Correction: Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease
by Enrique Audain, Anna Wilsdon, Jeroen Breckpot, Jose M. G. Izarzugaza, Tomas W. Fitzgerald, Anne-Karin Kahlert, Alejandro Sifrim, Florian W ünnemann, Yasset Perez-Riverol, Hashim Abdul-Khaliq, Mads Bak, Anne S. Bassett, D. Woodrow Benson, Felix Berger, Ingo Daehnert, Koenraad Devriendt, Sven Dittrich, Piers EF Daubeney, Vidu Garg, Karl Hackmann, Kirstin Hoff, Philipp Hofmann, Gregor Dombrowsky, Thomas Pickardt, Ulrike Bauer, Bernard D. Keavney, Sabine Klaassen, Hans-Heiner Kramer, Christian R. Marshall, Dianna M. Milewicz, Scott Lemaire, Joseph S. Coselli, Michael E. Mitchell, Aoy Tomita-Mitchell, Siddharth K. Praka...
Source: PLoS Genetics - September 21, 2021 Category: Genetics & Stem Cells Authors: Enrique Audain Source Type: research

Identifying causal variants by fine mapping across multiple studies
by Nathan LaPierre, Kodi Taraszka, Helen Huang, Rosemary He, Farhad Hormozdiari, Eleazar Eskin Increasingly large Genome-Wide Association Studies (GWAS) have yielded numerous variants associated with many complex traits, motivating the development of “fine mapping” methods to identify which of the associated variants are causal. Additionally, GWAS of the same trait for different populat ions are increasingly available, raising the possibility of refining fine mapping results further by leveraging different linkage disequilibrium (LD) structures across studies. Here, we introduce multiple study causal variants ...
Source: PLoS Genetics - September 20, 2021 Category: Genetics & Stem Cells Authors: Nathan LaPierre Source Type: research

Circadian regulation of the < i > Drosophila < /i > astrocyte transcriptome
by Samantha You, Alder M. Yu, Mary A. Roberts, Ivanna J. Joseph, F. Rob Jackson Recent studies have demonstrated that astrocytes cooperate with neurons of the brain to mediate circadian control of many rhythmic processes including locomotor activity and sleep. Transcriptional profiling studies have described the overall rhythmic landscape of the brain, but few have employed a pproaches that reveal heterogeneous, cell-type specific rhythms of the brain. Using cell-specific isolation of ribosome-bound RNAs inDrosophila, we constructed the first circadian “translatome” for astrocytes. This analysis identified 293...
Source: PLoS Genetics - September 20, 2021 Category: Genetics & Stem Cells Authors: Samantha You Source Type: research

Endothelial lipase mediates efficient lipolysis of triglyceride-rich lipoproteins
by Sumeet A. Khetarpal, Cecilia Vitali, Michael G. Levin, Derek Klarin, Joseph Park, Akhil Pampana, John S. Millar, Takashi Kuwano, Dhavamani Sugasini, Papasani V. Subbaiah, Jeffrey T. Billheimer, Pradeep Natarajan, Daniel J. Rader Triglyceride-rich lipoproteins (TRLs) are circulating reservoirs of fatty acids used as vital energy sources for peripheral tissues. Lipoprotein lipase (LPL) is a predominant enzyme mediating triglyceride (TG) lipolysis and TRL clearance to provide fatty acids to tissues in animals. Physiological and human genetic evidence support a primary role for LPL in hydrolyzing TRL TGs. We hypothesized t...
Source: PLoS Genetics - September 20, 2021 Category: Genetics & Stem Cells Authors: Sumeet A. Khetarpal Source Type: research

Antagonistic relationship of NuA4 with the non-homologous end-joining machinery at DNA damage sites
by Salar Ahmad, Val érie Côté, Xue Cheng, Gaëlle Bourriquen, Vasileia Sapountzi, Mohammed Altaf, Jacques Côté The NuA4 histone acetyltransferase complex, apart from its known role in gene regulation, has also been directly implicated in the repair of DNA double-strand breaks (DSBs), favoring homologous recombination (HR) in S/G2 during the cell cycle. Here, we investigate the antagonistic relationship of NuA4 with non-homologous end joining (NHEJ) factors. We show that budding yeast Rad9, the 53BP1 ortholog, can inhibit NuA4 acetyltransferase activity when bound to chromatinin vitro. ...
Source: PLoS Genetics - September 20, 2021 Category: Genetics & Stem Cells Authors: Salar Ahmad Source Type: research

On cross-ancestry cancer polygenic risk scores
by Lars G. Fritsche, Ying Ma, Daiwei Zhang, Maxwell Salvatore, Seunggeun Lee, Xiang Zhou, Bhramar Mukherjee Polygenic risk scores (PRS) can provide useful information for personalized risk stratification and disease risk assessment, especially when combined with non-genetic risk factors. However, their construction depends on the availability of summary statistics from genome-wide association studies (G WAS) independent from the target sample. For best compatibility, it was reported that GWAS and the target sample should match in terms of ancestries. Yet, GWAS, especially in the field of cancer, often lack diversity and a...
Source: PLoS Genetics - September 16, 2021 Category: Genetics & Stem Cells Authors: Lars G. Fritsche Source Type: research

Joint effects of genes underlying a temperature specialization tradeoff in yeast
by Faisal AlZaben, Julie N. Chuong, Melanie B. Abrams, Rachel B. Brem A central goal of evolutionary genetics is to understand, at the molecular level, how organisms adapt to their environments. For a given trait, the answer often involves the acquisition of variants at unlinked sites across the genome. Genomic methods have achieved landmark successes in pinpointing these adaptive loci. To figure out how a suite of adaptive alleles work together, and to what extent they can reconstitute the phenotype of interest, requires their transfer into an exogenous background. We studied the joint effect of adaptive, gain-of-functio...
Source: PLoS Genetics - September 14, 2021 Category: Genetics & Stem Cells Authors: Faisal AlZaben Source Type: research

The chromatin remodeler Chd1 supports MRX and Exo1 functions in resection of DNA double-strand breaks
by Marco Gnugnoli, Erika Casari, Maria Pia Longhese Repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) requires that the 5’-terminated DNA strands are resected to generate single-stranded DNA overhangs. This process is initiated by a short-range resection catalyzed by the MRX (Mre11-Rad50-Xrs2) complex, which is followed b y a long-range step involving the nuclease Exo1 or Dna2. Here we show that theSaccharomyces cerevisiae ATP-dependent chromatin-remodeling protein Chd1 participates in both short- and long-range resection by promoting MRX and Exo1 association with the DSB ends. Furthermore, ...
Source: PLoS Genetics - September 14, 2021 Category: Genetics & Stem Cells Authors: Marco Gnugnoli Source Type: research

Rare variants in the endocytic pathway are associated with Alzheimer ’s disease, its related phenotypes, and functional consequences
In this study, we focused on the effect of rare variants on AD by first applying a rare-variant gene-set burden analysis using genes in the endocytic pathway on over 3,000 individuals with European ancestry from three large whole-genome sequencing (WGS) studies. We identified significant associations of rare-variant burden within the endocytic pathway with AD, which were successfully replicated in independent datasets. We further demonstrated that this endocyti c rare-variant enrichment is associated with neurofibrillary tangles (NFTs) and age-related phenotypes, increasing the risk of obtaining severer brain damage, earli...
Source: PLoS Genetics - September 13, 2021 Category: Genetics & Stem Cells Authors: Lingyu Zhan Source Type: research

Deletion of < i > lrrk2 < /i > causes early developmental abnormalities and age-dependent increase of monoamine catabolism in the zebrafish brain
by Stefano Suzzi, Reiner Ahrendt, Stefan Hans, Svetlana A. Semenova, Avinash Chekuru, Paul Wirsching, Volker Kroehne, Sayg ın Bilican, Shady Sayed, Sylke Winkler, Sandra Spieß, Anja Machate, Jan Kaslin, Pertti Panula, Michael BrandLRRK2 gain-of-function is considered a major cause of Parkinson ’s disease (PD) in humans. However, pathogenicity of LRRK2 loss-of-function in animal models is controversial. Here we show that deletion of the entire zebrafishlrrk2 locus elicits a pleomorphic transient brain phenotype in maternal-zygotic mutant embryos (mzLrrk2). In contrast tolrrk2, the paralog genelrrk1 is virtually...
Source: PLoS Genetics - September 13, 2021 Category: Genetics & Stem Cells Authors: Stefano Suzzi Source Type: research

Region-specific H3K9me3 gain in aged somatic tissues in < i > Caenorhabditis elegans < /i >
In this study, we aimed to characterize the age- dependent changes of the epigenome and, in turn, to understand epigenetic processes that drive aging phenotypes. We focused on the aging-associated changes in the repressive histone marks H3K9me3 and H3K27me3 inC.elegans. We observed region-specific gain and loss of both histone marks, but the changes are more evident for H3K9me3. We further found alteration of heterochromatic boundaries in aged somatic tissues. Interestingly, we discovered that the most statistically significant changes reflected H3K9me3-marked regions that are formed during aging, and are absent in develop...
Source: PLoS Genetics - September 10, 2021 Category: Genetics & Stem Cells Authors: Cheng-Lin Li Source Type: research

A functionally divergent intrinsically disordered region underlying the conservation of stochastic signaling
by Ian S. Hsu, Bob Strome, Emma Lash, Nicole Robbins, Leah E. Cowen, Alan M. Moses Stochastic signaling dynamics expand living cells’ information processing capabilities. An increasing number of studies report that regulators encode information in their pulsatile dynamics. The evolutionary mechanisms that lead to complex signaling dynamics remain uncharacterized, perhaps becau se key interactions of signaling proteins are encoded in intrinsically disordered regions (IDRs), whose evolution is difficult to analyze. Here we focused on the IDR that controls the stochastic pulsing dynamics of Crz1, a transcription factor...
Source: PLoS Genetics - September 10, 2021 Category: Genetics & Stem Cells Authors: Ian S. Hsu Source Type: research

Mediator complex proximal Tail subunit MED30 is critical for Mediator core stability and cardiomyocyte transcriptional network
by Changming Tan, Siting Zhu, Zee Chen, Canzhao Liu, Yang E. Li, Mason Zhu, Zhiyuan Zhang, Zhiwei Zhang, Lunfeng Zhang, Yusu Gu, Zhengyu Liang, Thomas G. Boyer, Kunfu Ouyang, Sylvia M. Evans, Xi Fang Dysregulation of cardiac transcription programs has been identified in patients and families with heart failure, as well as those with morphological and functional forms of congenital heart defects. Mediator is a multi-subunit complex that plays a central role in transcription initiation by integr ating regulatory signals from gene-specific transcriptional activators to RNA polymerase II (Pol II). Recently, Mediator subunit 3...
Source: PLoS Genetics - September 10, 2021 Category: Genetics & Stem Cells Authors: Changming Tan Source Type: research

Germline genome modification through novel political, ethical, and social lenses
by Vicki Xafis, G. Owen Schaefer, Markus K. Labude, Yujia Zhu, Soren Holm, Roger Sik-Yin Foo, Poh San Lai, Ruth Chadwick Much has been written about gene modifying technologies (GMTs), with a particularly strong focus on human germline genome editing (HGGE) sparked by its unprecedented clinical research application in 2018, shocking the scientific community. This paper applies political, ethical, and social lenses t o aspects of HGGE to uncover previously underexplored considerations that are important to reflect on in global discussions. By exploring 4 areas—(1) just distribution of HGGE benefits through a realist ...
Source: PLoS Genetics - September 9, 2021 Category: Genetics & Stem Cells Authors: Vicki Xafis Source Type: research

Germline genome editing: Moratorium, hard law, or an informed adaptive consensus?
by Terry Kaan, Vicki Xafis, G. Owen Schaefer, Yujia Zhu, Markus K. Labude, Ruth Chadwick With the development of practical means of human germline genome editing (HGGE) in recent years, there have been calls for stricter regulation and oversight over HGGE interventions with potential for heritable changes in the germline. An international moratorium has been advocated. We examine the practicality of such a proposal, as well as of a regulation through the “traditional” mechanisms of international and municipal laws. We argue that these mechanisms are unlikely to achieve their intended objectives and that the be...
Source: PLoS Genetics - September 9, 2021 Category: Genetics & Stem Cells Authors: Terry Kaan Source Type: research

Genome-wide methylation data improves dissection of the effect of smoking on body mass index
by Carmen Amador, Yanni Zeng, Michael Barber, Rosie M. Walker, Archie Campbell, Andrew M. McIntosh, Kathryn L. Evans, David J. Porteous, Caroline Hayward, James F. Wilson, Pau Navarro, Chris S. Haley Variation in obesity-related traits has a genetic basis with heritabilities between 40 and 70%. While the global obesity pandemic is usually associated with environmental changes related to lifestyle and socioeconomic changes, most genetic studies do not include all relevant environmental covariat es, so the genetic contribution to variation in obesity-related traits cannot be accurately assessed. Some studies have described ...
Source: PLoS Genetics - September 9, 2021 Category: Genetics & Stem Cells Authors: Carmen Amador Source Type: research

Deficiency of Pol η in < i > Saccharomyces cerevisiae < /i > reveals the impact of transcription on damage-induced cohesion
by Pei-Shang Wu, Jan Grosser, Donald P. Cameron, Laura Baranello, Lena Str öm The structural maintenance of chromosome (SMC) complex cohesin mediates sister chromatid cohesion established during replication, and damage-induced cohesion formed in response to DSBs post-replication. The translesion synthesis polymerase Polη is required for damage-induced cohesion through a hi therto unknown mechanism. Since Polη is functionally associated with transcription, and transcription triggersde novo cohesion inSchizosaccharomyces pombe, we hypothesized that transcription facilitates damage-induced cohesion inSaccharomyc...
Source: PLoS Genetics - September 9, 2021 Category: Genetics & Stem Cells Authors: Pei-Shang Wu Source Type: research

Transcriptional progression during meiotic prophase I reveals sex-specific features and X chromosome dynamics in human fetal female germline
by Xueying Fan, Ioannis Moustakas, Vanessa Torrens-Juaneda, Qijing Lei, Geert Hamer, Leoni A. Louwe, Gonneke S. K. Pilgram, Karoly Szuhai, Roberto Matorras, Cristina Eguizabal, Lucette van der Westerlaken, Hailiang Mei, Susana M. Chuva de Sousa Lopes During gametogenesis in mammals, meiosis ensures the production of haploid gametes. The timing and length of meiosis to produce female and male gametes differ considerably. In contrast to males, meiotic prophase I in females initiates during development. Hence, the knowledge regarding progression through meiotic prophase I is mainly focused on human male spermatogenesis and f...
Source: PLoS Genetics - September 9, 2021 Category: Genetics & Stem Cells Authors: Xueying Fan Source Type: research

The Triangulation WIthin a STudy (TWIST) framework for causal inference within pharmacogenetic research
by Jack Bowden, Luke Pilling, Deniz T ürkmen, Chia-Ling Kuo, David Melzer In this paper we review the methodological underpinnings of the general pharmacogenetic approach for uncovering genetically-driven treatment effect heterogeneity. This typically utilises only individuals who are treated and relies on fairly strong baseline assumptions to estimate what we term the ‘genetically moderated treatment effect’ (GMTE). When these assumptions are seriously violated, we show that a robust but less efficient estimate of the GMTE that incorporates information on the population of untreated individuals can inste...
Source: PLoS Genetics - September 8, 2021 Category: Genetics & Stem Cells Authors: Jack Bowden Source Type: research

Discovery of photosynthesis genes through whole-genome sequencing of acetate-requiring mutants of < i > Chlamydomonas reinhardtii < /i >
by Setsuko Wakao, Patrick M. Shih, Katharine Guan, Wendy Schackwitz, Joshua Ye, Dhruv Patel, Robert M. Shih, Rachel M. Dent, Mansi Chovatia, Aditi Sharma, Joel Martin, Chia-Lin Wei, Krishna K. Niyogi Large-scale mutant libraries have been indispensable for genetic studies, and the development of next-generation genome sequencing technologies has greatly advanced efforts to analyze mutants. In this work, we sequenced the genomes of 660Chlamydomonas reinhardtii acetate-requiring mutants, part of a larger photosynthesis mutant collection previously generated by insertional mutagenesis with a linearized plasmid. We identified...
Source: PLoS Genetics - September 7, 2021 Category: Genetics & Stem Cells Authors: Setsuko Wakao Source Type: research

Genes in human obesity loci are causal obesity genes in < i > C < /i > . < i > elegans < /i >
We report 14 genes that promote obesity and 3 genes that prevent DIO when silenced inC.elegans. Further, we show that knock-down of the 3 DIO genes not only prevents excessive fat accumulation in primary and ectopic fat depots but also improves the health and extends the lifespan ofC.elegans overconsuming fructose. Importantly, the direction of the association between expression variants in these loci and obesity in mice and humans matches the phenotypic outcome of the loss-of-function of theC.elegans ortholog genes, supporting the notion that some of these genes would be causally linked to obesity across phylogeny. Theref...
Source: PLoS Genetics - September 7, 2021 Category: Genetics & Stem Cells Authors: Wenfan Ke Source Type: research

Bracoviruses recruit host integrases for their integration into caterpillar ’s genome
by Zehua Wang, Xiqian Ye, Yuenan Zhou, Xiaotong Wu, Rongmin Hu, Jiachen Zhu, Ting Chen, Elisabeth Huguet, Min Shi, Jean-Michel Drezen, Jianhua Huang, Xuexin Chen Some DNA viruses infect host animals usually by integrating their DNAs into the host genome. However, the mechanisms for integration remain largely unknown. Here, we find thatCotesia vestalis bracovirus (CvBV), a polydnavirus of the parasitic waspC.vestalis (Haliday), integrates its DNA circles into hostPlutella xylostella (L.) genome by two distinct strategies, conservatively and randomly, through high-throughput sequencing analysis. We confirmed that the conser...
Source: PLoS Genetics - September 7, 2021 Category: Genetics & Stem Cells Authors: Zehua Wang Source Type: research

CSYseq: The first Y-chromosome sequencing tool typing a large number of Y-SNPs and Y-STRs to unravel worldwide human population genetics
In this study, we present the first extensive chrY-specific targeted resequencing panel, the ‘CSYseq’, which simultaneously identifies slow mutating Y-SNPs as evolution markers and rapid mutating Y-STRs as patrilineage markers. The pa nel was validated by paired-end sequencing of 130 males, distributed over 65 deep-rooted pedigrees covering 1,279 generations. The CSYseq successfully targets 15,611 Y-SNPs including 9,014 phylogenetic informative Y-SNPs to identify 1,443 human evolutionary Y-subhaplogroup lineages worldwide. In add ition, the CSYseq properly targets 202 Y-STRs, including 81 slow, 68 moderate, 27 ...
Source: PLoS Genetics - September 7, 2021 Category: Genetics & Stem Cells Authors: Sofie Claerhout Source Type: research

Genomic anatomy of male-specific microchromosomes in a gynogenetic fish
by Miao Ding, Xi-Yin Li, Zhi-Xuan Zhu, Jun-Hui Chen, Meng Lu, Qian Shi, Yang Wang, Zhi Li, Xin Zhao, Tao Wang, Wen-Xuan Du, Chun Miao, Tian-Zi Yao, Ming-Tao Wang, Xiao-Juan Zhang, Zhong-Wei Wang, Li Zhou, Jian-Fang Gui Unisexual taxa are commonly considered short-lived as the absence of meiotic recombination is supposed to accumulate deleterious mutations and hinder the creation of genetic diversity. However, the gynogenetic gibel carp (Carassius gibelio) with high genetic diversity and wide ecological distribution has outlived its predicted extinction time of a strict unisexual reproduction population. Unlike other unise...
Source: PLoS Genetics - September 7, 2021 Category: Genetics & Stem Cells Authors: Miao Ding Source Type: research

The CovR regulatory network drives the evolution of Group B < i > Streptococcus < /i > virulence
In this study, we characterized the CovR regulatory network in a strain representative of the CC-17 hypervirulent lineage responsible of the majority of neonatal meningitis. Transcriptome and genome-wide binding analysis reveal the architecture of the CovR network characterized by the direct repression of a large array of virulence-associated genes and the extent of co-regulation at specific loci. Comparative functional analysis of the signaling network links strain-specificities to the regulation of the pan-genome, including the two specific hypervirulent adhesins and horizontally acquired genes, to mutations in CovR-regu...
Source: PLoS Genetics - September 7, 2021 Category: Genetics & Stem Cells Authors: Maria-Vittoria Mazzuoli Source Type: research

A scalable < i > Drosophila < /i > assay for clinical interpretation of human < i > PTEN < /i > variants in suppression of PI3K/AKT induced cellular proliferation
by Payel Ganguly, Landiso Madonsela, Jesse T. Chao, Christopher J. R. Loewen, Timothy P. O ’Connor, Esther M. Verheyen, Douglas W. Allan Gene variant discovery is becoming routine, but it remains difficult to usefully interpret the functional consequence or disease relevance of most variants. To fill this interpretation gap, experimental assays of variant function are becoming common place. Yet, it remains challenging to make these assays reproducible, scalable to high numbers of variants, and capable of assessing defined gene-disease mechanism for clinical interpretation aligned to the ClinGen Sequence Variant Inte...
Source: PLoS Genetics - September 7, 2021 Category: Genetics & Stem Cells Authors: Payel Ganguly Source Type: research

IGSF11 is required for pericentric heterochromatin dissociation during meiotic diplotene
by Bo Chen, Gengzhen Zhu, An Yan, Jing He, Yang Liu, Lin Li, Xuerui Yang, Chen Dong, Kehkooi Kee Meiosis initiation and progression are regulated by both germ cells and gonadal somatic cells. However, little is known about what genes or proteins connecting somatic and germ cells are required for this regulation. Our results show that deficiency for adhesion molecule IGSF11, which is expressed in both Sertoli cells and germ cells, leads to male infertility in mice. Combining a new meiotic fluorescent reporter system with testicular cell transplantation, we demonstrated that IGSF11 is required in both somatic cells and sper...
Source: PLoS Genetics - September 7, 2021 Category: Genetics & Stem Cells Authors: Bo Chen Source Type: research

Dynamic neurogenomic responses to social interactions and dominance outcomes in female paper wasps
by Floria M. K. Uy, Christopher M. Jernigan, Natalie C. Zaba, Eshan Mehrotra, Sara E. Miller, Michael J. Sheehan Social interactions have large effects on individual physiology and fitness. In the immediate sense, social stimuli are often highly salient and engaging. Over longer time scales, competitive interactions often lead to distinct social ranks and differences in physiology and behavior. Understanding how initial responses lead to longer-term effects of social interactions requires examining the changes in responses over time. Here we examined the effects of social interactions on transcriptomic signatures at two t...
Source: PLoS Genetics - September 3, 2021 Category: Genetics & Stem Cells Authors: Floria M. K. Uy Source Type: research

A putative < i > de novo < /i > evolved gene required for spermatid chromatin condensation in < i > Drosophila melanogaster < /i >
by Emily L. Rivard, Andrew G. Ludwig, Prajal H. Patel, Anna Grandchamp, Sarah E. Arnold, Alina Berger, Emilie M. Scott, Brendan J. Kelly, Grace C. Mascha, Erich Bornberg-Bauer, Geoffrey D. Findlay Comparative genomics has enabled the identification of genes that potentially evolvedde novo from non-coding sequences. Many such genes are expressed in male reproductive tissues, but their functions remain poorly understood. To address this, we conducted a functional genetic screen of over 40 putativede novo genes with testis-enriched expression inDrosophila melanogaster and identified one gene,atlas, required for male fertilit...
Source: PLoS Genetics - September 3, 2021 Category: Genetics & Stem Cells Authors: Emily L. Rivard Source Type: research

RDC complex executes a dynamic piRNA program during < i > Drosophila < /i > spermatogenesis to safeguard male fertility
by Peiwei Chen, Yicheng Luo, Alexei A. Aravin piRNAs are small non-coding RNAs that guide the silencing of transposons and other targets in animal gonads. InDrosophila female germline, many piRNA source loci dubbed “piRNA clusters” lack hallmarks of active genes and exploit an alternative path for transcription, which relies on the Rhino-Deadlock-Cutoff (RDC) complex. RDC was thought to be absent in testis, so it remains to date unknown how piRNA cluster transcription is regulated in the male germline. We found that components of RDC complex are expressed in male germ cells during early spermatogenesis, from g...
Source: PLoS Genetics - September 2, 2021 Category: Genetics & Stem Cells Authors: Peiwei Chen Source Type: research

Rhino breaks the deadlock in < i > Drosophila < /i > testis
by Anahi Molla Herman, Emilie Brasset (Source: PLoS Genetics)
Source: PLoS Genetics - September 2, 2021 Category: Genetics & Stem Cells Authors: Anahi Molla Herman Source Type: research

Chromosomal Mcm2-7 distribution and the genome replication program in species from yeast to humans
by Eric J. Foss, Smitha Sripathy, Tonibelle Gatbonton-Schwager, Hyunchang Kwak, Adam H. Thiesen, Uyen Lao, Antonio Bedalov The spatio-temporal program of genome replication across eukaryotes is thought to be driven both by the uneven loading of pre-replication complexes (pre-RCs) across the genome at the onset of S-phase, and by differences in the timing of activation of these complexes during S phase. To determine th e degree to which distribution of pre-RC loading alone could account for chromosomal replication patterns, we mapped the binding sites of the Mcm2-7 helicase complex (MCM) in budding yeast, fission yeast, mo...
Source: PLoS Genetics - September 2, 2021 Category: Genetics & Stem Cells Authors: Eric J. Foss Source Type: research

The genetic consequences of dog breed formation —Accumulation of deleterious genetic variation and fixation of mutations associated with myxomatous mitral valve disease in cavalier King Charles spaniels
by Erik Axelsson, Ingrid Ljungvall, Priyasma Bhoumik, Laura Bas Conn, Eva Muren, Åsa Ohlsson, Lisbeth Høier Olsen, Karolina Engdahl, Ragnvi Hagman, Jeanette Hanson, Dmytro Kryvokhyzha, Mats Pettersson, Olivier Grenet, Jonathan Moggs, Alberto Del Rio-Espinola, Christian Epe, Bruce Taillon, Nilesh Tawari, Shrinivas Mane, Troy Hawkins, Åke Hedhammar, Philippe Gruet, Jens Häggst röm, Kerstin Lindblad-Toh Selective breeding for desirable traits in strictly controlled populations has generated an extraordinary diversity in canine morphology and behaviour, but has also led to loss of genetic variatio...
Source: PLoS Genetics - September 2, 2021 Category: Genetics & Stem Cells Authors: Erik Axelsson Source Type: research

Epigenetic dynamics of centromeres and neocentromeres in < i > Cryptococcus deuterogattii < /i >
by Klaas Schotanus, Vikas Yadav, Joseph Heitman Deletion of native centromeres in the human fungal pathogenCryptococcus deuterogattii leads to neocentromere formation. Native centromeres span truncated transposable elements, while neocentromeres do not and instead span actively expressed genes. To explore the epigenetic organization of neocentromeres, we analyzed the distribution of the heterochromatic histone modification H3K9me2, 5mC DNA methylation and the euchromatin mark H3K4me2. Native centromeres are enriched for both H3K9me2 and 5mC DNA methylation marks and are devoid of H3K4me2, while neocentromeres do not exhib...
Source: PLoS Genetics - August 31, 2021 Category: Genetics & Stem Cells Authors: Klaas Schotanus Source Type: research

R-loops and regulatory changes in chronologically ageing fission yeast cells drive non-random patterns of genome rearrangements
by David A. Ellis, F élix Reyes-Martín, María Rodríguez-López, Cristina Cotobal, Xi-Ming Sun, Quentin Saintain, Daniel C. Jeffares, Samuel Marguerat, Víctor A. Tallada, Jürg Bähler Aberrant repair of DNA double-strand breaks can recombine distant chromosomal breakpoints. Chromosomal rearrangements compromise genome function and are a hallmark of ageing. Rearrangements are challenging to detect in non-dividing cell populations, because they reflect individually rare, heteroge neous events. The genomic distribution ofde novo rearrangements in non-dividing cells, and their ...
Source: PLoS Genetics - August 31, 2021 Category: Genetics & Stem Cells Authors: David A. Ellis Source Type: research

Multitrait GWAS to connect disease variants and biological mechanisms
by Hanna Julienne, Vincent Laville, Zachary R. McCaw, Zihuai He, Vincent Guillemot, Carla Lasry, Andrey Ziyatdinov, Cyril Nerin, Amaury Vaysse, Pierre Lechat, Herv é Ménager, Wilfried Le Goff, Marie-Pierre Dube, Peter Kraft, Iuliana Ionita-Laza, Bjarni J. Vilhjálmsson, Hugues Aschard Genome-wide association studies (GWASs) have uncovered a wealth of associations between common variants and human phenotypes. Here, we present an integrative analysis of GWAS summary statistics from 36 phenotypes to decipher multitrait genetic architecture and its link with biological mechanisms. Our framework incorporate...
Source: PLoS Genetics - August 30, 2021 Category: Genetics & Stem Cells Authors: Hanna Julienne Source Type: research

The Easter Egg Weevil ( < i > Pachyrhynchus < /i > ) genome reveals syntenic patterns in Coleoptera across 200 million years of evolution
by Matthew H. Van Dam, Analyn Anzano Cabras, James B. Henderson, Andrew J. Rominger, Cynthia P érez Estrada, Arina D. Omer, Olga Dudchenko, Erez Lieberman Aiden, Athena W. Lam Patterns of genomic architecture across insects remain largely undocumented or decoupled from a broader phylogenetic context. For instance, it is unknown whether translocation rates differ between insect orders. We address broad scale patterns of genome architecture across Insecta by examining syn teny in a phylogenetic framework from open-source insect genomes. To accomplish this, we add a chromosome level genome to a crucial lineage, Coleop...
Source: PLoS Genetics - August 30, 2021 Category: Genetics & Stem Cells Authors: Matthew H. Van Dam Source Type: research

The genetics and evolution of eye color in domestic pigeons ( < i > Columba livia < /i > )
by Si Si, Xiao Xu, Yan Zhuang, Xiaodong Gao, Honghai Zhang, Zhengting Zou, Shu-Jin Luo The eye color of birds, generally referring to the color of the iris, results from both pigmentation and structural coloration. Avian iris colors exhibit striking interspecific and intraspecific variations that correspond to unique evolutionary and ecological histories. Here, we identified the gen etic basis of pearl (white) iris color in domestic pigeons (Columba livia) to explore the largely unknown genetic mechanism underlying the evolution of avian iris coloration. Using a genome-wide association study (GWAS) in 92 pigeons, we mappe...
Source: PLoS Genetics - August 30, 2021 Category: Genetics & Stem Cells Authors: Si Si Source Type: research

Cancer associated mutations in Sec61 γ alter the permeability of the ER translocase
by Christopher M. Witham, Aleshanee L. Paxman, Lamprini Baklous, Robert F. L. Steuart, Benjamin L. Schulz, Carl J. Mousley Translocation of secretory and integral membrane proteins across or into the ER membrane occurs via the Sec61 complex, a heterotrimeric protein complex possessing two essential sub-units, Sec61p/Sec61α and Sss1p/Sec61γ and the non-essential Sbh1p/Sec61β subunit. In addition to forming a protein conducting channel, the Sec61 complex maintains the ER permeability barrier, preventing flow of molecules and ions. Loss of Sec61 integrity is detrimental and implicated in the progression of d...
Source: PLoS Genetics - August 30, 2021 Category: Genetics & Stem Cells Authors: Christopher M. Witham Source Type: research

Uterine Notch2 facilitates pregnancy recognition and corpus luteum maintenance via upregulating decidual Prl8a2
by Haili Bao, Yang Sun, Ningjie Yang, Na Deng, Zhangli Ni, Yedong Tang, Gaizhen Li, Lili Du, Yan-Ling Wang, Dunjin Chen, Haibin Wang, Shuangbo Kong The maternal recognition of pregnancy is a necessary prerequisite for gestation maintenance through prolonging the corpus luteum lifespan and ensuring progesterone production. In addition to pituitary prolactin and placental lactogens, decidual derived prolactin family members have been presumed t o possess luteotropic effect. However, there was a lack of convincing evidence to support this hypothesis. Here, we unveiled an essential role of uterine Notch2 in pregnancy recognit...
Source: PLoS Genetics - August 30, 2021 Category: Genetics & Stem Cells Authors: Haili Bao Source Type: research

AKTIP interacts with ESCRT I and is needed for the recruitment of ESCRT III subunits to the midbody
by Chiara Merigliano, Romina Burla, Mattia La Torre, Simona Del Giudice, Hsiangling Teo, Chong Wai Liew, Alexandre Chojnowski, Wah Ing Goh, Yolanda Olmos, Klizia Maccaroni, Maria Giubettini, Irene Chiolo, Jeremy G. Carlton, Domenico Raimondo, Fiammetta Vern ì, Colin L. Stewart, Daniela Rhodes, Graham D. Wright, Brian E. Burke, Isabella Saggio To complete mitosis, the bridge that links the two daughter cells needs to be cleaved. This step is carried out by the endosomal sorting complex required for transport (ESCRT) machinery. AKTIP, a protein discovered to be associated with telomeres and the nuclear membrane in in...
Source: PLoS Genetics - August 27, 2021 Category: Genetics & Stem Cells Authors: Chiara Merigliano Source Type: research

Allele-specific mitochondrial stress induced by Multiple Mitochondrial Dysfunctions Syndrome 1 pathogenic mutations modeled in < i > Caenorhabditis elegans < /i >
by Peter A. Kropp, Jing Wu, Michael Reidy, Sanjay Shrestha, Kyle Rhodehouse, Philippa Rogers, Michael N. Sack, Andy Golden Multiple Mitochondrial Dysfunctions Syndrome 1 (MMDS1) is a rare, autosomal recessive disorder caused by mutations in theNFU1 gene. NFU1 is responsible for delivery of iron-sulfur clusters (ISCs) to recipient proteins which require these metallic cofactors for their function. Pathogenic variants ofNFU1 lead to dysfunction of its target proteins within mitochondria. To date, 20NFU1 variants have been reported and the unique contributions of each variant to MMDS1 pathogenesis is unknown. Given that over...
Source: PLoS Genetics - August 27, 2021 Category: Genetics & Stem Cells Authors: Peter A. Kropp Source Type: research

A Y-linked anti-M üllerian hormone type-II receptor is the sex-determining gene in ayu, < i > Plecoglossus altivelis < /i >
by Masatoshi Nakamoto, Tsubasa Uchino, Eriko Koshimizu, Yudai Kuchiishi, Ryota Sekiguchi, Liu Wang, Ryusuke Sudo, Masato Endo, Yann Guiguen, Manfred Schartl, John H. Postlethwait, Takashi Sakamoto Whole-genome duplication and genome compaction are thought to have played important roles in teleost fish evolution. Ayu (or sweetfish),Plecoglossus altivelis, belongs to the superorder Stomiati, order Osmeriformes. Stomiati is phylogenetically classified as sister taxa of Neoteleostei. Thus, ayu holds an important position in the fish tree of life. Although ayu is economically important for the food industry and recreational fi...
Source: PLoS Genetics - August 26, 2021 Category: Genetics & Stem Cells Authors: Masatoshi Nakamoto Source Type: research

The impact of age on genetic risk for common diseases
by Xilin Jiang, Chris Holmes, Gil McVean Inherited genetic variation contributes to individual risk for many complex diseases and is increasingly being used for predictive patient stratification. Previous work has shown that genetic factors are not equally relevant to human traits across age and other contexts, though the reasons for suc h variation are not clear. Here, we introduce methods to infer the form of the longitudinal relationship between genetic relative risk for disease and age and to test whether all genetic risk factors behave similarly. We use a proportional hazards model within an interval-based censoring ...
Source: PLoS Genetics - August 26, 2021 Category: Genetics & Stem Cells Authors: Xilin Jiang Source Type: research

High-throughput screening and genome-wide analyses of 44 anticancer drugs in the 1000 Genomes cell lines reveals an association of the < i > NQO1 < /i > gene with the response of multiple anticancer drugs
by Farida S. Akhtari, Adrian J. Green, George W. Small, Tammy M. Havener, John S. House, Kyle R. Roell, David M. Reif, Howard L. McLeod, Timothy Wiltshire, Alison A. Motsinger-Reif Cancer patients exhibit a broad range of inter-individual variability in response and toxicity to widely used anticancer drugs, and genetic variation is a major contributor to this variability. To identify new genes that influence the response of 44 FDA-approved anticancer drug treatments widely u sed to treat various types of cancer, we conducted high-throughput screening and genome-wide association mapping using 680 lymphoblastoid cell lines ...
Source: PLoS Genetics - August 26, 2021 Category: Genetics & Stem Cells Authors: Farida S. Akhtari Source Type: research

Average semivariance yields accurate estimates of the fraction of marker-associated genetic variance and heritability in complex trait analyses
by Mitchell J. Feldmann, Hans-Peter Piepho, William C. Bridges, Steven J. Knapp The development of genome-informed methods for identifying quantitative trait loci (QTL) and studying the genetic basis of quantitative variation in natural and experimental populations has been driven by advances in high-throughput genotyping. For many complex traits, the underlying genetic varia tion is caused by the segregation of one or more ‘large-effect’ loci, in addition to an unknown number of loci with effects below the threshold of statistical detection. The large-effect loci segregating in populations are often necessary...
Source: PLoS Genetics - August 26, 2021 Category: Genetics & Stem Cells Authors: Mitchell J. Feldmann Source Type: research

Distribution of Holliday junctions and repair forks during < i > Escherichia coli < /i > DNA double-strand break repair
by Tahirah Yasmin, Benura Azeroglu, Charlotte A. Cockram, David R. F. Leach Accurate repair of DNA double-strand breaks (DSBs) is crucial for cell survival and genome integrity. InEscherichia coli, DSBs are repaired by homologous recombination (HR), using an undamaged sister chromosome as template. The DNA intermediates of this pathway are expected to be branched molecules that may include 4-way structures termed Holliday junctions (HJs), and 3-way structures such as D-loops and repair forks. Using a tool creating a site-specific, repairable DSB on only one of a pair of replicating sister chromosomes, we have determined h...
Source: PLoS Genetics - August 25, 2021 Category: Genetics & Stem Cells Authors: Tahirah Yasmin Source Type: research

Chromoanagenesis from radiation-induced genome damage in < i > Populus < /i >
by Weier Guo, Luca Comai, Isabelle M. Henry Chromoanagenesis is a genomic catastrophe that results in chromosomal shattering and reassembly. These extreme single chromosome events were first identified in cancer, and have since been observed in other systems, but have so far only been formally documented in plants in the context of haploid induction crosses. The frequency, origins, consequences, and evolutionary impact of such major chromosomal remodeling in other situations remain obscure. Here, we demonstrate the occurrence of chromoanagenesis in poplar (Populus sp.) trees produced from gamma-irradiated pollen. Specific...
Source: PLoS Genetics - August 25, 2021 Category: Genetics & Stem Cells Authors: Weier Guo Source Type: research

The Integrity of the HMR complex is necessary for centromeric binding and reproductive isolation in < i > Drosophila < /i >
by Andrea Lukacs, Andreas W. Thomae, Peter Krueger, Tamas Schauer, Anuroop V. Venkatasubramani, Natalia Y. Kochanova, Wasim Aftab, Rupam Choudhury, Ignasi Forne, Axel Imhof Postzygotic isolation by genomic conflict is a major cause for the formation of species. Despite its importance, the molecular mechanisms that result in the lethality of interspecies hybrids are still largely unclear. The genusDrosophila, which contains over 1600 different species, is one of the best characterized model systems to study these questions. We showed in the past that the expression levels of the two hybrid incompatibility factorsHmr andLhr...
Source: PLoS Genetics - August 23, 2021 Category: Genetics & Stem Cells Authors: Andrea Lukacs Source Type: research

Endothelial Semaphorin 3fb regulates Vegf pathway-mediated angiogenic sprouting
by Charlene Watterston, Rami Halabi, Sarah McFarlane, Sarah J. Childs Vessel growth integrates diverse extrinsic signals with intrinsic signaling cascades to coordinate cell migration and sprouting morphogenesis. The pro-angiogenic effects of Vascular Endothelial Growth Factor (VEGF) are carefully controlled during sprouting to generate an efficiently patterned vasc ular network. We identify crosstalk between VEGF signaling and that of the secreted ligand Semaphorin 3fb (Sema3fb), one of two zebrafish paralogs of mammalian Sema3F. Thesema3fb gene is expressed by endothelial cells in actively sprouting vessels. Loss ofsema...
Source: PLoS Genetics - August 23, 2021 Category: Genetics & Stem Cells Authors: Charlene Watterston Source Type: research