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  • HIV Diversity Considerations in the Application of the Intact Proviral DNA Assay (IPDA)
    bioRxiv. Genet. Pub Date : 2020-05-29
    Natalie N Kinloch; Yanqin Ren; Winnifer D Conce Alberto; Winnie Dong; Pragya Khadka; Szu Han Huang; Talia M Mota; Andrew Wilson; Aniqa Shahid; Don Kirkby; Marianne Harris; Colin Kovacs; Erika Benko; Mario A Ostrowski; Perla M Del Rio Estrada; Avery Wimpelberg; Christopher Cannon; W. David Hardy; Lynsay MacLaren; Harris Goldstein; Chanson J Brumme; Guinevere Q Lee; Rebecca M Lynch; Zabrina L Brumme;

    The Intact Proviral DNA Assay (IPDA) was developed to address the critical need for a precise and scalable method for intact HIV reservoir quantification1. This duplexed droplet digital PCR (ddPCR) assay simultaneously targets the HIV Packaging Signal (Ψ) and the Rev Responsive Element (RRE) within Envelope (env) to distinguish genomically intact proviruses against a large background of defective ones2

    更新日期:2020-05-29
  • Hmx3a does not require its homeodomain for its essential functions in zebrafish spinal cord, ear and lateral line development.
    bioRxiv. Genet. Pub Date : 2020-05-28
    Samantha J. England; Gustavo A. Cerda; Angelica M Kowalchuk; Taylor Sorice; Ginny M Grieb; Katharine E. Lewis

    Transcription factors that contain a homeodomain DNA-binding domain have crucial functions in most aspects of cellular function and embryonic development in both animals and plants. Hmx proteins are a sub-family of NK homeodomain-containing proteins that have fundamental roles in development of sensory structures such as the eye and the ear. However, Hmx functions in spinal cord development have not

    更新日期:2020-05-28
  • Identifying non-identical-by-descent rare variants in population-scale whole genome sequencing data
    bioRxiv. Genet. Pub Date : 2020-05-28
    Kelsey E Johnson; Benjamin Franklin Voight

    The site frequency spectrum in human populations is not accurately modeled by an infinite sites model, which assumes that all mutations are unique. Despite the pervasiveness of recurrent mutations, we lack computational methods to identify these events at specific sites in population sequencing data. Rare alleles that are identical-by-descent (IBD) are expected to segregate on a long, shared haplotype

    更新日期:2020-05-28
  • The Axenfeld-Rieger syndrome gene FOXC1 contributes to left-right patterning
    bioRxiv. Genet. Pub Date : 2020-05-28
    Paul W Chrystal; Curtis R French; Francesca Jean; Serhiy Havrylov; Suey van Baarle; Ann-Marie Peturson; Pengfei Xu; J Gage Crump; David B Pilgrim; Ordan J Lehmann; Andrew Jan Waskiewicz

    Normal body situs requires precise spatiotemporal expression of the Nodal-Lefty-Pitx2 cascade in the lateral plate mesoderm. The ultimate output of this patterning is establishment of the left-right axis, which provides vital cues for correct organ formation and function. Mutations, deletions and duplications in PITX2 and FOXC1 lead to the rare genetic disease Axenfeld-Rieger syndrome (ARS). While

    更新日期:2020-05-28
  • Lifestyle Risk Score for aggregating multiple lifestyle factors: Handling missingness of individual lifestyle components in meta-analysis of gene-by-lifestyle interactions
    bioRxiv. Genet. Pub Date : 2020-05-28
    Hanfei Xu; Karen Schwander; Michael R Brown; Wenyi Wang; RJ Waken; Eric Boerwinkle; L Adrienne Cupples; Lisa de las Fuentes; Diana van Heemst; Oyomoare Osazuwa-Peters; Paul S de Vries; Ko Willems van Dijk; Yun Ju Sung; Xiaoyu Zhang; Alanna C Morrison; DC Rao; Raymond Noordam; Ching-Ti Liu

    Recent studies consider lifestyle risk score (LRS), an aggregation of multiple lifestyle exposures, in identifying association of gene-lifestyle interaction with disease traits. However, not all cohorts have data on all lifestyle factors, leading to increased heterogeneity in the environmental exposure in collaborative meta-analyses. We compared and evaluated four approaches (Naïve, Safe, Complete

    更新日期:2020-05-28
  • Genetic, lifestyle and environmental risk factors for chronic pain revealed through GWAS
    bioRxiv. Genet. Pub Date : 2020-05-28
    Mischa Lundberg; Adrian Isaac Campos Gonzalez; Scott F. Farrell; Geng Wang; Michele Sterling; Miguel E. Rentería; Trung Thanh Ngo; Gabriel Cuellar Partida

    Chronic pain (CP) is a leading cause of disability worldwide with complex aetiologies that remain elusive. Here we addressed this issue by performing a GWAS on a large UK Biobank sample (N=188,352 cases & N=69,627 controls) which identified two independent loci associated with CP near ADAMTS6 and LEMD2. Gene-based tests revealed additional CP-associated genes (DCAKD, NMT1, MLN, IP6K3). Across 1328

    更新日期:2020-05-28
  • Characterization of systemic genomic instability in budding yeast
    bioRxiv. Genet. Pub Date : 2020-05-28
    Nadia Maria Vieira Sampaio; V. P. Ajith; Ruth A Watson; Lydia R Heasley; Parijat Chakraborty; Aline Rodrigues-Prause; Ewa P Malc; Piotr A Mieczkowski; Koodali T Nishant; Juan Lucas Argueso

    Conventional models of genome evolution are centered around the principle that mutations form independently of each other and build up slowly over time. We characterized the occurrence of bursts of genome-wide loss-of-heterozygosity (LOH) in Saccharomyces cerevisiae, providing support for an additional non-independent and faster mode of mutation accumulation. We initially characterized a yeast clone

    更新日期:2020-05-28
  • Variation in genetic relatedness is determined by the aggregate recombination process
    bioRxiv. Genet. Pub Date : 2020-05-28
    Carl Veller; Nathaniel B. Edelman; Pavitra Muralidhar; Martin A. Nowak

    The genomic proportion that two relatives share identically by descent—their genetic relatedness—can vary depending on the history of recombination and segregation in their pedigree. This variation is important in many applications of genetics, including pedigree-based estimation of the genetic variance and heritability of traits, and estimation of pedigree relationships from sequence data. Here, we

    更新日期:2020-05-28
  • Sex-biased reduction in reproductive success drives selective constraint on human genes
    bioRxiv. Genet. Pub Date : 2020-05-28
    Eugene J Gardner; Matthew DC Neville; Kaitlin E Samocha; Kieron Barclay; Martin Kolk; Mari EK Niemi; George Kirov; Hilary C Martin; Matthew E Hurles

    Genome-wide sequencing of human populations has revealed substantial variation among genes in the intensity of purifying selection acting on damaging genetic variants. While genes under the strongest selective constraint are highly enriched for Mendelian disorders, most of these genes are not associated with disease and therefore the nature of the selection acting on them is not known. Here we show

    更新日期:2020-05-28
  • A C. elegans Zona Pellucida domain protein functions via its ZPc domain
    bioRxiv. Genet. Pub Date : 2020-05-28
    Jennifer D. Cohen; Jessica G. Bermudez; Matthew C. Good; Meera V Sundaram

    Zona Pellucida domain (ZP) proteins are critical components of the body's external-most protective layers, apical extracellular matrices (aECMs). Although their loss or dysfunction is associated with many diseases, it remains unclear how ZP proteins assemble in aECMs. Current models suggest that ZP proteins polymerize via their ZPn subdomains, while ZPc subdomains modulate ZPn behavior. Using the model

    更新日期:2020-05-28
  • Medical relevance of common protein-altering variants in GPCR genes across 337,205 individuals in the UK Biobank
    bioRxiv. Genet. Pub Date : 2020-05-28
    Christopher DeBoever; A. J. Venkatakrishnan; Joseph M Paggi; Franziska M Heydenreich; Suli-Anne Laurin; Matthieu Masureel; Yosuke Tanigawa; Guhan Venkataraman; Michel Bouvier; Ron O Dror; Manuel A Rivas

    G protein-coupled receptors (GPCRs) drive an array of critical physiological functions and are an important class of drug targets, though a map of which GPCR genetic variants are associated with phenotypic variation is lacking. We performed a phenome-wide association analysis for 269 common protein-altering variants in 156 GPCRs and 275 phenotypes, including disease outcomes and diverse quantitative

    更新日期:2020-05-28
  • Fast and accurate approximation of the joint site frequency spectrum of multiple populations
    bioRxiv. Genet. Pub Date : 2020-05-28
    Ethan M Jewett

    The site frequency spectrum (SFS) is a statistic that summarizes the distribution of derived allele frequencies in a sample of DNA sequences. The SFS provides useful information about genetic variation within and among populations and it can used to make population genetic inferences. Methods for computing the SFS based on the diffusion approximation are computationally efficient when computing all

    更新日期:2020-05-28
  • GCA: An R package for genetic connectedness analysis using pedigree and genomic data
    bioRxiv. Genet. Pub Date : 2020-05-28
    Haipeng Yu; Gota Morota

    Background: Genetic connectedness is a critical component of genetic evaluation as it assesses the comparability of predicted genetic values across units. Genetic connectedness also plays an essential role in quantifying the linkage between reference and validation sets in whole-genome prediction. Despite its importance, there is no user-friendly software tool available to calculate connectedness statistics

    更新日期:2020-05-28
  • Inferring the ancestry of parents and grandparents from genetic data
    bioRxiv. Genet. Pub Date : 2020-05-28
    Jingwen Pei; Yiming Zhang; Rasmus Nielsen; Yufeng Wu

    Inference of admixture proportions is a classical statistical problem in population genetics. Standard methods implicitly assume that both parents of an individual have the same admixture fraction. However, this is rarely the case in real data. In this paper, we show that the distribution of admixture tract lengths in a genome contains information about the admixture proportions of the ancestors of

    更新日期:2020-05-28
  • Effect of methanol fixation on single-cell RNA sequencing data
    bioRxiv. Genet. Pub Date : 2020-05-28
    Xinlei Wang; Lei Yu; Angela Ruohao Wu

    Single-cell RNA sequencing (scRNA-seq) has led to remarkable progress in our understanding of tissue heterogeneity in health and disease. Recently, the need for scRNA-seq sample fixation has emerged in many scenarios, such as when samples need long-term transportation, or when experiments need to be temporally synchronized. Methanol fixation is a simple and gentle method that has been routinely applied

    更新日期:2020-05-28
  • Lysosomal dysfunction impairs mitochondrial quality control and predicts neurodegeneration in TBCKE
    bioRxiv. Genet. Pub Date : 2020-05-27
    Jesus A Tintos-Hernandez; Adrian Santana; Kierstin N Keller; Xilma R Ortiz-Gonzalez

    Biallelic variants in TBC1-domain containing kinase (TBCK) cause intellectual disability in children. It remains unclear how variants in TBCK lead to a neurodevelopmental disorder and what biological factors modulate the variability of clinical severity. Previous studies showed increased autophagosomes in patients sharing the truncating (p.R126X) Boricua homozygous TBCK variant, who exhibit a severe

    更新日期:2020-05-27
  • High-resolution yeast quiescence profiling in human-like media reveals interacting influences of auxotrophy and nutrient availability
    bioRxiv. Genet. Pub Date : 2020-05-27
    Sean L Santos; Samantha Laflin; Audrie Broadway; Cosby Burnett; Joline Hartheimer; John W Rodgers; Daniel L Smith; John L Hartman

    Yeast cells survive in stationary phase culture by entering quiescence, which is measured by colony forming capacity upon nutrient re-exposure. Yeast chronological lifespan (CLS) studies, employing the comprehensive collection of gene knockout strains, have correlated weakly between independent laboratories, which is hypothesized to reflect differential interaction between the deleted genes, auxotrophy

    更新日期:2020-05-27
  • Natural variation in the regulation of neurodevelopmental genes modifies flight performance in Drosophila
    bioRxiv. Genet. Pub Date : 2020-05-27
    Adam Spierer; Jim A Mossman; Samuel Pattillo Smith; Lorin Crawford; Sohini Ramachandran; David M Rand

    The winged insects of the order Diptera are colloquially named for their most recognizable phenotype: flight. These insects rely on flight for a number of important life history traits, like dispersal, foraging, and courtship. Despite the importance of flight, relatively little is known about the genetic architecture of variation for flight performance. Accordingly, we sought to uncover the genetic

    更新日期:2020-05-27
  • Defining a critical enhancer near Nanog using chromatin-focused approaches identifies RNA Pol II recruitment as required for expression
    bioRxiv. Genet. Pub Date : 2020-05-27
    Puja Agrawal; Steven Blinka; Kirthi Pulakanti; Michael H Reimer; Sridhar Rao

    Transcriptional enhancers have been defined by their ability to operate independent of distance and orientation in plasmid-based reporter assays of gene expression. Currently, histone marks are used heavily to identify and define enhancers but both methods do not consider the endogenous role of an enhancer in the context of native chromatin. We employed a combination of genomic editing, single cell

    更新日期:2020-05-27
  • Discovery of novel haplotypes for complex traits in landraces
    bioRxiv. Genet. Pub Date : 2020-05-27
    Manfred Mayer; Armin C. Hoelker; Eric Gonzalez-Segovia; Thomas Presterl; Milena Ouzunova; Albrecht E. Melchinger; Chris-Carolin Schoen

    Genetic variation is of crucial importance for selection and genetic improvement of crops. Landraces are valuable sources of diversity for germplasm improvement, but for quantitative traits efficient strategies for their targeted utilization are lacking. Here, we propose a genome-based strategy for making native diversity accessible for traits with limited genetic variation in elite germplasm. We generated

    更新日期:2020-05-27
  • Convergent and distributed effects of the schizophrenia-associated 3q29 deletion on the human neural transcriptome
    bioRxiv. Genet. Pub Date : 2020-05-27
    Esra Sefik; Ryan H. Purcell; Megan Merritt-Garza; Sridhar Karne; Jessica Randall; The Emory 3q29 Project; Elaine F. Walker; Gary J. Bassell; Jennifer G. Mulle

    The 1.6Mb 3q29 deletion (3q29Del) confers >40-fold increased risk for schizophrenia (SZ) and is also a risk factor for intellectual disability (ID) and autism spectrum disorders (ASD). No single gene in this interval is definitively associated with SZ, ID, or ASD, prompting the hypothesis that neurodevelopmental sequelae emerge upon loss of multiple functionally-connected genes. However, 3q29 interval

    更新日期:2020-05-27
  • 3D chromatin organization changes modulate adipogenesis and osteogenesis
    bioRxiv. Genet. Pub Date : 2020-05-27
    Ruo-Han Hao; Yan Guo; Jing Guo; Yu Rong; Shi Yao; Yi-Xiao Chen; Shan-Shan Dong; Dong-Li Zhu; Hao Chen; Tie-Lin Yang

    Human mesenchymal stem cells (hMSCs) can be differentiated into adipocytes and osteoblasts. While the transcriptomic and epigenomic changes during adipogenesis and osteogenesis have been characterized, what happens to the chromatin loops is hardly known. Here we induced hMSCs to adipogenic and osteogenic differentiation, and performed 2 kb resolution Hi-C experiments for loop detection and generated

    更新日期:2020-05-27
  • Site-specific recombination between inverted target sites generates dicentric/acentric chromosomes.
    bioRxiv. Genet. Pub Date : 2020-05-27
    Simon W.A. Titen; Makenna T. B. Johnson; Mario Capecchi; Kent G Golic

    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

    更新日期:2020-05-27
  • Rapid self-selecting and clone free integration of transgenes into engineered CRISPR safe harbor locations in Caenorhabditis elegans
    bioRxiv. Genet. Pub Date : 2020-05-27
    Zachary Christopher Stevenson; Megan J. Moerdyk-Schauwecker; Brennen Jamison; Patrick C. Phillips

    Precision genome editing for model organisms has revolutionized functional analysis and validation of a wide variety of molecular systems. To date, the capacity to insert transgenes into the model nematode Caenorhabditis elegans has focused on utilizing either transposable elements or CRISPR-based safe harbor strategies. These methods require laborious screening processes that often result in false

    更新日期:2020-05-27
  • Lysosomal cystine efflux opposes mTORC1 reactivation through the TCA cycle
    bioRxiv. Genet. Pub Date : 2020-05-26
    Patrick Jouandin; Zvonimir Marelja; Andrey Parkhitko; Miriam Dambowsky; John M Asara; Ivan Nemazanyy; Christian C Dibble; Matias Simons; Norbert Perrimon

    Adaptation to nutrient scarcity involves an orchestrated response of metabolic and signaling pathways to maintain homeostasis. We provide evidence that lysosomal export of cystine coordinates remobilization of internal nutrient stores with reactivation of the growth regulator TORC1 signaling upon fasting in the Drosophila fat body. Mechanistically, cystine is reduced to cysteine and metabolized to

    更新日期:2020-05-26
  • Minimally invasive brain injections for viral-mediated transgenesis: New tools for behavioral genetics in sticklebacks
    bioRxiv. Genet. Pub Date : 2020-05-26
    Noelle James; Alison M Bell

    Behavioral genetics in non-model organisms is currently gated by technological limitations. However, with the growing availability of genome editing and functional genomic tools, complex behavioral traits such as social behavior can now be explored in diverse organisms. Here we present a minimally invasive neurosurgical procedure for a classic behavioral, ecological and evolutionary system: threespine

    更新日期:2020-05-26
  • Evaluation of eight protocols for genomic DNA extraction of Hypostomus commersoni (Valenciennes, 1836), Siluriformes: Loricariidae.
    bioRxiv. Genet. Pub Date : 2020-05-25
    Priscila Mezzomo; Albanin Aparecida Mielniczki-Pereira; Tanise Luisa Sausen; Jorge Reppold Marinho; Rogério Luis Cansian

    The principle and the techniques applied in DNA extraction play a pivotal role in the obtention of a purified genetic material. The present study investigates the efficiency of eight protocols in the DNA extraction of Hypostomus commersoni, an essential component of South American freshwater ichthyofauna. The quality of samples was assessed through spectrophotometry, gel electrophoresis, and PCR-RAPD

    更新日期:2020-05-25
  • Natural Genetic Variation in Drosophila melanogaster Reveals Genes Associated with Coxiella burnetii Infection
    bioRxiv. Genet. Pub Date : 2020-05-25
    Rosa Marena Guzman; Zachary P. Howard; Ziying Liu; Ryan D. Oliveira; Alisha T. Massa; Anders Omsland; Stephen White; Alan G. Goodman

    The gram-negative bacterium Coxiella burnetii is the causative agent of Query (Q) fever in humans and coxiellosis in livestock. Association between host genetic background and Coxiella burnetii pathogenesis has been demonstrated both in humans and animals; however, specific genes associated with severity of infection remain unknown. We employed the Drosophila Genetics Reference Panel to perform a genome-wide

    更新日期:2020-05-25
  • Bi-allelic variants in TSPOAP1, encoding the active zone protein RIMBP1, cause autosomal recessive dystonia
    bioRxiv. Genet. Pub Date : 2020-05-25
    Niccolo Emanuele Mencacci; Marisa M Brockmann; Jinye Dai; Sander Pajusalu; Burcu Atasu; Paulina Gonzalez-Latapi; Christopher Patzke; Michael Schwake; Arianna Tucci; Alan Pittmann; Javier Simon-Sanchez; Gemma Carvill; Bettina Balint; Sarah Wiethoff; Thomas W Warner; Apostolos Papandreou; Audrey Soo; Reet Rein; Liis Kadastik-Eerme; Sanna Puusepp; Karit Reinson; Tiiu Tomberg; Gabriela Pino; Joaquin Campos;

    Dystonia is a debilitating hyperkinetic movement disorder, frequently transmitted as a monogenic trait. Here, we describe homozygous frameshift, nonsense and missense variants in TSPOAP1, encoding the active zone RIM-binding protein 1 (RIMBP1), as a novel genetic cause of autosomal recessive dystonia in seven subjects from three unrelated families. Subjects carrying loss-of-function variants presented

    更新日期:2020-05-25
  • The comprehensive genetic architecture of brain white matter
    bioRxiv. Genet. Pub Date : 2020-05-25
    Bingxin Zhao; Tengfei Li; Yue Yang; Xifeng Wang; Tianyou Luo; Yue Shan; Ziliang Zhu; Di Xiong; Yun Li; Jason L Stein; Hongtu Zhu

    White matter keeps human brain globally connected and shapes communication and connectivity patterns among brain regions. White matter microstructure influences brain structural integrity and may underpin brain functions and disorders. Although under strong genetic control, a large number of genetic variants of white matter remain undiscovered. Here we analyzed the genetic architecture of white matter

    更新日期:2020-05-25
  • Chromatin memory generated by cohesin-like interaction at looping sites
    bioRxiv. Genet. Pub Date : 2020-05-25
    Andrea Papale; David Holcman

    How long could a chromatin loop be stabilized inside the nucleus? Such a time is crucial for chromatin organization maintenance and stability. To answer this question, we explore several physical scenarios, where the loop maintenance is due to diffusing cross-linkers such as cohesin and CTCF that can bind and unbind at the base of chromatin loops. We find that this mechanism is sufficient to guarantee

    更新日期:2020-05-25
  • Relationship of DUX4 and target gene expression in FSHD myocytes
    bioRxiv. Genet. Pub Date : 2020-05-25
    Jonathan Chau; Xiangduk Kong; Nam Viet Nguyen; Katherine Williams; Rabi Tawil; Tohru Kiyono; Ali Mortazavi; Kyoko Yokomori

    Facioscapulohumeral dystrophy (FSHD) is linked to misexpression of the transcription factor, DUX4. Although DUX4 target gene expression is often readily detectable, analysis of DUX4 expression has been limited due to its low expression in patient samples. Recently, single cell/nucleus RNA-sequencing was used to detect the native expression of DUX4 for the first time, but important spatial relationships

    更新日期:2020-05-25
  • Novel missense mutation E585K in retinitis pigmentosa leads to compromised RPGR splicing diversity
    bioRxiv. Genet. Pub Date : 2020-05-25
    Yanshan Liu; Ji-Feng Wan; Chun-Yan Ren; Zhou-Heng Xu; Xu-Bin Pan; Jia-Qi Pan; Nuo-Nan Gao; Shao-Qiang Liu; Jia-Li Zhang; Qian-Hao Yao; Ji-Hong Wang; En-Min Li; Jun-Hua Rao; Ping Hou; Jian-Huan Chen

    Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene, are the major cause of X-linked retinitis pigmentosa (RP). Herein we used whole-exome sequencing to screen possible novel RPGR mutations in RP patients, and identified a novel missense mutation E585K in a patient with early onset but slow disease progression, and a frameshift deletion E998Gfs*78 in a patient with RP sine pigmento and

    更新日期:2020-05-25
  • A Two-Part Strategy using Genomic Selection in Hybrid Crop Breeding Programs
    bioRxiv. Genet. Pub Date : 2020-05-25
    Owen M. Powell; R. Chris Gaynor; Gregor M. Gorjanc; Christian R. Werner; John M Hickey

    Hybrid crop breeding programs using a two-part strategy produced the most genetic gain, but a maximum avoidance of inbreeding crossing scheme was required to increase long-term genetic gain. The two-part strategy uses outbred parents to complete multiple generations per year to reduce the generation interval of hybrid crop breeding programs. The maximum avoidance of inbreeding crossing scheme manages

    更新日期:2020-05-25
  • Development of new cowpea (Vigna unguiculata) mutant genotypes, analysis of their agromorphological variation, genetic diversity and Population structure
    bioRxiv. Genet. Pub Date : 2020-05-25
    Made Diouf; Sara Diallo; Francois Abaye Badiane; Oumar Diack; Diaga DIOUF

    Cowpea is one of the most important legume grain in the SubSaharian region of Africa used for human consumption and animal feeding but its production is hampered by biotic and abiotic constraints raising the need to broaden its genetic basis. For this purpose, the seeds of two cowpea varieties Melakh and Yacine were respectively irradiated with 300 and 340 Gy. The developed mutant populations were

    更新日期:2020-05-25
  • Arterial endoglin does not protect against arteriovenous malformations
    bioRxiv. Genet. Pub Date : 2020-05-25
    Helen M. Arthur; Esha Singh; Helen Phillips

    Endoglin (ENG) forms a receptor complex with ALK1 in endothelial cells (ECs) to promote BMP9/10 signalling. Loss of function mutations in either ENG or ALK1 genes lead to the inherited vascular disorder Hereditary Haemorrhagic Telangiectasia (HHT), characterised by arteriovenous malformations (AVMs). However, the vessel-specific role of ENG and ALK1 proteins in protecting against AVMs is unclear. For

    更新日期:2020-05-25
  • Inferring the Allelic Series in a Multiparental Population
    bioRxiv. Genet. Pub Date : 2020-05-24
    Wesley L. Crouse; Samir N.P. Kelada; William Valdar

    Multiparental populations (MPPs) are experimental populations in which the genome of every individual is a mosaic of known founder haplotypes. These populations are useful for detecting quantitative trait loci (QTL) because tests of association can leverage inferred founder haplotype descent. It is difficult, however, to determine how haplotypes at a locus group into distinct functional alleles, termed

    更新日期:2020-05-24
  • Inclusion of Variants Discovered from Diverse Populations Improves Polygenic Risk Score Transferability
    bioRxiv. Genet. Pub Date : 2020-05-24
    Taylor B. Cavazos; John S. Witte

    The majority of polygenic risk scores (PRS) have been developed and optimized in individuals of European ancestry, and may have limited generalizability across other ancestral populations. Understanding aspects of PRS that contribute to this issue and determining solutions is complicated by disease-specific genetic architecture and limited knowledge of trans-ethnic sharing of causal variants and effect

    更新日期:2020-05-24
  • The emergence of SARS-CoV-2 in Europe and the US
    bioRxiv. Genet. Pub Date : 2020-05-23
    Michael Worobey; Jonathan Pekar; Brendan B. Larsen; Martha I. Nelson; Verity Hill; Jeffrey B. Joy; Andrew Rambaut; Marc A. Suchard; Joel O. Wertheim; Philippe Lemey

    Accurate understanding of the global spread of emerging viruses is critically important for public health response and for anticipating and preventing future outbreaks. Here, we elucidate when, where and how the earliest sustained SARS-CoV-2 transmission networks became established in Europe and the United States (US). Our results refute prior findings erroneously linking cases in January 2020 with

    更新日期:2020-05-23
  • GWAS AND GENOMIC SELECTION FOR INCREASED ANTHOCYANIN CONTENT IN PURPLE CORN
    bioRxiv. Genet. Pub Date : 2020-05-23
    John A. Juvik; Laura A. Chatham

    Purple corn offers an attractive source of economical natural anthocyanin-based colorant for use in foods and beverages. Yet to maximize the scalability and meet growing demands, both anthocyanin concentrations and agronomic performance must improve in purple corn varieties. We studied flux through the flavonoid biosynthesis pathway using GWAS data derived from a diverse purple corn landrace with anthocyanin-rich

    更新日期:2020-05-23
  • A fully joint Bayesian quantitative trait locus mapping of human protein abundance in plasma
    bioRxiv. Genet. Pub Date : 2020-05-23
    Hélène Ruffieux; Jérôme Carayol; Radu Popescu; Mary-Ellen Harper; Robert Dent; Wim Saris; Arne Astrup; Jorg Hager; Anthony Davison; Armand Valsesia

    Molecular quantitative trait locus (QTL) analyses are increasingly popular to explore the genetic architecture of complex traits, but existing studies do not leverage shared regulatory patterns and suffer from a large multiplicity burden, which hampers the detection of weak signals such as trans associations. Here, we present a fully multivariate proteomic QTL (pQTL) analysis performed with our recently

    更新日期:2020-05-23
  • Exploiting the GTEx resources to decipher the mechanisms at GWAS loci
    bioRxiv. Genet. Pub Date : 2020-05-23
    Alvaro N Barbeira; Rodrigo Bonazzola; Eric R Gamazon; Yanyu Liang; YoSon Park; Sarah Kim-Hellmuth; Gao Wang; Zhuoxun Jiang; Dan Zhou; Farhad Hormozdiari; Boxiang Liu; Abhiram Rao; Andrew R Hamel; Milton D Pividori; François Aguet; GTEx GWAS Working Group; Lisa Bastarache; Daniel M Jordan; Marie Verbanck; Ron Do; GTEx Consortium; Matthew Stephens; Kristin Ardlie; Mark McCarthy; Stephen B Montgomery;

    The resources generated by the GTEx consortium offer unprecedented opportunities to advance our understanding of the biology of human diseases. Here, we present an in-depth examination of the phenotypic consequences of transcriptome regulation and a blueprint for the functional interpretation of genome-wide association study-discovered loci. Across a broad set of complex traits and diseases, we demonstrate

    更新日期:2020-05-23
  • Interpreting the pathogenicity of Joubert Syndrome missense variants in Caenorhabditis elegans
    bioRxiv. Genet. Pub Date : 2020-05-22
    Karen I. Lange; Sofia Tsiropoulou; Katarzyna Kucharska; Oliver E. Blacque

    Ciliopathies are a large class of inherited disorders caused by defects in cilia. Variants in ciliopathy genes are highly pleiotropic and represent excellent case studies for interrogating genotype-phenotype correlation. However, in most cell and animal studies, ciliopathy mechanisms are not investigated using alleles as they occur in patients. We have employed Caenorhabditis elegans to model and characterise

    更新日期:2020-05-22
  • Genomic Epidemiology of Escherichia coli Isolates from a Tertiary Referral Center in Lilongwe, Malawi
    bioRxiv. Genet. Pub Date : 2020-05-22
    Gerald Tegha; Emily Ciccone; Robert Krysiak; James Kaphatika; Tarsizio Chikaonda; Isaac Ndhlovu; David van Duin; Irving Hoffman; Jonathan James Juliano; Jeremy James Wang

    Antimicrobial resistance (AMR) is a global threat, including in sub-Saharan Africa. However, little is known about the genetics of resistant bacteria in the region. In Malawi, there is growing concern about increasing rates of antimicrobial resistance to most empirically used antimicrobials. The highly drug resistant Escherichia coli sequence type (ST) 131, which is associated with the extended spectrum

    更新日期:2020-05-22
  • Population-scale single-cell RNA-seq profiling across dopaminergic neuron differentiation
    bioRxiv. Genet. Pub Date : 2020-05-22
    Julie Jerber; Daniel D Seaton; Anna SE Cuomo; Natsuhiko Kumasaka; James Haldane; Juliette Steer; Minal Patel; Daniel Pearce; Malin Andersson; Marc Jan Bonder; Ed Mountjoy; Maya Ghoussaini; Madeline A Lancaster; HipSci Consortium; John C Marioni; Florian T Merkle; Oliver Stegle; Daniel J Gaffney

    Common genetic variants can have profound effects on cellular function, but studying these effects in primary human tissue samples and during development is challenging. Human induced pluripotent stem cell (iPSC) technology holds great promise for assessing these effects across different differentiation contexts. Here, we use an efficient pooling strategy to differentiate 215 iPS cell lines towards

    更新日期:2020-05-22
  • Mutation of NEKL-4/NEK10 and TTLL genes opposes loss of the CCPP-1 deglutamylase and prevents neuronal ciliary degeneration
    bioRxiv. Genet. Pub Date : 2020-05-22
    Kade M Power; Jyothi S Akella; Amanda Gu; Jonathon D Walsh; Sebastian Belotti; Margaret Morash; Winnie Zhang; Nicole Ross; Andy Golden; Harold E Smith; Maureen M Barr; Robert O'Hagan

    Ciliary microtubules are subject to post-translational modifications that act as a Tubulin Code to regulate motor traffic, binding proteins and stability. In humans, loss of CCP1, a cytosolic carboxypeptidase and tubulin deglutamylating enzyme, causes infantile-onset neurodegeneration. In C.elegans, mutations in ccpp-1, the homolog of CCP1, result in progressive degeneration of neuronal cilia and loss

    更新日期:2020-05-22
  • Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus.
    bioRxiv. Genet. Pub Date : 2020-05-22
    Iain Mathieson; Felix Day; Nicola Barban; Felix Tropf; David Brazel; eQTLGen Consortium; BIOS Consortium; Ahmad Vaez; Natalie van Zuydam; Barbara Bitarello; Harold Snieder; Marcel den Hoed; Ken Ong; Melinda Mills; John Perry; Human Reproductive Behaviour Consortium

    Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and also identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identify 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology across the life course, including

    更新日期:2020-05-22
  • Factors enforcing the species boundary between the human pathogens Cryptococcus neoformans and Cryptococcus deneoformans
    bioRxiv. Genet. Pub Date : 2020-05-21
    Shelby Jordan Priest; Marco A. Coelho; Verónica Mixão; Shelly Clancey; Yitong Xu; Sheng Sun; Toni Gabaldón; Joseph Heitman

    Hybridization has resulted in the origin and variation in extant species, and hybrids continue to arise despite pre- and post-zygotic barriers that limit their formation and evolutionary success. One important system that maintains species boundaries in prokaryotes and eukaryotes is the mismatch repair pathway, which blocks homeologous recombination between divergent DNA sequences. Previous studies

    更新日期:2020-05-21
  • Combining auxin-induced degradation and RNAi screening identifies novel genes involved in lipid bilayer stress sensing in Caenorhabditis elegans
    bioRxiv. Genet. Pub Date : 2020-05-21
    Richard Venz; Anastasiia Korosteleva; Collin Yves Ewald

    Alteration of the lipid composition of biological membranes interferes with their function and can cause tissue damage by triggering apoptosis. Upon lipid bilayer stress, the endoplasmic reticulum mounts a stress response that is similar to the unfolded protein response. However, only a few genes are known to regulate lipid bilayer stress. Here, we performed a suppressor screen that combined the auxin-inducible

    更新日期:2020-05-21
  • Nutrient sensing pathways regulating adult reproductive diapause in C. elegans
    bioRxiv. Genet. Pub Date : 2020-05-21
    Moriah Eustice; Jeff M Reece; Daniel Konzman; Salil Ghosh; Jhulian Alston; Tyler Hansen; Andy Golden; John Hanover

    Genetic and environmental manipulations, such as dietary restriction (DR), can improve both health span and lifespan in a wide range of organisms, including humans. Changes in nutrient intake trigger often overlapping metabolic pathways that can generate distinct or even opposite outputs depending on several factors, such as when DR occurs in the lifecycle of the organism or the nature of the changes

    更新日期:2020-05-21
  • Population-specific causal disease effect sizes in functionally important regions impacted by selection
    bioRxiv. Genet. Pub Date : 2020-05-21
    Huwenbo Shi; Steven Gazal; Masahiro Kanai; Evan M Koch; Armin P Schoech; Katherine M Siewert; Samuel S Kim; Yang Luo; Tiffany Amariuta; Hailiang Huang; Yukinori Okada; Soumya Raychaudhuri; Shamil R Sunyaev; Alkes L Price

    Many diseases and complex traits exhibit population-specific causal effect sizes with trans-ethnic genetic correlations significantly less than 1, limiting trans-ethnic polygenic risk prediction. We developed a new method, S-LDXR, for stratifying squared trans-ethnic genetic correlation across genomic annotations, and applied S-LDXR to genome-wide association summary statistics for 31 diseases and

    更新日期:2020-05-21
  • Development of diagnostic PCR and LAMP markers for MALE STERILITY 1 (MS1) in Cryptomeria japonica D. Don
    bioRxiv. Genet. Pub Date : 2020-05-20
    Yoichi Hasegawa; Saneyoshi Ueno; Fu-Jin Wei; Asako Matsumoto; Tokuko Ujino-Ihara; Yoshinari Moriguchi; Masahiro Kasahara; Takeshi Fujino; Shuji Shigenobu; Katsushi Yamaguchi; Takahiro Bino; Tetsuji Hakamata

    Objective: Due to the allergic nature of the pollen of Cryptomeria japonica, the most important Japanese forestry conifer, a pollen-free cultivar is preferred. Mutant trees detected in nature have been used for the production of a pollen-free cultivar. In order to reduce the time and cost needed for the production and breeding, we aimed to develop simple diagnostic molecular markers for mutant alleles

    更新日期:2020-05-20
  • Mitochondrial D-loop sequence variation and maternal lineage in the endangered Cleveland Bay horse
    bioRxiv. Genet. Pub Date : 2020-05-20
    Andy Dell; Mark Curry; Kelly Yarnell; Gareth Starbuck; Philippe B Wilson

    Genetic diversity and maternal ancestry line relationships amongst a sample of 96 Cleveland Bay horses were investigated using a 479bp length of mitochondrial D-loop sequence. The analysis yielded at total of 11 haplotypes with 27 variable positions, all of which have been described in previous equine mitochondrial DNA d-loop studies. Four main haplotype clusters were present in the Cleveland Bay breed

    更新日期:2020-05-20
  • Genome-wide association study of circulating liver enzymes reveals an expanded role for manganese transporter SLC30A10 in liver health
    bioRxiv. Genet. Pub Date : 2020-05-20
    Lucas D. Ward; Ho-Chou Tu; Chelsea Quenneville; Alex O. Flynn-Carroll; Margaret M. Parker; Aimee M. Deaton; Patrick A. J. Haslett; Gregory Hinkle; Paul Nioi

    To better understand molecular pathways underlying liver health and disease, we performed genome-wide association studies (GWAS) on circulating levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) across 408,300 subjects from four ethnic groups in the UK Biobank, focusing on variants associating with both enzymes. Of these variants, the strongest effect is a rare (MAF in White

    更新日期:2020-05-20
  • Genome-wide landscape of RNA-binding protein dysregulation reveals a major impact on psychiatric disorder risk
    bioRxiv. Genet. Pub Date : 2020-05-20
    Christopher Y Park; Jian Zhou; Aaron K Wong; Kathleen M Chen; Chandra L Theesfeld; Robert Darnell; Olga G. Troyanskaya

    Despite the strong genetic basis of psychiatric disorders, the molecular origins of these diseases are still largely unmapped. RNA-binding proteins (RBPs) are responsible for most post- transcriptional regulation, from splicing to translational to localization. RBPs thus act as key gatekeepers of cellular homeostasis, especially in the brain. Here, we leverage a deep learning approach to interrogate

    更新日期:2020-05-20
  • Neighbor QTL: an interval mapping method for quantitative trait loci underlying neighbor effects
    bioRxiv. Genet. Pub Date : 2020-05-20
    Yasuhiro Sato; Kazuya Takeda; Atsushi J Nagano

    Phenotypes of sessile organisms rely not only on their own genotype but also on the genotypes of neighboring individuals. Previously, we incorporated such neighbor effects into a single-marker regression using the Ising model of ferromagnetism. However, little is known about how to incorporate neighbor effects in quantitative trait locus (QTL) mapping. In this study, we propose a new method for interval

    更新日期:2020-05-20
  • Tissue-specific multiOMICs analysis of atrial fibrillation
    bioRxiv. Genet. Pub Date : 2020-05-20
    Ines Assum; Julia Krause; Markus O Scheinhardt; Elke Hammer; Christian Mueller; Christin S Boerschel; Uwe Voelker; Lenard Conradi; Bastiaan Geelhoed; Tanja Zeller; Renate Schnabel; Matthias Heinig

    Genome-wide association studies (GWAS) for atrial fibrillation (AF) have uncovered numerous disease-associated variants. Their underlying molecular mechanisms, especially consequences for mRNA and protein expression remain largely elusive. Thus, novel multiOMICs approaches are needed for deciphering the underlying molecular networks. Here, we integrated genomics, transcriptomics, and proteomics of

    更新日期:2020-05-20
  • Emerging phylogenetic structure of the SARS-CoV-2 pandemic
    bioRxiv. Genet. Pub Date : 2020-05-19
    Nicholas M Fountain-Jones; Raima Carol Appaw; Scott Carver; Xavier Didelot; Erik M Volz; Michael Charleston

    Since spilling over into humans, SARS-CoV-2 has rapidly spread across the globe, accumulating significant genetic diversity. The structure of this genetic diversity, and whether it reveals epidemiological insights, are fundamental questions for understanding the evolutionary trajectory of this virus. Here we use a recently developed phylodynamic approach to uncover phylogenetic structures underlying

    更新日期:2020-05-19
  • Non-linear randomized Haseman-Elston regression for estimation of gene-environment heritability
    bioRxiv. Genet. Pub Date : 2020-05-19
    Matthew Kerin; Jonathan Marchini

    Gene-environment (GxE) interactions are one of the least studied aspects of the genetic architecture of human traits and diseases. The environment of an individual is inherently high dimensional, evolves through time and can be expensive and time consuming to measure. The UK Biobank study, with all 500,000 participants having undergone an extensive baseline questionnaire, represents a unique opportunity

    更新日期:2020-05-19
  • Paternal multigenerational exposure to an obesogenic diet drives epigenetic predisposition to metabolic disorders
    bioRxiv. Genet. Pub Date : 2020-05-19
    Georges Raad; Fabrizio Serra; Luc Martin; Marie-Alix Derieppe; Jerome Gilleron; Vera L Costa; Didier F Pisani; Ez-Zoubir Amri; Michele Trabucchi; Valerie Grandjean

    Obesity is a growing societal scourge responsible for approximately 4 million deaths worldwide. Recent studies have uncovered that paternal excessive weight induced by an unbalanced diet affects the metabolic health of offspring. These reports mainly employed single-generation male exposure. However, the consequences of multigenerational unbalanced diet feeding on the metabolic health of progeny remain

    更新日期:2020-05-19
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