Genetics

doi: 10.1534/genetics/215.nppmid: N/A

doi: 10.1093/genetics/215.nppmid: N/A

Life history effects on neutral diversity levels of autosomes and sex chromosomes, pp. 1133–1142 Guy Amster and Guy Sella Understanding the determinants of neutral diversity patterns on autosomes and sex chromosomes provides a bedrock for our interpretation of population genetic data. Sex-specific age-structure and variation in reproductive success have long been thought to affect neutral diversity, but theoretical descriptions of these effects were complicated and/or lacked in generality, stymying attempts to relate diversity patterns of species with their life history. Amster and Sella derive general yet simple expressions for these effects, which clarify how they impact neutral diversity and should enable studies of relative diversity levels on the autosomes and sex chromosomes in many taxa. Tolerance to hypoxia is promoted by FOXO regulation of the innate immunity transcription factor NF-κB/relish in Drosophila, pp. 1013–1025 Elizabeth C. Barretto, Danielle M. Polan, Amy N. Beevor-Potts, Byoungchun Lee, and Savraj S. Grewal Our cells and organs need oxygen from the air we breathe in order to survive. However, although air contains twenty percent oxygen, our cells are exposed to much lower levels. In addition, our cells are often deprived of oxygen in diseases such as stroke, heart disease, and cancer. This lack of oxygen, known as hypoxia, leads to the tissue damage seen in these diseases. An important challenge in biology is to understand how cells and organs can respond to, and cope with, low oxygen. Barretto et al. identified activation of the transcription factor FOXO as a key mechanism flies use to promote survival in low oxygen. In addition, they show that one way that FOXO works is by activating Relish, a factor known to be important for immune responses. Hence, their work demonstrates that organisms may cope with low oxygen conditions by co-opting immune-like responses. A transcriptional regulatory map of iron homeostasis reveals a new control circuit for capsule formation in Cryptococcus neoformans, pp. 1171–1189 Eunsoo Do, Yong-Joon Cho, Donghyeun Kim, James Kronstad, and Won Hee Jung To overcome host iron restriction, the human fungal pathogen Cryptococcus neoformans uses several iron uptake mechanisms to cause disease. In this study, Do et al. used ChIP-seq and RNA-seq analysis to identify genes directly regulated by Cir1 and HapX. They identified the genes that are downstream targets of each protein and constructed comprehensive genome wide-transcriptional regulatory networks in response to iron availability. In addition, they found that Cir1 and HapX are iron-binding proteins suggesting that iron may directly influence the activities of these proteins. Together, their data provide new insights into the regulatory networks for iron acquisition and homeostasis in C. neoformans. Systematic humanization of the yeast cytoskeleton discerns functionally replaceable from divergent human genes, pp. 1153–1169 Riddhiman K. Garge, Jon M. Laurent, Aashiq H. Kachroo, and Edward M. Marcotte To understand the extent of functional divergence across duplicated genes in core eukaryotic systems, Garge et al. systematically tested ∼81% of human orthologs (comprising 89 new complementation pairs) across 7 major cytoskeletal gene families via simple growth rescue assays. In all, the authors found that ∼26% of tested human genes across 5 of 7 cytoskeletal families could complement their yeast equivalents. Probing functional complementation in more detail, they found varying extents to which human orthologs functionally rescue yeast cytoskeletal family-specific roles, including cell morphology, meiosis, and mating. Such cases complementation assays now provide yeast-based reagents to better understand human cytoskeletal gene function. Spontaneous tumor regression in Tasmanian devils associated with RASL11A activation, pp. 1143–1152 Mark J. Margres, Manuel Ruiz-Aravena, Rodrigo Hamede, Kusum Chawla, Austin Patton, Matthew F. Lawrance, Alexandra K. Fraik, Amanda R. Stahlke, Brian W. Davis, Elaine A. Ostrander, Menna E. Jones, Hamish McCallum, Patrick J. Paddison, Paul A. Hohenlohe, David Hockenbery, and Andrew Storfer Spontaneous cancer regression in humans is uncommon, but understanding the mechanisms is key for advancing treatment. Using Devil Facial Tumor Disease as a model, Margres et al. employed comparative and functional genomics to study rare instances of tumor regression in wild Tasmanian devils. The authors identified a single mutation that differed between regressed and non-regressed tumors that activated the expression of RASL11A. Inducement of RASL11A expression significantly reduced tumor growth rates in vitro. RASL11A is also under-expressed in human prostate and colon cancer. Their work suggests that RASL11A could be used as gene therapy treatment for human cancers and the Tasmanian devil. Potassium channel-associated bioelectricity of the dermomyotome determines fin patterning in zebrafish, pp. 1067–1084 Martin R. Silic, Qiuyu Wu, Brian H. Kim, Greg Golling, Kenny H. Chen, Renata Freitas, Alexander A. Chubykin, Suresh K. Mittal, and GuangJun Zhang It has long been recognized that the morphological complexity of vertebrates is established by spatially- and temporally-regulated cell signaling. For decades, studies of the molecular mechanisms of body patterning have focused on conserved signaling molecules and transcription factors, which has led to major insights into how the embryo is patterned. However, the roles of bioelectric signaling in developmental patterning remain largely unknown. In this paper, Silic et al. identify a potassium channel-based bioelectric signaling mechanism that regulates fin size in zebrafish. In addition, they provide the first evidence that fin size is determined by dermomyotome bioelectric properties. Spontaneous polyploids and antimutators compete during the evolution of Saccharomyces cerevisiae mutator cells, pp. 959–974 Maxwell A. Tracy, Mitchell B. Lee, Brady L. Hearn, Ian T. Dowsett, Luke C. Thurber, Jason Loo, Anisha M. Loeb, Kent Preston, Miles I. Tuncel, Niloufar Ghodsian, Anna Bode, Thao T. Tang, Andy R. Chia, and Alan J. Herr “Mutator” tumor cells that cannot correct DNA replication errors exhibit an extremely high mutation rate that accelerates their evolution. But this gamble puts them at risk for extinction. Haploid mutator yeast escape this problem through genome duplication, which buffers cells from lethal mutations, or “antimutator” alleles that lower mutation rate. Tracy et al. modeled mutator-driven tumors facing extinction using diploid yeast. Tetraploids arose with a 1% frequency, while the rest acquired antimutator mutations. With diploids that model heterozygous POLE mutator alleles found in cancer, cultures had many independent adapted subclones. A similar process occurring in tumors would maintain substantial intra-tumoral genetic heterogeneity. Multi-trait genome-wide analyses of the brain imaging phenotypes in UK Biobank, pp. 947–958 Chong Wu Wu introduced a new method termed aMAT for multi-trait analysis of any number of traits. The author conducted extensive simulations, confirming that aMAT yields well-controlled Type I error rates and achieves high statistical power across a wide range of scenarios. He then applied aMAT to GWAS summary statistics for a set of 58 volumetric imaging derived phenotypes from the UK Biobank. aMAT identified 24 distinct risk loci, 13 of which were missed by standard GWAS. Bioinformatic analyses show that the linked genes are enriched in volumetric gene sets such as hippocampal subfield CA4 volume. In CBE — Life Sciences Education (LSE) Diving into the details: constructing a framework of random call components, CBE—Life Sciences Education Vol. 19:doi.org/10.1187/cbe.19-07-0130 Alex H. Waugh and Tessa C. Andrews Calling on students in class helps them engage with content, demonstrate knowledge, and foster discussion. However, research shows that asking for volunteers to answer questions often skews toward overrepresentation of male and non-minority student voices. Random call can increase the diversity of voices in the classroom, making the classroom more inclusive. Waugh and Andrews examine the factors involved in the choice of random calling and the methods to optimize its outcome. Qualitative analysis of interviews of faculty adopters highlights the costs and benefits faculty weighed and techniques deemed critical for success: 1) explain the reason for use of random call, 2) allow students to discuss the question beforehand in groups, 3) ask the question of the discussion group, and 4) be respectful and positive. Having identified these parameters, future research can now explore the relative importance of these features of random calls on positive outcomes. Copyright © 2020 by the Genetics Society of America This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Hoppe, Thorsten; Cohen, Ehud

doi: 10.1534/genetics.120.301283pmid: 32759342

Sustaining a healthy proteome is a lifelong challenge for each individual cell of an organism. However, protein homeostasis or proteostasis is constantly jeopardized since damaged proteins accumulate under proteotoxic stress that originates from ever-changing metabolic, environmental, and pathological conditions. Proteostasis is achieved via a conserved network of quality control pathways that orchestrate the biogenesis of correctly folded proteins, prevent proteins from misfolding, and remove potentially harmful proteins by selective degradation. Nevertheless, the proteostasis network has a limited capacity and its collapse deteriorates cellular functionality and organismal viability, causing metabolic, oncological, or neurodegenerative disorders. While cell-autonomous quality control mechanisms have been described intensely, recent work on Caenorhabditis elegans has demonstrated the systemic coordination of proteostasis between distinct tissues of an organism. These findings indicate the existence of intricately balanced proteostasis networks important for integration and maintenance of the organismal proteome, opening a new door to define novel therapeutic targets for protein aggregation diseases. Here, we provide an overview of individual protein quality control pathways and the systemic coordination between central proteostatic nodes. We further provide insights into the dynamic regulation of cellular and organismal proteostasis mechanisms that integrate environmental and metabolic changes. The use of C. elegans as a model has pioneered our understanding of conserved quality control mechanisms important to safeguard the organismal proteome in health and disease.

Nonet, Michael L

doi: 10.1534/genetics.120.303388pmid: 32513816

The application of CRISPR technology has greatly facilitated the creation of transgenic Caenorhabditis elegans lines. However, methods to insert multi-kilobase DNA constructs remain laborious even with these advances. Here, I describe a new approach for introducing large DNA constructs into the C. elegans genome at specific sites using a combination of Flp and Cre recombinases. The system utilizes specialized integrated landing sites that express GFP ubiquitously flanked by single loxP, FRT, and FRT3 sites. DNA sequences of interest are inserted into an integration vector that contains a sqt-1 self-excising cassette and FRT and FRT3 sites. Plasmid DNA is injected into the germline of landing site animals. Transgenic animals are identified as Rol progeny, and the sqt-1 marker is subsequently excised with heat shock Cre expression. Integration events were obtained at a rate of approximately one integration per three injected F0 animals—a rate substantially higher than any current approach. To demonstrate the robustness of the approach, I compared the efficiency of the Gal4/UAS, QF (and QF2)/QUAS, tetR(and rtetR)/tetO, and LexA/lexO bipartite expression systems by assessing expression levels in combinations of driver and reporter GFP constructs and a direct promoter GFP fusion each integrated at multiple sites in the genome. My data demonstrate that all four bipartite systems are functional in C. elegans. Although the new integration system has several limitations, it greatly reduces the effort required to create single-copy insertions at defined sites in the C. elegans genome.

Titen, Simon W A; Johnson, Makenna T B; Capecchi, Mario; Golic, Kent G

doi: 10.1534/genetics.120.303394pmid: 32586890

Site-specific recombinases are widely used tools for analysis of genetics, development, and cell biology, and many schemes have been devised to alter gene expression by recombinase-mediated DNA rearrangements. Because the FRT and lox target sites for the commonly used FLP and Cre recombinases are asymmetrical, and must pair in the same direction to recombine, construct design must take into account orientation of the target sites. Both direct and inverted configurations have been used. However, the outcome of recombination between target sites on sister chromatids is frequently overlooked. This is especially consequential with inverted target sites, where exchange between oppositely oriented target sites on sisters will produce dicentric and acentric chromosomes. By using constructs that have inverted target sites in Drosophila melanogaster and in mice, we show here that dicentric chromosomes are produced in the presence of recombinase, and that the frequency of this event is quite high. The negative effects on cell viability and behavior can be significant, and should be considered when using such constructs.

Moeinizade, Saba; Kusmec, Aaron; Hu, Guiping; Wang, Lizhi; Schnable, Patrick S

doi: 10.1534/genetics.120.303305pmid: 32482640

Plant breeders make selection decisions based on multiple traits, such as yield, plant height, flowering time, and disease resistance. A commonly used approach in multi-trait genomic selection is index selection, which assigns weights to different traits relative to their economic importance. However, classical index selection only optimizes genetic gain in the next generation, requires some experimentation to find weights that lead to desired outcomes, and has difficulty optimizing nonlinear breeding objectives. Multi-objective optimization has also been used to identify the Pareto frontier of selection decisions, which represents different trade-offs across multiple traits. We propose a new approach, which maximizes certain traits while keeping others within desirable ranges. Optimal selection decisions are made using a new version of the look-ahead selection (LAS) algorithm, which was recently proposed for single-trait genomic selection, and achieved superior performance with respect to other state-of-the-art selection methods. To demonstrate the effectiveness of the new method, a case study is developed using a realistic data set where our method is compared with conventional index selection. Results suggest that the multi-trait LAS is more effective at balancing multiple traits compared with index selection.

Wu, Chong

doi: 10.1534/genetics.120.303242pmid: 32540950

Wu introduced a new method termed aMAT for multi-trait analysis of any number of traits. The author conducted extensive simulations, confirming that aMAT yields well-controlled Type I error....

Tracy, Maxwell A; Lee, Mitchell B; Hearn, Brady L; Dowsett, Ian T; Thurber, Luke C; Loo, Jason; Loeb, Anisha M; Preston, Kent; Tuncel, Miles I; Ghodsian, Niloufar; Bode, Anna; Tang, Thao T; Chia, Andy R; Herr, Alan J

Dedukh, Dmitrij; Majtánová, Zuzana; Marta, Anatolie; Pšenička, Martin; Kotusz, Jan; Klíma, Jiří; Juchno, Dorota; Boron, Alicja; Janko, Karel

doi: 10.1534/genetics.119.302988pmid: 32518062

Hybrid sterility is a hallmark of speciation, but the underlying molecular mechanisms remain poorly understood. Here, we report that speciation may regularly proceed through a stage at which gene flow is completely interrupted, but hybrid sterility occurs only in male hybrids whereas female hybrids reproduce asexually. We analyzed gametogenic pathways in hybrids between the fish species Cobitis elongatoides and C. taenia, and revealed that male hybrids were sterile owing to extensive asynapsis and crossover reduction among heterospecific chromosomal pairs in their gametes, which was subsequently followed by apoptosis. We found that polyploidization allowed pairing between homologous chromosomes and therefore partially rescued the bivalent formation and crossover rates in triploid hybrid males. However, it was not sufficient to overcome sterility. In contrast, both diploid and triploid hybrid females exhibited premeiotic genome endoreplication, thereby ensuring proper bivalent formation between identical chromosomal copies. This endoreplication ultimately restored female fertility but it simultaneously resulted in the obligate production of clonal gametes, preventing any interspecific gene flow. In conclusion, we demonstrate that the emergence of asexuality can remedy hybrid sterility in a sex-specific manner and contributes to the speciation process.

Aklilu, Behailu B; Peurois, François; Saintomé, Carole; Culligan, Kevin M; Kobbe, Daniela; Leasure, Catherine; Chung, Michael; Cattoor, Morgan; Lynch, Ryan; Sampson, Lauren; Fatora, John; Shippen, Dorothy E

doi: