Powerful Genetic Association Analysis for Common or Rare Variants with High-Dimensional Structured Traits [Statistical Genetics and Genomics]
Many genetic association studies collect a wide range of complex traits. As these traits may be correlated and share a common genetic mechanism, joint analysis can be statistically more powerful and biologically more meaningful. However, most existing tests for multiple traits cannot be used for high-dimensional and possibly structured traits, such as network-structured transcriptomic pathway expressions. To overcome potential limitations, in this article we propose the dual kernel-based association test (DKAT) for testing the association between multiple traits and multiple genetic variants, both common and rare. In DKAT,...
Source: Genetics - August 4, 2017 Category: Genetics & Stem Cells Authors: Zhan, X., Zhao, N., Plantinga, A., Thornton, T. A., Conneely, K. N., Epstein, M. P., Wu, M. C. Tags: Statistical Genetics and Genomics Source Type: research
An Efficient FLP-Based Toolkit for Spatiotemporal Control of Gene Expression in Caenorhabditis elegans [Methods, Technology, and Resources]
Site-specific recombinases are potent tools to regulate gene expression. In particular, the Cre (cyclization recombination) and FLP (flipase) enzymes are widely used to either activate or inactivate genes in a precise spatiotemporal manner. Both recombinases work efficiently in the popular model organism Caenorhabditis elegans, but their use in this nematode is still only sporadic. To increase the utility of the FLP system in C. elegans, we have generated a series of single-copy transgenic strains that stably express an optimized version of FLP in specific tissues or by heat induction. We show that recombination efficienci...
Source: Genetics - August 4, 2017 Category: Genetics & Stem Cells Authors: Munoz-Jimenez, C., Ayuso, C., Dobrzynska, A., Torres-Mendez, A., Ruiz, P. d. l. C., Askjaer, P. Tags: Methods, Technology, and Resources Source Type: research
Toward Universal Forward Genetics: Using a Draft Genome Sequence of the Nematode Oscheius tipulae To Identify Mutations Affecting Vulva Development [Methods, Technology, and Resources]
Mapping-by-sequencing has become a standard method to map and identify phenotype-causing mutations in model species. Here, we show that a fragmented draft assembly is sufficient to perform mapping-by-sequencing in nonmodel species. We generated a draft assembly and annotation of the genome of the free-living nematode Oscheius tipulae, a distant relative of the model Caenorhabditis elegans. We used this draft to identify the likely causative mutations at the O. tipulae cov-3 locus, which affect vulval development. The cov-3 locus encodes the O. tipulae ortholog of C. elegans mig-13, and we further show that Cel-mig-13 mutan...
Source: Genetics - August 4, 2017 Category: Genetics & Stem Cells Authors: Besnard, F., Koutsovoulos, G., Dieudonne, S., Blaxter, M., Felix, M.-A. Tags: Methods, Technology, and Resources Source Type: research
Investigation of Seizure-Susceptibility in a Drosophila melanogaster Model of Human Epilepsy with Optogenetic Stimulation [Methods, Technology, and Resources]
We examined seizure-susceptibility in a Drosophila model of human epilepsy using optogenetic stimulation of ReaChR (red-activatable channelrhodopsin). Photostimulation of the seizure-sensitive mutant parabss1 causes behavioral paralysis that resembles paralysis caused by mechanical stimulation, in many aspects. Electrophysiology shows that photostimulation evokes abnormal seizure-like neuronal firing in parabss1 followed by a quiescent period resembling synaptic failure and apparently responsible for paralysis. The pattern of neuronal activity concludes with seizure-like activity just prior to recovery. We tentatively iden...
Source: Genetics - August 4, 2017 Category: Genetics & Stem Cells Authors: Saras, A., Wu, V. V., Brawer, H. J., Tanouye, M. A. Tags: Methods, Technology, and Resources Source Type: research
High-Throughput Characterization of Cascade type I-E CRISPR Guide Efficacy Reveals Unexpected PAM Diversity and Target Sequence Preferences [Methods, Technology, and Resources]
Interactions between Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) RNAs and CRISPR-associated (Cas) proteins form an RNA-guided adaptive immune system in prokaryotes. The adaptive immune system utilizes segments of the genetic material of invasive foreign elements in the CRISPR locus. The loci are transcribed and processed to produce small CRISPR RNAs (crRNAs), with degradation of invading genetic material directed by a combination of complementarity between RNA and DNA and in some cases recognition of adjacent motifs called PAMs (Protospacer Adjacent Motifs). Here we describe a general, high-throughput...
Source: Genetics - August 4, 2017 Category: Genetics & Stem Cells Authors: Xu Hua Fu, B., Wainberg, M., Kundaje, A., Fire, A. Z. Tags: Methods, Technology, and Resources Source Type: research
Polycomb and Trithorax Group Genes in Drosophila [Gene Expression]
Polycomb group (PcG) and Trithorax group (TrxG) genes encode important regulators of development and differentiation in metazoans. These two groups of genes were discovered in Drosophila by their opposing effects on homeotic gene (Hox) expression. PcG genes collectively behave as genetic repressors of Hox genes, while the TrxG genes are necessary for HOX gene expression or function. Biochemical studies showed that many PcG proteins are present in two protein complexes, Polycomb repressive complexes 1 and 2, which repress transcription via chromatin modifications. TrxG proteins activate transcription via a variety of mechan...
Source: Genetics - August 4, 2017 Category: Genetics & Stem Cells Authors: Kassis, J. A., Kennison, J. A., Tamkun, J. W. Tags: Gene Expression Source Type: research
ISSUE HIGHLIGHTS [Issue Highlights]
(Source: Genetics)
Source: Genetics - August 4, 2017 Category: Genetics & Stem Cells Tags: Issue Highlights Source Type: research
DNA Damage Tolerance Pathway Choice Through Uls1 Modulation of Srs2 SUMOylation in Saccharomyces cerevisiae [Genome Integrity and Transmission]
DNA damage tolerance and homologous recombination pathways function to bypass replication-blocking lesions and ensure completion of DNA replication. However, inappropriate activation of these pathways may lead to increased mutagenesis or formation of deleterious recombination intermediates, often leading to cell death or cancer formation in higher organisms. Post-translational modifications of PCNA regulate the choice of repair pathways at replication forks. Its monoubiquitination favors translesion synthesis, while polyubiquitination stimulates template switching. Srs2 helicase binds to small ubiquitin-related modifier (S...
Source: Genetics - May 5, 2017 Category: Genetics & Stem Cells Authors: Kramarz, K., Mucha, S., Litwin, I., Barg-Wojas, A., Wysocki, R., Dziadkowiec, D. Tags: Genome Integrity and Transmission Source Type: research
Coordination of Double Strand Break Repair and Meiotic Progression in Yeast by a Mek1-Ndt80 Negative Feedback Loop [Genome Integrity and Transmission]
During meiosis, homologous chromosomes are physically connected by crossovers and sister chromatid cohesion. Interhomolog crossovers are generated by the highly regulated repair of programmed double strand breaks (DSBs). The meiosis-specific kinase Mek1 is critical for this regulation. Mek1 downregulates the mitotic recombinase Rad51, indirectly promoting interhomolog strand invasion by the meiosis-specific recombinase Dmc1. Mek1 also promotes the formation of crossovers that are distributed throughout the genome by interference and is the effector kinase for a meiosis-specific checkpoint that delays entry into Meiosis I u...
Source: Genetics - May 5, 2017 Category: Genetics & Stem Cells Authors: Prugar, E., Burnett, C., Chen, X., Hollingsworth, N. M. Tags: Genome Integrity and Transmission Source Type: research
Nonhomologous End-Joining with Minimal Sequence Loss Is Promoted by the Mre11-Rad50-Nbs1-Ctp1 Complex in Schizosaccharomyces pombe [Genome Integrity and Transmission]
While the Mre11-Rad50-Nbs1 (MRN) complex has known roles in repair processes like homologous recombination and microhomology-mediated end-joining, its role in nonhomologous end-joining (NHEJ) is unclear as Saccharomyces cerevisiae, Schizosaccharomyces pombe, and mammals have different requirements for repairing cut DNA ends. Most double-strand breaks (DSBs) require nucleolytic processing prior to DNA ligation. Therefore, we studied repair using the Hermes transposon, whose excision leaves a DSB capped by hairpin ends similar to structures generated by palindromes and trinucleotide repeats. We generated single Hermes insert...
Source: Genetics - May 5, 2017 Category: Genetics & Stem Cells Authors: Li, Y., Wang, J., Zhou, G., Lajeunesse, M., Le, N., Stawicki, B. N., Corcino, Y. L., Berkner, K. L., Runge, K. W. Tags: Genome Integrity and Transmission Source Type: research
Annealing of Complementary DNA Sequences During Double-Strand Break Repair in Drosophila Is Mediated by the Ortholog of SMARCAL1 [Genome Integrity and Transmission]
DNA double-strand breaks (DSBs) pose a serious threat to genomic integrity. If unrepaired, they can lead to chromosome fragmentation and cell death. If repaired incorrectly, they can cause mutations and chromosome rearrangements. DSBs are repaired using end-joining or homology-directed repair strategies, with the predominant form of homology-directed repair being synthesis-dependent strand annealing (SDSA). SDSA is the first defense against genomic rearrangements and information loss during DSB repair, making it a vital component of cell health and an attractive target for chemotherapeutic development. SDSA has also been p...
Source: Genetics - May 5, 2017 Category: Genetics & Stem Cells Authors: Holsclaw, J. K., Sekelsky, J. Tags: Genome Integrity and Transmission Source Type: research
A Pooled Sequencing Approach Identifies a Candidate Meiotic Driver in Drosophila [Genome Integrity and Transmission]
Meiotic drive occurs when a selfish element increases its transmission frequency above the Mendelian ratio by hijacking the asymmetric divisions of female meiosis. Meiotic drive causes genomic conflict and potentially has a major impact on genome evolution, but only a few drive loci of large effect have been described. New methods to reliably detect meiotic drive are therefore needed, particularly for discovering moderate-strength drivers that are likely to be more prevalent in natural populations than strong drivers. Here, we report an efficient method that uses sequencing of large pools of backcross (BC1) progeny to test...
Source: Genetics - May 5, 2017 Category: Genetics & Stem Cells Authors: Wei, K. H.- C., Reddy, H. M., Rathnam, C., Lee, J., Lin, D., Ji, S., Mason, J. M., Clark, A. G., Barbash, D. A. Tags: Genome Integrity and Transmission Source Type: research
Accuracy of Demographic Inferences from the Site Frequency Spectrum: The Case of the Yoruba Population [Population and Evolutionary Genetics]
Some methods for demographic inference based on the observed genetic diversity of current populations rely on the use of summary statistics such as the Site Frequency Spectrum (SFS). Demographic models can be either model-constrained with numerous parameters, such as growth rates, timing of demographic events, and migration rates, or model-flexible, with an unbounded collection of piecewise constant sizes. It is still debated whether demographic histories can be accurately inferred based on the SFS. Here, we illustrate this theoretical issue on an example of demographic inference for an African population. The SFS of the Y...
Source: Genetics - May 5, 2017 Category: Genetics & Stem Cells Authors: Lapierre, M., Lambert, A., Achaz, G. Tags: Population and Evolutionary Genetics Source Type: research
Exploring Evolutionary Relationships Across the Genome Using Topology Weighting [Population and Evolutionary Genetics]
We describe our method for topology weighting by iterative sampling of subtrees (Twisst), and test it on both simulated and real genomic data. Overall, we show that this is an informative and versatile approach, suitable for exploring relationships in almost any genomic dataset. Scripts to implement the method described are available at http://github.com/simonhmartin/twisst. (Source: Genetics)
Source: Genetics - May 5, 2017 Category: Genetics & Stem Cells Authors: Martin, S. H., Van Belleghem, S. M. Tags: Population and Evolutionary Genetics Source Type: research
A Phylogenetic Codon Substitution Model for Antibody Lineages [Genetics of Immunity]
Phylogenetic methods have shown promise in understanding the development of broadly neutralizing antibody lineages (bNAbs). However, the mutational process that generates these lineages, somatic hypermutation, is biased by hotspot motifs which violates important assumptions in most phylogenetic substitution models. Here, we develop a modified GY94-type substitution model that partially accounts for this context dependency while preserving independence of sites during calculation. This model shows a substantially better fit to three well-characterized bNAb lineages than the standard GY94 model. We also demonstrate how our m...
Source: Genetics - May 5, 2017 Category: Genetics & Stem Cells Authors: Hoehn, K. B., Lunter, G., Pybus, O. G. Tags: Genetics of Immunity Source Type: research
