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Split-wrmScarlet and split-sfGFP: Tools for faster, easier fluorescent labeling of endogenous proteins in Caenorhabditis elegans bioRxiv. Genet. Pub Date : 2021-01-17 Jérôme Goudeau; Catherine S Sharp; Jonathan Paw; Laura Savy; Manuel D Leonetti; Andrew G York; Dustin L Updike; Cynthia Kenyon; Maria Ingaramo
We create and share a new red fluorophore, along with a set of strains, reagents and protocols, to make it faster and easier to label endogenous C. elegans proteins with fluorescent tags. CRISPR-mediated fluorescent labeling of C. elegans proteins is an invaluable tool, but it is much more difficult to insert fluorophore-size DNA segments than it is to make small gene edits. In principle, high-affinity
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Arsenic hexoxide has differential effects on cell proliferation and genome-wide gene expression in human primary mammary epithelial and MCF7 cells bioRxiv. Genet. Pub Date : 2021-01-16 Donguk Kim; Na Yeon Park; Keunsoo Kang; Stuart K Calderwood; Dong-Hyung Cho; Ill Ju Bae; Heeyoun Bunch
Arsenic is reportedly a biphasic inorganic compound for its toxicity and anticancer effects in humans [1, 2]. Recent studies have shown that certain arsenic compounds including arsenic hexoxide (AS4O6; hereafter, AS6) induce programmed cell death and cell cycle arrest in human cancer cells and murine cancer models [3, 4]. However, the mechanisms by which AS6 suppresses cancer cells are incompletely
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Somatic uniparental disomy mitigates the most damaging EFL1 allele combination in Shwachman-Diamond syndrome bioRxiv. Genet. Pub Date : 2021-01-15 Sangmoon Lee; Chang H Shin; Jawon Lee; Seong D Jeong; Che R Hong; Jun-Dae Kim; Ah-Ra Kim; Soo J Son; Oleksandr Kokhan; Taekyeong Yoo; Jae S Ko; Young B Sohn; Ok-Hwa Kim; Jung M Ko; Tae-Joon Cho; Nathan T Wright; Je K Seong; Suk-Won Jin; Hyoung J Kang; Hyeon H Kim; Murim Choi
Shwachman-Diamond syndrome (SDS; OMIM: #260400) is caused by variants in SBDS (Shwachman-Bodian-Diamond syndrome gene), which encodes a protein that plays an important role in ribosome assembly. Recent reports suggest that recessive variants in EFL1 are also responsible for SDS. However, the precise genetic mechanism that leads to EFL1-induced SDS remains incompletely understood. Here we present three
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Large-scale genetic association and single cell accessible chromatin mapping defines cell type-specific mechanisms of type 1 diabetes risk bioRxiv. Genet. Pub Date : 2021-01-15 Joshua Chiou; Ryan Geusz; Mei-Lin Okino; Jee Yun Han; Michael Miller; Paola Benaglio; Serina Huang; Katha Korgaonkar; Sandra Heller; Alexander Kleger; Sebastian Preissl; David Gorkin; Maike Sander; Kyle J Gaulton
Translating genome-wide association studies (GWAS) of complex disease into mechanistic insight requires a comprehensive understanding of risk variant effects on disease-relevant cell types. To uncover cell type-specific mechanisms of type 1 diabetes (T1D) risk, we combined genetic association mapping and single cell epigenomics. We performed the largest to-date GWAS of T1D in 489,679 samples imputed
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Clinically Relevant Gene Editing in Hematopoietic Stem Cells for the Treatment of Pyruvate Kinase Deficiency Hemolytic Anemia bioRxiv. Genet. Pub Date : 2021-01-15 Sara Fañanas Baquero; Oscar Quintana-Bustamante; Daniel Patrick Dever; Omaira Alberquilla; Rebeca Sanchez; Joab Camarena; Isabel Ojeda-Pérez; Mercedes Dessy Rodríguez; Rolf Turk; Mollie S Schubert; Jose Luis Lopez Lorenzo; Paola Bianchi; Juan Antonio Bueren; Mark A. Behlke; Matthew Porteus; Jose Carlos Segovia
Pyruvate Kinase Deficiency is an autosomal recessive disorder caused by mutations in the PKLR gene, causing chronic non-spherocytic hemolytic anemia. PKLR gene encodes for the erythroid pyruvate kinase protein (RPK) implicated in the last step of the anaerobic glycolysis in erythrocytes. The defective enzyme fails to maintain normal ATP levels, producing severe hemolytic anemia. Here, we address the
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MLH1/3 variants causing aneuploidy, pregnancy loss, and premature reproductive aging bioRxiv. Genet. Pub Date : 2021-01-15 Priti Singh; Robert Fragoza; Cecilia S Blengini; Tina N Tran; Gianno Pannafino; Najla Al-Sweel; Kerry Schimenti; Karen Schindler; Eric Alani; Haiyuan Yu; John C. Schimenti
Most spontaneous pregnancy losses are a result of embryonic aneuploidy stemming from mis-segregation of chromosomes during meiosis. Proper disjunction of homologous chromosomes is dependent upon precise control of crossing-over, a process requiring the mismatch repair (MMR) genes MLH1 and MLH3. Both are required for fertility and completion of meiosis in mice. People inheriting variants in these genes
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Two novel loci underlie natural differences in Caenorhabditis elegans macrocyclic lactone responses bioRxiv. Genet. Pub Date : 2021-01-14 Erik C Andersen; Kathryn S. Evans; Janneke Wit; Lewis Stevens; Steffen R. Hahnel; Briana Rodriguez; Grace Park; Mostafa Zamanian; Shannon C. Brady; Ellen Chao; Katherine Introcaso; Robyn E. Tanny
Parasitic nematodes cause a massive worldwide burden on human health along with a loss of livestock and agriculture productivity. Anthelmintics have been widely successful in treating parasitic nematodes. However, resistance is increasing, and little is known about the molecular and genetic causes of resistance. The free-living roundworm Caenorhabditis elegans provides a tractable model to identify
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Novel Variance-Component TWAS method for studying complex human diseases with applications to Alzheimer's dementia bioRxiv. Genet. Pub Date : 2021-01-14 Shizhen Tang; Aron Buchman; Phillip De Jager; David Bennett; Michael Epstein; Jingjing Yang
Transcriptome-wide association studies (TWAS) have been widely used to integrate transcriptomic and genetic data to study complex human diseases. Within a test dataset lacking transcriptomic data, existing TWAS methods first impute gene expression by creating a weighted sum that aggregates SNPs with their corresponding cis-eQTL effects on reference transcriptome. Existing TWAS methods then employ a
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Significant East Asian affinity of Chinese Hui genomic structure suggesting their predominant cultural diffusion model in the genetic formation process bioRxiv. Genet. Pub Date : 2021-01-14 Yan Liu; Junbao Yang; Renkuan Tang; Didi Yuan; Yicheng Yang; Peixin Wang; Shudan Deng; Simei Zeng; Hongliang Li; Gang Chen; Xing Zou; Mengge Wang; Guanglin He
Ancestral origin and genomic history of Chinese Hui people remain to be explored due to the paucity of genome-wide data. Some evidence argued that an eastward migration of Central Asian given rise to modern Hui people, which was inferred as the demic diffusion hypothesis, and others favored the cultural diffusion hypothesis that posited indigenous East Asian adopted Muslim-like culture and formed the
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Low generalizability of polygenic scores in African populations due to genetic and environmental diversity bioRxiv. Genet. Pub Date : 2021-01-14 Lerato Majara; Allan Kalungi; Nastassja Koen; Heather Zar; Dan J Stein; Eugene Kinyanda; Elizabeth G Atkinson; Alicia R Martin
African populations are vastly underrepresented in genetic studies but have the most genetic variation and face wide-ranging environmental exposures globally. Because systematic evaluations of genetic prediction had not yet been conducted in ancestries that span African diversity, we calculated polygenic risk scores (PRS) in simulations across Africa and in empirical data from South Africa, Uganda
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Model-based genotype and ancestry estimation for potential hybrids with mixed-ploidy bioRxiv. Genet. Pub Date : 2021-01-14 Vivaswat Shastry; Paula E Adams; Dorothea Lindtke; Elizabeth G Mandeville; Thomas L Parchman; Zachariah Gompert; C. Alex Buerkle
Non-random mating among individuals can lead to spatial clustering of genetically similar individuals and population stratification. This deviation from panmixia is commonly observed in natural populations. Consequently, individuals can have parentage in single populations or involving hybridization between differentiated populations. Accounting for this mixture and structure is important when mapping
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Semi-coordinated allelic-bursting shape dynamic random monoallelic expression in pregastrulation embryos bioRxiv. Genet. Pub Date : 2021-01-14 Hemant C Naik; Kishore Hari; Deepshikha Chandel; Susmita Mandal; Mohit Kumar Jolly; SRIMONTA GAYEN
In recent years, allele-specific single-cell RNA-seq (scRNA-seq) analysis has demonstrated wide-spread dynamic random monoallelic expression of autosomal genes (aRME) in different cell types. However, the prevalence of dynamic aRME during pre-gastrulation development remains unknown. Here, we show that dynamic aRME is wide-spread in different lineages of pre-gastrulation embryos. Additionally, the
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Why are rare variants hard to impute? Coalescent models reveal theoretical limits in existing algorithms. bioRxiv. Genet. Pub Date : 2021-01-14 Yichen Si; Brett Vanderwerff; Sebastian Zoellner
Genotype imputation is an indispensable step in human genetic studies. Large reference panels with deeply sequenced genomes now allow interrogating variants with minor allele frequency <1% without sequencing. While it is critical to consider limits of this approach, imputation methods for rare variants have only done so empirically; the theoretical basis of their imputation accuracy has not been explored
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Correcting statistical bias in correlation-based kinship estimators bioRxiv. Genet. Pub Date : 2021-01-13 Wei Jiang; Xiangyu Zhang; Siting Li; Shuang Song; Hongyu Zhao
Accurate estimate of relatedness is important for genetic data analyses, such as association mapping and heritability estimation based on data collected from genome-wide association studies. Inaccurate relatedness estimates may lead to spurious associations and biased heritability estimations. Individual-level genotype data are often used to estimate kinship coefficient between individuals. The commonly
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DsbA-L protects against diabetic renal injury through the adipo-renal axis bioRxiv. Genet. Pub Date : 2021-01-13 Peng Hua Lin; Feng Ling Zeng; Ming Yang; Chun Hu; Li Zhao; Hui Xiang Chen; Ping Ya Wei
Disulfide-bond A oxidoreductase-like protein (DsbA-L) is an adiponectin- interacting protein that is highly expressed in adipose tissue. The adipo-renal axis involves adipocyte release of signaling molecules that are recruited to kidney and regulate kidney function. We have found that the DsbA-L modulated the progression of diabetic nephropathy, but the precise mechanism of this modulation is unknown
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Genome-wide functional screen of 3'UTR variants uncovers causal variants for human disease and evolution bioRxiv. Genet. Pub Date : 2021-01-13 Dustin Griesemer; James R Xue; Steven K Reilly; Jacob C Ulirsch; Kalki Kukreja; Joe Davis; Masahiro Kanai; David K Yang; Stephen B Montgomery; Carl D Novina; Ryan Tewhey; Pardis C Sabeti
3'untranslated region (3'UTR) variants are strongly associated with human traits and diseases, yet few have been causally identified. We developed the Massively Parallel Reporter Assay for 3'UTRs (MPRAu) to sensitively assay 12,173 3'UTR variants. We applied MPRAu to six human cell lines, focusing on genetic variants associated with genome-wide association studies (GWAS) and human evolutionary adaptation
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Plasma amyloid β levels are driven by genetic variants near APOE, BACE1, APP, PSEN2: A genome-wide association study in over 12,000 non-demented participants bioRxiv. Genet. Pub Date : 2021-01-13 Vincent Damotte; Sven J. van der Lee; Vincent Chouraki; Benjamin Grenier-Boley; Jeannette Simino; Hieab Adams; Giuseppe Tosto; Charles White; Natalie Terzikhan; Carlos Cruchaga; Maria J. Knol; Shuo Li; Susanna Schraen; Megan L. Grove; Claudia L. Satizabal; Najaf Amin; Claudine Berr; Steven Younkin; Alzheimer's Disease Neuroimaging Initiative; Rebecca F. Gottesman; Luc Buée; Alexa Beiser; David S. Knopman;
INTRODUCTION: There is increasing interest in plasma Aβ as an endophenotype and biomarker of Alzheimer's disease (AD). Identifying the genetic determinants of plasma Aβ levels may elucidate important processes that determine plasma Aβ measures. METHODS: We included 12,369 non-demented participants derived from eight population-based studies. Imputed genetic data and plasma Aβ1-40, Aβ1-42 levels and
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Human leukocyte antigen class II gene diversity tunes antibody repertoires to common pathogens bioRxiv. Genet. Pub Date : 2021-01-12 Taushif Khan; Mahbuba Rahman; Ikhlak Ahmed; Fatima Al Ali; Puthen Veettil Jithesh; Nico Marr
Allelic diversity of HLA class II genes may help maintain humoral immunity against infectious diseases. We investigated the relative contribution of specific HLA class II alleles, haplotypes and genotypes on the variation of antibody responses to a variety of common pathogens in a cohort of 800 adults representing the general Arab population. We found that classical HLA class II gene heterozygosity
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GWAS of three molecular traits highlights core genes and pathways alongside a highly polygenic background bioRxiv. Genet. Pub Date : 2021-01-12 Nasa Sinnott-Armstrong; Sahin Naqvi; Manuel A Rivas; Jonathan K Pritchard
Genome-wide association studies (GWAS) have been used to study the genetic basis of a wide variety of complex diseases and other traits. We describe UK Biobank GWAS results for three molecular traits-urate, IGF-1, and testosterone-with better-understood biology than most other complex traits. We find that many of the most significant hits are readily and surprisingly interpretable. We observe huge
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High-content single-cell combinatorial indexing bioRxiv. Genet. Pub Date : 2021-01-12 Ryan M Mulqueen; Dmitry Pokholok; Brendan L O'Connell; Casey A Thornton; Fan Zhang; Brian J O'Roak; Jason Link; Galip Gurkan Yardimci; Rosalie C Sears; Frank J Steemers; Andrew C Adey
Single-cell genomics assays have emerged as a dominant platform for interrogating complex biological systems. Methods to capture various properties at the single-cell level typically suffer a tradeoff between cell count and information content, which is defined by the number of unique and usable reads acquired per cell. We and others have described workflows that utilize single-cell combinatorial indexing
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How robust are cross-population signatures of polygenic adaptation in humans? bioRxiv. Genet. Pub Date : 2021-01-12 Alba Refoyo-Martínez; Siyang Liu; Anja Moltke Jørgensen; Xin Jin; Anders Albrechtsen; Alicia R. Martin; Fernando Racimo
Over the past decade, summary statistics from genome-wide association studies (GWASs) have been used to detect and quantify polygenic adaptation in humans. Several studies have reported signatures of natural selection at sets of SNPs associated with complex traits, like height and body mass index. However, more recent studies suggest that some of these signals may be caused by biases from uncorrected
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YHP: Y-chromosome Haplogroup Predictor for predicting male lineages based on Y-STRs bioRxiv. Genet. Pub Date : 2021-01-12 Mengyuan Song; Feng Song; Chenxi Zhao; Yiping Hou
Human Y chromosome reflects the evolutionary process of males. Male lineage tracing by Y chromosome is of great use in evolutionary, forensic, and anthropological studies when male samples exist or especially when the biological sample is a mixture of male and female individuals. Identifying the male lineage based on the specific distribution of Y haplogroups narrows down the investigation scope. Integrating
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The genetic landscape of Ethiopia: diversity, intermixing and the association with culture bioRxiv. Genet. Pub Date : 2021-01-12 Saioa Lopez; Ayele Tarekegn; Gavin Band; Lucy van Dorp; Nancy Bird; Sam Morris; Tamiru Oljira; Ephrem Mekonnen; Endashaw Bekele; Roger Blench; Mark G. Thomas; Neil Bradman; Garrett Hellenthal
The rich linguistic, ethnic and cultural diversity of Ethiopia provides an unprecedented opportunity to understand the level to which cultural factors correlate with -- and shape -- genetic structure in human populations. Using primarily novel genetic variation data covering 1,214 Ethiopians representing 68 different ethnic groups, together with information on individuals' birthplaces, linguistic/religious
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Characterization of a novel variant in the HR1 domain of MFN2 in a patient with ataxia, optic atrophy and sensorineural hearing loss bioRxiv. Genet. Pub Date : 2021-01-11 Govinda Sharma; Rasha Sabouny; Matthew Joel; Kristina Martens; Jason de Koning; Davide Martino; Gerald Pfeffer; Timothy E Shutt
Pathogenic variants in MFN2 cause Charcot-Marie-Tooth disease (CMT) type 2A (CMT2A) and are the leading cause of the axonal subtypes of CMT. CMT2A is characterized by predominantly distal motor weakness and muscle atrophy, with highly variable severity and onset age. Notably, some MFN2 variants can also lead to other phenotypes such as optic atrophy, hearing loss and lipodystrophy. Despite the clear
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QTL Mapping in Outbred Tetraploid (and Diploid) Diallel Populations bioRxiv. Genet. Pub Date : 2021-01-11 Rodrigo R. Amadeu; Patricio Munoz; Chaozhi Zheng; Jeffrey B. Endelman
Over the last decade, multiparental populations have become a mainstay of genetics research in diploid species. Our goal was to extend this paradigm to autotetraploids by creating computational tools for the analysis of connected F1 populations derived from a set of shared parents. In a companion paper, software to reconstruct F1 progeny in terms of parental haplotypes was described. For this study
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Adenosine receptor and its downstream targets, mod(mdg4) and Hsp70, work as a signaling pathway modulating cytotoxic damage in Drosophila bioRxiv. Genet. Pub Date : 2021-01-11 Yu-Hsien Lin; Houda Ouns Maaroufi; Lucie Kucerova; Lenka Rouhova; Tomas Filips; Michal Zurovec
Adenosine (Ado) is an important signaling molecule involved in stress responses. Studies in mammalian models have shown that Ado regulates signaling mechanisms involved in 'danger-sensing' and tissue-protection. Yet, little is known about the role of Ado signaling in Drosophila. In the present study, we observed lower extracellular Ado concentration and suppressed expression of Ado transporters in
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Systematic detection of brain protein-coding genes under positive selection during primate evolution and their roles in cognition bioRxiv. Genet. Pub Date : 2021-01-10 Guillaume Dumas; Simon Malesys; Thomas Bourgeron
The human brain differs from that of other primates, but the genetic basis of these differences remains unclear. We investigated the evolutionary pressures acting on almost all human protein-coding genes (N=11,667; 1:1 orthologs in primates) based on their divergence from those of early hominins, such as Neanderthals, and non-human primates. We confirm that genes encoding brain-related proteins are
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Genetic modulation of initial sensitivity to Δ9-tetrahydrocannabinol (THC) among the BXD family of mice bioRxiv. Genet. Pub Date : 2021-01-09 Cory Parks; Chris M Rogers; J. Pjotr Prins; Robert W. Williams; Hao Chen; Byron C. Jones; Bob M Moore; Megan K Mulligan
Cannabinoid receptor 1 activation by the major psychoactive component in cannabis, Δ9-tetrahydrocannabinol (THC), produces motor impairments, hypothermia, and analgesia upon acute exposure. In previous work, we demonstrated significant sex and strain differences in acute responses to THC following administration of a single dose (10 mg/kg, i.p.) in C57BL/6J (B6) and DBA/2J (D2) inbred mice. To determine
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Distinct spermiogenic phenotypes underlie sperm elimination in the Segregation Distorter meiotic drive system bioRxiv. Genet. Pub Date : 2021-01-09 Marion Herbette; Xiaolu Wei; Ching-Ho Chang; Amanda M Larracuente; Benjamin Loppin; Raphaelle Dubruille
Segregation Distorter (SD) is a male meiotic drive system in Drosophila melanogaster. Males heterozygous for a selfish SD chromosome rarely transmit the homologous SD+ chromosome. It is well established that distortion results from an interaction between Sd, the primary distorting locus on the SD chromosome and its target, a satellite DNA called Rsp, on the SD+ chromosome. However, the molecular and
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ConVarT: a search engine for orthologous variants and functional inference of human genetic variants bioRxiv. Genet. Pub Date : 2021-01-09 Mustafa S. Pir; Halil I. Bilgin; Ahmet Sayici; Fatih Coskun; Furkan M. Torun; Pei Zhao; Yahong Kang; Sebiha Cevik; Oktay I. Kaplan
The availability of genetic variants, together with phenotypic annotations from model organisms, facilitates comparing these variants with equivalent variants in humans. However, existing databases and search tools do not make it easy to scan for equivalent variants, namely orthologous variants, between humans and other organisms. Therefore, we developed an integrated search engine called ConVarT (http://www
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RNA-directed DNA methylation prevents rapid and heritable reversal of transposon silencing under heat stress in Zea mays. bioRxiv. Genet. Pub Date : 2021-01-08 Damon Lisch; Wei Guo; Dafang Wang
In large complex plant genomes, RNA-directed DNA methylation (RdDM) ensures that epigenetic silencing is maintained at the boundary between genes and flanking transposable elements. In maize, RdDM is dependent on Modifer of Paramutation 1 (Mop1 ), a putative RNA dependent RNA polymerase. Here we show that although RdDM is essential for the maintenance of DNA methylation of a silenced MuDR transposon
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Pathways and signatures of mutagenesis at targeted DNA nicks bioRxiv. Genet. Pub Date : 2021-01-08 Nancy Maizels; Yinbo Zhang; Luther Davis
Nicks are the most frequent form of DNA damage and a potential source of mutagenesis in human cells. By deep sequencing, we have identified factors and pathways that promote and limit mutagenic repair at targeted nicks. BRCA2 inhibits all categories of mutational events at nicks, including indels, SNVs and HDR. DNA2 and RPA promote 5' resection. Most insertions at nicks consist of a single C incorporated
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Dicer promotes genome stability via the bromodomain transcriptional co-activator Brd4. bioRxiv. Genet. Pub Date : 2021-01-08 Michael Gutbrod; Benjamin Roche; Joshua Steinberg; Asad Lakhani; Kenneth Chang; Andrea Schorn; Robert A Martienssen
RNA interference is essential for transcriptional silencing and genome stability, but conservation of this role in mammals has been difficult to demonstrate. Dicer1-/- mouse embryonic stem cells have microRNA-independent proliferation defects, and we conducted a CRISPR-Cas9 screen to restore viability. We identified suppressor mutations in transcriptional activators, H3K9 methyltransferases, and chromosome
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Monitoring the promoter activity of long noncoding RNAs and stem cell differentiation through knock-in of sgRNA flanked by tRNA in an intron bioRxiv. Genet. Pub Date : 2021-01-08 Yu-Ting Zhao; Yangming Wang
Mammalian genomes encode thousands of long noncoding RNAs (lncRNAs) that are often expressed in a tissue and cell specific manner. Therefore, a reporter that can faithfully reflect the expression or activity of lncRNAs can provide tools useful not only for uncovering the regulators of lncRNAs, but also for tracking cell fate and disease status. Here, we design a sgRNA precursor in an intron (GRIT)
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Oxidative stress alters transcript localization of disease-causing genes in the retinal pigment epithelium bioRxiv. Genet. Pub Date : 2021-01-08 Tadeusz J Kaczynski; Elizabeth D Au; Michael H Farkas
Nuclear retention is a mechanism whereby RNA transcripts are held in the nucleus to maintain a proper nuclear-to-cytoplasmic balance or as a stockpile for use in responding to stimuli. Many mechanisms are employed to determine whether transcripts are retained or exported to the cytoplasm, though the extent to which tissue- or cell-type, stressors, or disease pathogenesis affect this process remains
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To denoise or to cluster? That is not the question. Optimizing pipelines for COI metabarcoding and metaphylogeography bioRxiv. Genet. Pub Date : 2021-01-08 Adrià Antich; Creu Palacín; Owen S Wangensteen; Xavier Turon
The recent blooming of metabarcoding applications to biodiversity studies comes with some relevant methodological debates. One such issue concerns the treatment of reads by denoising or by clustering methods, which have been wrongly presented as alternatives. It has also been suggested that denoised sequence variants should replace clusters as the basic unit of metabarcoding analyses, missing the fact
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Therapeutic adenine base editing corrects nonsense mutation and improves visual function in a mouse model of Leber congenital amaurosis bioRxiv. Genet. Pub Date : 2021-01-08 Dong Hyun Jo; Hyeon-Ki Jang; Chang Sik Cho; Jun Hee Han; Gahee Ryu; Youngri Jung; Sangsu Bae; Jeong Hun Kim
Leber congenital amaurosis (LCA) is an inherited retinal degeneration that causes severe visual dysfunction in children and adolescents. In patients with LCA, pathogenic variants are evident in specific genes, such as RPE65, which are related to the functions of retinal pigment epithelium and photoreceptors. Base editing confers a way to correct pathogenic substitutions without double-stranded breaks
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The impact of PNPLA3 and TM6SF2 in cirrhosis related complications bioRxiv. Genet. Pub Date : 2021-01-08 Haruki Uojima; Xue Shao; Taeang Arai; Yuji ogawa; Toru Setsu; Masanori Atsukawa; Yoshihiro Furuichi; Yoshitaka Arase; Kazue Horio; Hisashi Hidaka; Takahide Nakazawa; Makoto Kako; Tatehiro Kagawa; Katsuhiko Iwakiri; Atsushi Nakajima; Shuji Terai; Yasuhito Tanaka; Wasaburo Koizumi
Patatin-like phospholipase domain-containing 3 (PNPLA3) and transmembrane 6-superfamily member 2 (TM6SF2) polymorphisms have major impact for fibrosis due to steatohepatitis. However, there are scant data about correlations between cirrhosis-related complications and the polymorphisms of these genes. Therefore, we aimed to determine the role of the PNPLA3 and TM6SF2 polymorphisms in fibrosis progression
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Barth syndrome cellular models have dysregulated respiratory chain complex I and mitochondrial quality control due to abnormal cardiolipin bioRxiv. Genet. Pub Date : 2021-01-08 Arianna F. Anzmann; Olivia L. Sniezek; Alexandra Pado; Veronica Busa; Frédéric Maxime Vaz; Simion D. Kreimer; Robert Norman Cole; Anne Le; Brian James Kirsch; Steven M. Claypool; Hilary J. Vernon
Barth syndrome (BTHS) is an X-linked genetic condition caused by defects in TAZ, which encodes a transacylase involved in the remodeling of the inner mitochondrial membrane phospholipid, cardiolipin (CL). As such, CL has been implicated in numerous mitochondrial functions, and the role of defective CL in the clinical pathology of BTHS is under intense investigation. We used untargeted proteomics, shotgun
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Contraction-expansion dynamics of reef species in response to sea-level changes bioRxiv. Genet. Pub Date : 2021-01-08 Thierry B Hoareau; Petrus Pretorius
The contraction-expansion model (CEM) describes the dynamics of species that survived in refugia during the last glacial maximum (LGM) and expanded their range when environmental conditions slowly improved from the Late Glacial through to the Holocene. The CEM has been proposed to describe the dynamics of reef species in response to sea-level fluctuations from a range of disciplines, but genetic inferences
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Increasing calling accuracy, coverage, and read depth in sequence data by the use of haplotype blocks bioRxiv. Genet. Pub Date : 2021-01-08 Torsten Pook; Adnane Nemri; Eric Gerardo Gonzalez Segovia; Henner Simianer; Chris Carolin Schoen
High-throughput genotyping of large numbers of lines remains a key challenge in plant genetics, requiring geneticists and breeders to find a balance between data quality and the number of genotyped lines under a variety of different existing technologies when resources are limited. In this work, we are proposing a new imputation pipeline ("HBimpute") that can be used to generate high-quality genomic
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A Multi-dimensional Integrative Scoring Framework for Predicting Functional Regions in the Human Genome bioRxiv. Genet. Pub Date : 2021-01-08 Xihao Li; Godwin Yung; Hufeng Zhou; Ryan Sun; Zilin Li; Yaowu Liu; Iuliana Ionita-Laza; Xihong Lin
Attempts to identify and prioritize functional DNA elements in coding and noncoding regions, particularly through use of in silico functional annotation data, continue to increase in popularity. However, specific functional roles may vary widely from one variant to another, making it challenging to summarize different aspects of variant function. Here we propose Multi-dimensional Annotation Class Integrative
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The Genetics and Evolution of Eye Color in Domestic Pigeons (Columba livia) bioRxiv. Genet. Pub Date : 2021-01-08 Si Si; Xiao Xu; Yan Zhuang; Xiaodong Gao; Honghai Zhang; Zhengting Zou; Shu-Jin Luo
The avian eye color, generally referred to the color of the iris, results from both pigments and structural coloration. Avian iris colors exhibit striking interspecific and, in some domestic species, intraspecific variations, suggesting unique evolutionary and ecological histories. Here we tackled the genetic basis of the pearl (white) iris color in domestic pigeons (Columba livia), to elucidate the
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Genetic composition of queen conch (Lobatus gigas) population on Pedro Bank, Jamaica and its use in fisheries management bioRxiv. Genet. Pub Date : 2021-01-07 Azra P Blythe-Mallett; Karl A Aiken; Iris Segura-Garcia; Nathan K Truelove; Mona K Webber; Marcia E Roye; Stephen J Box
The queen conch fishery in Jamaica is sustained by Pedro Bank, which is the main harvesting site located approximately 80 km south-west from Kingston. Due to its relative size, Pedro Bank has been subdivided into zones for management purposes by the Fisheries Division and the Veterinary Services Division. Understanding whether these sub-divisions reflect different sub-populations is critical for managing
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Determining pathogenicity of variants of uncertain significance and identification of a founder variant in the epilepsy-associated gene, SZT2 bioRxiv. Genet. Pub Date : 2021-01-07 Jeffrey D Calhoun; Miriam C Aziz; Hannah C Happ; Jonathan Gunti; Colleen Gleason; Najma Mohamed; Kristy Zeng; Meredith Hiller; Emily Bryant; Divakar Mithal; Irena Bellinski; Lisa Kinsley; Mona Grimmel; Eva MC Schwaibold; Constance Smith-Hicks; Anna Chassevent; Marcello Scala; Andrea Accogli; Annalaura Torella; Pasquale Striano; Valeria Capra; Lynne M Bird; Issam Ben-Sahra; Nina Ekhilevich; Tova Hershkovitz;
Biallelic pathogenic variants in SZT2 result in a neurodevelopmental disorder with shared features, including early-onset epilepsy, developmental delay, macrocephaly, and corpus callosum abnormalities. SZT2 is as a critical scaffolding protein in the amino acid sensing arm of the mTOR signaling pathway. Due to its large size (3432 amino acids), lack of crystal structure, and absence of functional domains
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Chromosomal Characteristics of Salt Stress Heritable Gene Expression in the Rice Genome bioRxiv. Genet. Pub Date : 2021-01-06 Matthew T McGowan; Zhiwu Zhang; Stephen P Ficklin
Background Gene expression is potentially an important heritable quantitative trait that mediates between genetic variation and higher-level complex phenotypes through time and condition-dependent regulatory interactions. Increasing quantities of high-throughput DNA and RNA sequencing and standardization of research populations has resulted in the accumulation of overlapping -omics data allowing for
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Coding Triplets in the Transfer RNA acceptor Arm and Their Role in Present and Past tRNA Recognition bioRxiv. Genet. Pub Date : 2021-01-06 Ilana Agmon; Itay Fayerverker; Tal Mor
Background: The evolutionary pathway of tRNA established the linking of the genetic code and protein synthesis, thus, revealing the characteristics of the prebiotic tRNA is crucial for presenting a feasible scenario for the emergence of life. Results: Analysis of bacterial tRNA sequences reveals that for nine amino acids, mostly those considered to be the most ancient ones, the acceptor-TΨC arm carries
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Genomic mating in outbred species: predicting cross usefulness with additive and total genetic covariance matrices bioRxiv. Genet. Pub Date : 2021-01-06 Marnin D Wolfe; Ariel W. Chan; Peter Kulakow; Ismail Rabbi; Jean-Luc Jannink
Diverse crops are both outbred and clonally propagated. Breeders typically use truncation selection of parents and invest significant time, land and money evaluating the progeny of crosses to find exceptional genotypes. We developed and tested genomic mate selection criteria suitable for organisms of arbitrary homozygosity level where the full-sibling progeny are of direct interest as future parents
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Heat shock protein gene expression is higher and more variable with thermal stress and mutation accumulation in Daphnia bioRxiv. Genet. Pub Date : 2021-01-06 Henry Scheffer; Jeremy Coate; Eddie K. H. Ho; Sarah Schaack
Understanding the genetic architecture of the stress response and its ability to evolve in response to different stressors requires an integrative approach. Here we quantify gene expression changes in response to two stressors associated with global climate change and habitat lossheat shock and mutation accumulation. We measure expression levels for two Heat Shock Proteins (HSP90 and HSP60)members
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Timing and localization of myasthenia gravis-related gene expression bioRxiv. Genet. Pub Date : 2021-01-06 Dana L.E. Vergoossen; Arlin Keo; Ahmed Mahfouz; Maartje G. Huijbers
Myasthenia gravis (MG) is an acquired autoimmune disorder caused by autoantibodies binding acetylcholine receptors (AChR), muscle-specific kinase (MuSK), agrin or low-density lipoprotein receptor-related protein 4 (Lrp4). These autoantibodies inhibit neuromuscular transmission by blocking the function of these proteins, and thereby cause fluctuating skeletal muscle weakness. Several reports suggest
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Integration of Protein Interactome Networks with Congenital Heart Disease Variants Reveals Candidate Disease Genes bioRxiv. Genet. Pub Date : 2021-01-05 Barbara Gonzalez Teran; Maureen Pittman; Franco Felix; Desmond Richmond-Buccola; Reuben Thomas; Krishna Choudhary; Elisabetta Moroni; Giorgio Colombo; Michael Alexanian; Bonnie Cole; Kaitlen Samse-Knapp; Michael McGregor; Casey A. Gifford; Ruth Huttenhain; Bruce D. Gelb; Bruce R Conklin; Brian L. Black; Benoit G. Bruneau; Nevan J. Krogan; Katherine S. Pollard; Deepak Srivastava
Congenital heart disease (CHD) is present in 1% of live births, yet identification of causal mutations remains a challenge despite large-scale genomic sequencing efforts. We hypothesized that genetic determinants for CHDs may lie in protein interactomes of GATA4 and TBX5, two transcription factors that cause CHDs. Defining their interactomes in human cardiac progenitors via affinity purification-mass
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Genome Wide Association Study in the New Haven Lexinome Project Identifies GARRE1 as a Novel Gene for Reading Performance bioRxiv. Genet. Pub Date : 2021-01-05 Andrew K Adams; Emily L Guertin; Dongnhu T Truong; Elizabeth G Atkinson; Mellissa M.C. DeMille; Joan M. Bosson-Heenan; Jan C. Frijters; Jeffrey R. Gruen
Despite high prevalence and high heritability, few candidate genes have been identified for reading disability. To identify novel genetic variants we performed a genome-wide association study (GWAS) using high-depth whole genome sequencing and predicated on reading performance in 407 subjects enrolled in a longitudinal study of response-to-intervention, called the New Haven Lexinome Project. The primary
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Effect of high proportion concentrate dietary on Yak jejunal structure, physiological function and protein composition during cold season bioRxiv. Genet. Pub Date : 2021-01-05 Jianlei Jia; Chunnian Liang; Xiaoyun Wu; Lin Xiong; Pengjia Bao; Qian Chen; Ping Yan
The current study aimed to investigate the damage of long-term high concentrate diet feeding pattern on Yak jejunal structure, physiological function and protein composition during cold season. Twelve Datong male Yak (Bos grunniens) with the same age from cold season were randomly selected and slaughtered to determine Yak jejunal digestive enzyme activity, morphology and protein composition on different
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Probing the aggregated effects of purifying selection per individual on 1,380 medical phenotypes in the UK biobank bioRxiv. Genet. Pub Date : 2021-01-05 Ha My T Vy; Daniel M Jordan; Daniel J Balick; Ron Do
Understanding the relationship between natural selection and phenotypic variation has been a long-standing challenge in human population genetics. With the emergence of biobank-scale datasets, along with new statistical metrics to approximate strength of purifying selection at the variant level, it is now possible to correlate a proxy of individual relative fitness with a range of medical phenotypes
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High-resolution QTL mapping with Diversity Outbred mice identifies genetic variants that impact gut microbiome composition bioRxiv. Genet. Pub Date : 2021-01-05 Florencia Schlamp; David Y Zhang; Juan Felipe Beltran; Elissa Cosgrove; Petr Simecek; Matthew Edwards; Julia K Goodrich; Ruth E Ley; Gary A. Churchill; Andrew G. Clark
The composition of the gut microbiome is impacted by a complex array of factors, from nutrient composition and availability, to physical factors like temperature, pH, and flow rate, as well as interactions among the members of the microbial community. Many of these factors are affected by the host, raising the question of how host genetic variation impacts microbiome composition. Though human studies
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Alzheimer's genetic risk effects on cerebral blood flow are spatially consistent and proximal to gene expression across the lifespan bioRxiv. Genet. Pub Date : 2021-01-05 Hannah L Chandler; Richard G Wise; David E Linden; Julie Williams; Kevin Murphy; Thomas M Lancaster; Alzheimers Disease Neuroimaging Initiative (ADNI)
Cerebrovascular dysregulation is a hallmark feature of Alzheimers disease (AD), where alterations in cerebral blood flow (CBF) are observed decades prior to symptom onset. Genome wide association studies (GWAS) show that AD has a polygenic aetiology, providing a tool for studying AD susceptibility across the lifespan. Here, we ascertain whether AD genetic risk effects on CBF previously observed (Chandler
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RapidoPGS: A rapid polygenic score calculator for summary GWAS data without validation dataset bioRxiv. Genet. Pub Date : 2021-01-05 Guillermo Reales; Elena Vigorito; Martin Kelemen; Chris Wallace
Motivation: Polygenic scores (PGS) aim to genetically predict complex traits at an individual level. PGS are typically trained on genome-wide association summary statistics and require an independent test dataset to tune parameters. More recent methods allow parameters to be tuned on the training data, removing the need for independent test data, but approaches are computationally intensive. Based
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Selection of popcorn genotypes tolerant to Spodoptera frugiperda and key traits related to the identification of tolerance bioRxiv. Genet. Pub Date : 2021-01-04 Amanda Tami Kuroda; Jocimar Costa Rosa; Luiz Felipe Antunes de Almeida; Giovana Dal Lago Garcia; Gustavo Arana Demitto; Renata Maria Bento de Souza; Fernando Alves de Albuquerque; Carlos Alberto Scapim
The Spodoptera frugiperda, is one of the most deleterious pests of popcorn and the identification of tolerant genotypes is determinant in breeding programs. The objective of this study was to select popcorn genotypes tolerant to S. frugiperda and the key traits related to the identification of tolerance. The popcorn varieties UEM J1, Composto Márcia, Arachida, Composto Gaúcho and Zapalote Chico (resistant
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Mutational analysis of DinG-family helicase YoaA: its expression and interaction with replication clamp-loader protein HolC in E. coli bioRxiv. Genet. Pub Date : 2021-01-04 Vincent A. Sutera; Thalia H Sass; Scott E Leopard; Lingling Wu; David J Glass; Gabriela G Giordano; Yonatan Zur; Susan T. Lovett
The XP-D/DinG family of DNA helicases participate in a variety of ways to preserve genomic stability in all three domains of life. We investigate here the genetic role of one of these proteins, YoaA, of Escherichia coli. In E. coli, YoaA has been identified as having a role in tolerance to the nucleoside azidothymidine (AZT), a DNA replication inhibitor. It is of particular interest because of its
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Genetic Diversity of Dianthus Plants Revealed by SRAP Markers bioRxiv. Genet. Pub Date : 2021-01-04 Jing Wang; Jian Li; Gensheng Shi; Huazheng Hao; Zhongrui Ji; Zhongxiong Lai; Guoming Xing