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David Aristizabal-Corrales, Jinpu Yang, Fei Li
Centromere plays an essential role in chromosome segregation. In most eukaryotes, centromeres are epigenetically defined by the conserved histone H3 variant, CENP-A. Proper centromere assembly is dependent upon the tight regulation of CENP-A level. Cell-cycle regulation of CENP-A transcription appears to be a universal features across eukaryotes. But the molecular mechanism underlying the temporal control of CENP-A transcription and how such regulation contributes to centromere function remain elusive. CENP-A in fission yeast has been shown to be transcribed before S phase...
January 11, 2019: Genetics
Ravi Valluru, Elodie E Gazave, Samuel B Fernandes, John N Ferguson, Roberto Lozano, Pradeep Hirannaiah, Tao Zuo, Patrick J Brown, Andrew D B Leakey, Michael A Gore, Edward S Buckler, Nonoy Bandillo
Sorghum ( Sorghum bicolor L.) is a major food cereal for millions of people worldwide. The sorghum genome, like other species, accumulates deleterious mutations, likely impacting its fitness. The lack of recombination, drift, and the coupling with favorable loci impede the removal of deleterious mutations from the genome by selection. To study how deleterious variants impact phenotypes, we identified putative deleterious mutations among ~5.5M segregating variants of 229 diverse biomass sorghum lines. We provide the whole-genome estimate of the deleterious burden in sorghum, showing that about 33 percent of nonsynonymous substitutions are putatively deleterious...
January 8, 2019: Genetics
Pierre-Henri Clergeot, Nicolas O Rode, Sylvain Glémin, Mikael Brandström-Durling, Katarina Ihrmark, Åke Olson
Many eukaryote species including taxa such as fungi or algae have a lifecycle with substantial haploid and diploid phases. A recent theoretical model predicts that such haploid-diploid lifecycles are stable over long evolutionary time scales when segregating deleterious mutations have stronger effects in homozygous diploids than in haploids and when they are partially recessive in heterozygous diploids. The model predicts that effective dominance, a measure that accounts for these two effects, should be close to 0...
December 31, 2018: Genetics
John K Kelly, Kimberly A Hughes
We develop a set of analytical and simulation tools for Evolve-and-Resequence (E&R) experiments and apply them to a new study of rapid evolution in Drosophila simulans Likelihood test statistics applied to pooled population sequencing data suggest parallel evolution of 138 polymorphisms (SNPs) across the genome. This number is reduced by orders of magnitude from previous studies (thousands or tens of thousands), owing to differences in both experimental design and statistical analysis. Whole genome simulations calibrated from several Drosophila genetic datasets indicate that major features of the genome-wide response could be generated by as few as 30 loci under strong directional selection with a corresponding hitch-hiking effect...
December 28, 2018: Genetics
Christopher L Baker, Michael Walker, Seda Arat, Guruprasad Ananda, Pavlina Petkova, Natalie R Powers, Hui Tian, Catrina Spruce, Bo Ji, Dylan Rausch, Kwangbom Choi, Petko M Petkov, Gregory W Carter, Kenneth Paigen
The epigenetic landscape varies greatly among cell types. Although a variety of writers, readers, and erasers of epigenetic features are known, we have little information about the underlying regulatory systems controlling the establishment and maintenance of these features. Here, we have explored how natural genetic variation impacts the epigenome in mice. Studying levels of H3K4me3, a histone modification at sites such as promoters, enhancers, and recombination hotspots, we found tissue-specific trans -regulation of H3K4me3 levels in four highly diverse cell types: male germ cells, embryonic stem (ES) cells, hepatocytes and cardiomyocytes...
December 28, 2018: Genetics
Arushi Varshney, Hadley VanRenterghem, Peter Orchard, Alan P Boyle, Michael L Stitzel, Duygu Ucar, Stephen C J Parker
Epigenomic signatures from histone marks and transcription factor (TF) binding sites have been used to annotate putative gene regulatory regions. However, a direct comparison of these diverse annotations is missing, and it is unclear how genetic variation within these annotations affects gene expression. Here, we compare five widely-used annotations of active regulatory elements that represent high densities of one or more relevant epigenomic marks: super and typical (non-super) enhancers, stretch enhancers, high-occupancy target (HOT) regions, and broad domains, across the four matched human cell types for which they are available...
December 28, 2018: Genetics
Zhenghan Wang, Ofelia Tacchelly-Benites, Geoffrey P Noble, Megan K Johnson, Jean-Philippe Gagné, Guy G Poirier, Yashi Ahmed
Aberrant activation of the Wnt signal transduction pathway triggers the development of colorectal cancer. The ADP-ribose polymerase Tankyrase (TNKS) mediates proteolysis of Axin, a negative regulator of Wnt signaling, and provides a promising therapeutic target for Wnt-driven diseases. Proteolysis of TNKS substrates is mediated through their ubiquitination by the poly-ADP-ribose (pADPr)-dependent RING-domain E3 ubiquitin ligase RNF146/Iduna. Like TNKS, RNF146 promotes Axin proteolysis and Wnt pathway activation in some cultured cell lines, but in contrast with TNKS, RNF146 is dispensable for Axin degradation in colorectal carcinoma cells...
December 28, 2018: Genetics
Yu-Yang Jiang, Wolfgang Maier, Ralf Baumeister, Ewa Joachimiak, Zheng Ruan, Natarajan Kannan, Diamond Clarke, Panagiota Louka, Mayukh Guha, Joseph Frankel, Jacek Gaertig
In a single cell, ciliates maintain a complex pattern of cortical organelles that are arranged along the anteroposterior and circumferential axes. The underlying molecular mechanisms of intracellular pattern formation in ciliates are largely unknown. Ciliates divide by tandem duplication, a process that remodels the parental cell into two daughters aligned head-to-tail. In the elo1-1 mutant of Tetrahymena thermophila , the segmentation boundary/division plane forms too close to the posterior end of the parental cell, producing a large anterior and a small posterior daughter cell, respectively...
December 28, 2018: Genetics
Julien Chaillot, Faiza Tebbji, Jaideep Malick, Adnane Sellam
In most species, size homeostasis appears to be exerted in late G1 phase as cells commit to division, called Start in yeast and the Restriction Point in metazoans. This size threshold couples cell growth to division and thereby establishes long-term size homeostasis. Our former investigations have shown that hundreds of genes markedly altered cell size under homeostatic growth conditions in the opportunistic yeast Candida albicans , but surprisingly only few of these overlapped with size control genes in the budding yeast Saccharomyces cerevisiae Here, we investigated one of the divergent potent size regulators in C...
December 28, 2018: Genetics
Karl W Broman, Daniel M Gatti, Petr Simecek, Nicholas A Furlotte, Pjotr Prins, Śaunak Sen, Brian S Yandell, Gary A Churchill
R/qtl2 is an interactive software environment for mapping quantitative trait loci (QTL) in experimental populations. The R/qtl2 software expands the scope of the widely-used R/qtl software package to include multi-parent populations derived from more than two founder strains, such as the Collaborative Cross and Diversity Outbred mice, heterogeneous stocks, and MAGIC plant populations. R/qtl2 is designed to handle modern high-density genotyping data and high-dimensional molecular phenotypes including gene expression and proteomics...
December 27, 2018: Genetics
Jihye Kim, Andrey Ziyatdinov, Vincent Laville, Frank B Hu, Eric Rimm, Peter Kraft, Hugues Aschard
With growing human genetic and epidemiologic data, there has been increased interest for the study of gene-by-environment (G-E) interaction effects. Still, major questions remain on how to test jointly a large number of interactions between multiple SNPs and multiple exposures. In this study, we first compared the relative performance of four fixed effect joint analysis approaches using simulated data, (1) omnibus test, (2) multi-exposure and genetic risk score (GRS) test, (3) multi-SNP and environmental risk score (ERS) test, and (4) GRS-ERS test, considering up to 10 exposures and 300 SNPs...
December 21, 2018: Genetics
Richard Bowman, Nathan Balukof, Talitha Ford, Sarit Smolikove
During meiotic prophase I sister chromatid cohesion is established in a way that supports the assembly of the synaptonemal complex (SC). The SC connects homologous chromosomes, directing meiotic recombination to create crossovers. In this paper we identify two proteins that cooperate to import and load meiotic cohesins, thus indirectly promoting SC assembly. AKIR-1 is a protein with a previously identified meiotic role in SC disassembly. akir-1 mutants have no obvious defects in sister chromatid cohesion. We identified ima-2 , a gene encoding for an α-importin nuclear transport protein, as a gene interacting with akir-1 Analysis of akir-1;ima-2 double mutants reveals a decrease in the number of germline nuclei and the formation of polycomplexes (PC) (an SC protein aggregate)...
December 18, 2018: Genetics
Geoffrey W Meissner, Aljoscha Nern, Robert H Singer, Allan M Wong, Oz Malkesman, Xi Long
Identifying the neurotransmitters used by specific neurons is a critical step in understanding the function of neural circuits. However, methods for the consistent and efficient detection of neurotransmitter markers remain limited. Fluorescence in situ hybridization (FISH) enables direct labeling of type-specific mRNA in neurons. Recent advances in FISH allow this technique to be carried out in intact tissue samples such as whole-mount Drosophila melanogaster brains. Here, we present a FISH platform for high-throughput detection of eight common neurotransmitter phenotypes in Drosophila brains...
December 18, 2018: Genetics
Belén Gómez-González, Harshil Patel, Anne Early, John F X Diffley
DNA replication forks that are stalled by DNA damage activate an S phase checkpoint that prevents irreversible fork arrest and cell death. The increased cell death caused by DNA damage in budding yeast cells lacking the Rad53 checkpoint protein kinase is partially suppressed by deletion of the EXO1 gene. Using a whole-genome sequencing approach, we identified two additional genes, RXT2 and RPH1, whose mutation can also partially suppress this DNA damage sensitivity. We provide evidence that RXT2 and RPH1 act in a common pathway, which is distinct from the EXO1 pathway...
December 17, 2018: Genetics
Kevin Gomez, Jason Bertram, Joanna Masel
Genetic covariances represent a combination of pleiotropy and linkage disequilibrium, shaped by the population's history. Observed genetic covariance is most often interpreted in pleiotropic terms. In particular, functional constraints restricting which phenotypes are physically possible can lead to a stable G matrix with high genetic variance in fitness-associated traits and high pleiotropic negative covariance along the phenotypic curve of constraint. In contrast, population genetic models of relative fitness assume endless adaptation without constraint, through a series of selective sweeps that are well described by recent traveling wave models...
December 17, 2018: Genetics
Andrew D Klocko, Miki Uesaka, Tereza Ormsby, Michael R Rountree, Elizabeth T Wiles, Keyur K Adhvaryu, Shinji Honda, Eric U Selker
In the filamentous fungus Neurospora crassa , constitutive heterochromatin is marked by tri-methylation of histone H3 lysine 9 (H3K9me3) and DNA methylation. We identified mutations in the Neurospora d efective i n m ethylation-1 ( dim-1 ) gene that cause defects in cytosine methylation and implicate a putative AAA-ATPase chromatin remodeler. Although it was well established that chromatin remodelers can impact transcription by influencing DNA accessibility with nucleosomes, little was known about the role of remodelers on chromatin that is normally not transcribed, including regions of constitutive heterochromatin...
December 15, 2018: Genetics
Emily C Glassberg, Ziyue Gao, Arbel Harpak, Xun Lan, Jonathan K Pritchard
Gene expression variation is a major contributor to phenotypic variation in human complex traits. Selection on complex traits may therefore be reflected in constraint on gene expression. Here, we explore the effects of stabilizing selection on cis -regulatory genetic variation in humans. We analyze patterns of expression variation at copy number variants and find evidence for selection against large increases in gene expression. Using allele-specific expression (ASE) data, we further show evidence of selection against smaller-effect variants...
December 15, 2018: Genetics
Sameer B Shah, David Parmiter, Christian Constantine, Paul Elizalde, Michael Naldrett, Tatiana S Karpova, John S Choy
The Dam1 complex is an essential component of the outer kinetochore that mediates attachments between spindle microtubules and chromosomes. Dam1p, a subunit of the Dam1 complex, binds to microtubules and is regulated by Aurora B/Ipl1p phosphorylation. We find that overexpression of cAMP-dependent protein kinase (PKA) catalytic subunits (i.e. TPK1 , TPK2 , TPK3 ) is lethal in DAM1 mutants and increases the rate of chromosome loss in wild-type cells. Replacing an evolutionarily conserved PKA site (S31) in Dam1p with a non-phosphorylatable alanine suppressed the high copy PKA dosage lethality in dam1-1 Consistent with Dam1p as a target of PKA we find that in vitro PKA can directly phosphorylate S31 in Dam1p and we observed phosphorylation of S31 in Dam1p purified from asynchronously growing yeast cells...
December 13, 2018: Genetics
Chiara V Colombo, Luca Menin, Riccardo Ranieri, Diego Bonetti, Michela Clerici, Maria Pia Longhese
The Mre11-Rad50-Xrs2 (MRX) complex acts together with the Sae2 protein to initiate resection of DNA double-strand breaks (DSBs) and to regulate a checkpoint response that couples cell cycle progression with DSB repair. Sae2 supports resistance to DNA damage and downregulates the signalling activities of MRX, Tel1 and Rad53 checkpoint proteins at the sites of damage. How these functions are connected to each other is not known. Here, we describe the separation-of-function sae2-ms mutant that, similar to SAE2 deletion, upregulates MRX and Tel1 signalling activities at DSBs by reducing Mre11 endonuclease activity...
December 11, 2018: Genetics
Amjad Islam, Faiza Tebbji, Jaideep Mallick, Hannah Regan, Vanessa Dumeaux, Raha Parvizi Omran, Malcolm Whiteway
In the life cycle of the fungal pathogen Candida albicans, the formation of filamentous cells is a differentiation process that is critically involved in host tissue invasion and in adaptation to host cell and environmental stresses . Here we have used the GRACETM library to identify genes controlling invasiveness and filamentation; conditional repression of the library revealed 69 mutants that triggered these processes. Intriguingly, the genes encoding the SUMO E3 ligase Mms21 and all other tested members of the sumoylation pathway were both non-essential and capable of triggering filamentation upon repression, suggesting an important role for sumoylation in controlling filamentation in C...
December 7, 2018: Genetics
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