly. Here, we used the yeast Saccharomyces cerevisiae as a simple eukaryotic model to screen for mutations resulting in a synthetic lethality with 5-Amino-4-Imidazole CarboxAmide Ribonucleoside (AICAR) treatment. Indeed, AICAR has been reported to inhibit the proliferation of multiple cancer cell lines. Here, we found that loss of several histone-modifying enzymes, including Bre1 (histone H2B ubiquitination) and Set1 (histone H3 lysine 4 methylation), greatly enhanced AICAR inhibition on growth via combined-effects of both the drug and the mutations on G1 cyclins...
October 5, 2016: Genetics
Michelle D Parmenter, Melissa M Gray, Caley A Hogan, Irene N Ford, Karl W Broman, Christopher J Vinyard, Bret A Payseur
Organisms on islands often undergo rapid morphological evolution, providing a platform for understanding mechanisms of phenotypic change. Many examples of evolution on islands involve the vertebrate skeleton. Although the genetic basis of skeletal variation has been studied in laboratory strains, especially in the house mouse Mus musculus domesticus, the genetic determinants of skeletal evolution in natural populations remain poorly understood. We used house mice living on the remote Gough Island - the largest wild house mice on record - to understand the genetics of rapid skeletal evolution in nature...
September 30, 2016: Genetics
François Vallée, Aurélien Luciani, Murray P Cox
Archeology, linguistics and increasingly genetics are clarifying how populations moved from mainland Asia, through Island Southeast Asia, and out into the Pacific during the farming revolution. Yet key features of this process remain poorly understood, particularly how social behaviors intersected with demographic drivers to create the patterns of genomic diversity observed across Island Southeast Asia today. Such questions are ripe for computer modeling. Here, we construct an agent-based model to simulate human mobility across Island Southeast Asia from the Neolithic period to the present, with a special focus on interactions between individuals with Asian, Papuan and mixed Asian-Papuan ancestry...
September 28, 2016: Genetics
Nafees Ahamad, Sumit Kumar Verma, Shakil Ahmed
DNA double strand breaks (DSBs) are critical lesions that can lead to chromosomal aberrations and genomic instability. In response to DNA damage, Chk1, a serine/threonine kinase is responsible for cell cycle arrest to prevent damaged cells from progressing through the cell cycle. Here we have reported that the disruption of wat1, a WD repeat containing protein leads to the phosphorylation of Chk1. The double deletion of chk1 and wat1 pose a grave effect on the survival of fission yeast cells and the spontaneous recombination rate was also high in double deletion of wat1 and chk1 as compared to the single mutant...
September 28, 2016: Genetics
Glenda Lassi, Silvia Maggi, Edoardo Balzani, Ilaria Cosentini, Celina Garcia-Garcia, Valter Tucci
Abnormal feeding behavior is one of the main symptoms of Prader-Willi syndrome (PWS). By studying a PWS mouse mutant line, which carries a paternally inherited deletion of the small nucleolar RNA 116 (Snord116), we observed significant changes in working-for-food behavioral responses at various timescales. In particular, we report that PWS mutant mice show a significant delay compared to wild-type littermate controls in responding to both hour-scale and seconds-to-minutes- scale time intervals. This timing shift in mutant mice is associated with better performance in the working-for-food task and results in better decision making in these mutant mice...
September 26, 2016: Genetics
Marcus M Dillon, Vaughn S Cooper
Mutation accumulation (MA) experiments employ the strategy of minimizing the population size of evolving lineages to greatly reduce effects of selection on newly arising mutations. Thus, most mutations fix within MA lines independently of their fitness effects. This approach, more recently combined with genome sequencing, has detailed the rates, spectra, and biases of different mutational processes. However, a quantitative understanding of the fitness effects of mutations virtually unseen by selection has remained an untapped opportunity...
September 26, 2016: Genetics
Zhanna Lipatova, Uddalak Majumdar, Nava Segev
Ypt/Rab GTPases, key regulators of intracellular trafficking pathways, are activated by guanine-nucleotide exchange factors (GEFs). Here, we identify a novel GEF complex, TRAPP IV, which regulates Ypt1-mediated autophagy. In the yeast Saccharomyces cerevisiae, Ypt1 GTPase is required for the initiation of secretion and autophagy, suggesting that it regulates these two distinct pathways. However, whether these pathways are coordinated by Ypt1 and by what mechanism, is still unknown. TRAPP is a conserved modular complex that acts as a Ypt/Rab GEF...
September 26, 2016: Genetics
Enrique Santiago, Armando Caballero
Mutation, genetic drift and selection are considered the main factors shaping genetic variation in nature. There is a lack, however, of general predictions accounting for the complex interrelations between these factors. In this context, we derive a system of two equations for the joint prediction of the effective population size (Ne) and the rate of fixation of deleterious mutations in the background selection model. The definition of Ne corresponds to the long-term effect of drift, which is the asymptotic value of a series of Ne(t) terms representing the intensity of drift acting on mutations that appeared t generations backwards in time...
September 26, 2016: Genetics
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