Phase 3. Functional Variant Discovery
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Frameshift Indels Generate Highly Immunogenic Tumor Neoantigens Tumor-Specifi C Neoantigens Are the Targets of T Cells in the Neoantigens
Published OnlineFirst July 21, 2017; DOI: 10.1158/2159-8290.CD-RW2017-135 RESEARCH WATCH Apoptosis Major finding: An NMR-based fragment Mechanism: BIF-44 binds to a deep hy- Impact: Allosteric BAX sensitization screen identified a BAX-interacting com- drophobic pocket to induce conformation may represent a therapeutic strategy pound, BIF-44, that enhances BAX activity . changes that sensitize BAX activation . to promote apoptosis of cancer cells . BAX CAN BE ALLOSTERICALLY SENSITIZED TO PROMOTE APOPTOSIS The proapoptotic BAX protein is comprised of BH3 motif of the BIM protein. BIF-44 bound nine α-helices (α1–α9) and is a critical regulator competitively to the same region as vMIA, in a of the mitochondrial apoptosis pathway. In the deep hydrophobic pocket formed by the junction conformationally inactive state, BAX is primar- of the α3–α4 and α5–α6 hairpins that normally ily cytosolic and can be activated by BH3-only maintain BAX in an inactive state. Binding of BIF- activator proteins, which bind to ab α6/α6 “trig- 44 induced a structural change that resulted in ger site” to induce a conformational change that allosteric mobilization of the α1–α2 loop, which activates BAX and promotes its oligomerization. is involved in BH3-mediated activation, and the Conversely, antiapoptotic BCL2 proteins or the cytomeg- BAX BH3 helix, which is involved in propagating BAX oli- alovirus vMIA protein can bind to and inhibit BAX. Efforts gomerization, resulting in sensitization of BAX activation. In to therapeutically enhance apoptosis have largely focused addition to identifying a BAX allosteric sensitization site and on inhibiting antiapoptotic proteins. -
Small Variants Frequently Asked Questions (FAQ) Updated September 2011
Small Variants Frequently Asked Questions (FAQ) Updated September 2011 Summary Information for each Genome .......................................................................................................... 3 How does Complete Genomics map reads and call variations? ........................................................................... 3 How do I assess the quality of a genome produced by Complete Genomics?................................................ 4 What is the difference between “Gross mapping yield” and “Both arms mapped yield” in the summary file? ............................................................................................................................................................................. 5 What are the definitions for Fully Called, Partially Called, Half-Called and No-Called?............................ 5 In the summary-[ASM-ID].tsv file, how is the number of homozygous SNPs calculated? ......................... 5 In the summary-[ASM-ID].tsv file, how is the number of heterozygous SNPs calculated? ....................... 5 In the summary-[ASM-ID].tsv file, how is the total number of SNPs calculated? .......................................... 5 In the summary-[ASM-ID].tsv file, what regions of the genome are included in the “exome”? .............. 6 In the summary-[ASM-ID].tsv file, how is the number of SNPs in the exome calculated? ......................... 6 In the summary-[ASM-ID].tsv file, how are variations in potentially redundant regions of the genome counted? ..................................................................................................................................................................... -
Whole Genome Sequencing Identifies Novel Structural Variant in a Large Indian Family Affected with X - Linked Agammaglobulinemia
medRxiv preprint doi: https://doi.org/10.1101/2020.10.05.20200949; this version posted October 6, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license . Whole Genome Sequencing identifies novel structural variant in a large Indian family affected with X - linked agammaglobulinemia 1,2,# 3,5,#,$ 3,4 3 Abhinav Jain , Geeta Madathil Govindaraj , Athulya Edavazhippurath , Nabeel Faisal , Rahul C 1 1,2 6 3 1 1 Bhoyar , Vishu Gupta , Ramya Uppuluri , Shiny Padinjare Manakkad , Atul Kashyap , Anoop Kumar , 1,2 1,2 7 7 3 Mohit Kumar Divakar , Mohamed Imran , Sneha Sawant , Aparna Dalvi , Krishnan Chakyar , 7 6 1,2,$ 1,2,$ Manisha Madkaikar , Revathi Raj , Sridhar Sivasubbu , Vinod Scaria 1 CSIR-Institute of Genomics and Integrative Biology, Mathura Road, New Delhi, Delhi, India 2 Academy of Scientific and Innovative Research (AcSIR), Mathura Road, New Delhi, Delhi, India 3 Department of Pediatrics, Government Medical College Kozhikode, Kozhikode, Kerala, India 4 Multidisciplinary Research Unit, Government College Kozhikode, Kozhikode, Kerala, India 5 FPID Regional Diagnostic Centre, Government Medical College Kozhikode, Kozhikode, Kerala India 6 Department of Pediatric Hematology, Oncology, Blood and Marrow Transplantation, Apollo Hospitals, 320, Padma complex, Anna salai, Teynampet, Chennai, Tamil Nadu, India 7 Department of Pediatric Immunology and Leukocyte Biology, ICMR-National Institute of Immunohaematology, KEM Hospital, Parel, Mumbai, Maharashtra, India. # Joint first authors $ Corresponding author Vinod Scaria: [email protected] Sridhar Sivasubbu: [email protected] Geeta Madathil Govindaraj: [email protected] NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. -
Mutational Landscape of Spontaneous Base Substitutions and Small Indels in Experimental Caenorhabditis Elegans Populations of Differing Size
| INVESTIGATION Mutational Landscape of Spontaneous Base Substitutions and Small Indels in Experimental Caenorhabditis elegans Populations of Differing Size Anke Konrad, Meghan J. Brady, Ulfar Bergthorsson, and Vaishali Katju1 Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas 77845 ORCID IDs: 0000-0003-3994-460X (A.K.); 0000-0003-1419-1349 (U.B.); 0000-0003-4720-9007 (V.K.) ABSTRACT Experimental investigations into the rates and fitness effects of spontaneous mutations are fundamental to our understanding of the evolutionary process. To gain insights into the molecular and fitness consequences of spontaneous mutations, we conducted a mutation accumulation (MA) experiment at varying population sizes in the nematode Caenorhabditis elegans, evolving 35 lines in parallel for 409 generations at three population sizes (N = 1, 10, and 100 individuals). Here, we focus on nuclear SNPs and small insertion/deletions (indels) under minimal influence of selection, as well as their accrual rates in larger populations under greater selection efficacy. The spontaneous rates of base substitutions and small indels are 1.84 (95% C.I. 6 0.14) 3 1029 substitutions and 6.84 (95% C.I. 6 0.97) 3 10210 changes/site/generation, respectively. Small indels exhibit a deletion bias with deletions exceeding insertions by threefold. Notably, there was no correlation between the frequency of base substitutions, nonsynonymous substitutions, or small indels with population size. These results contrast with our previous analysis of mitochondrial DNA mutations and nuclear copy-number changes in these MA lines, and suggest that nuclear base substitutions and small indels are under less stringent purifying selection compared to the former mutational classes. -
Exome Sequencing and Functional Validation in Zebrafish Identify
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector REPORT Exome Sequencing and Functional Validation in Zebrafish Identify GTDC2 Mutations as a Cause of Walker-Warburg Syndrome M. Chiara Manzini,1,2 Dimira E. Tambunan,1,2 R. Sean Hill,1,2 Tim W. Yu,1,2 Thomas M. Maynard,3 Erin L. Heinzen,4 Kevin V. Shianna,4 Christine R. Stevens,5 Jennifer N. Partlow,1,2 Brenda J. Barry,1,2 Jacqueline Rodriguez,1,2 Vandana A. Gupta,1,6 Abdel-Karim Al-Qudah,7 Wafaa M. Eyaid,8 Jan M. Friedman,9,10 Mustafa A. Salih,11 Robin Clark,12 Isabella Moroni,13 Marina Mora,14 Alan H. Beggs,1,6 Stacey B. Gabriel,5 and Christopher A. Walsh1,2,5,* Whole-exome sequencing (WES), which analyzes the coding sequence of most annotated genes in the human genome, is an ideal approach to studying fully penetrant autosomal-recessive diseases, and it has been very powerful in identifying disease-causing muta- tions even when enrollment of affected individuals is limited by reduced survival. In this study, we combined WES with homozygosity analysis of consanguineous pedigrees, which are informative even when a single affected individual is available, to identify genetic mutations responsible for Walker-Warburg syndrome (WWS), a genetically heterogeneous autosomal-recessive disorder that severely affects the development of the brain, eyes, and muscle. Mutations in seven genes are known to cause WWS and explain 50%–60% of cases, but multiple additional genes are expected to be mutated because unexplained cases show suggestive linkage to diverse loci. -
Genomic Approaches for Understanding the Genetics of Complex Disease
Downloaded from genome.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Perspective Genomic approaches for understanding the genetics of complex disease William L. Lowe Jr.1 and Timothy E. Reddy2,3 1Division of Endocrinology, Metabolism and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA; 2Department of Biostatistics and Bioinformatics, Duke University Medical School, Durham, North Carolina 27708, USA; 3Center for Genomic and Computational Biology, Duke University Medical School, Durham, North Carolina 27708, USA There are thousands of known associations between genetic variants and complex human phenotypes, and the rate of novel discoveries is rapidly increasing. Translating those associations into knowledge of disease mechanisms remains a fundamental challenge because the associated variants are overwhelmingly in noncoding regions of the genome where we have few guiding principles to predict their function. Intersecting the compendium of identified genetic associations with maps of regulatory activity across the human genome has revealed that phenotype-associated variants are highly enriched in candidate regula- tory elements. Allele-specific analyses of gene regulation can further prioritize variants that likely have a functional effect on disease mechanisms; and emerging high-throughput assays to quantify the activity of candidate regulatory elements are a promising next step in that direction. Together, these technologies have created the ability to systematically and empirically test hypotheses about the function of noncoding variants and haplotypes at the scale needed for comprehensive and system- atic follow-up of genetic association studies. Major coordinated efforts to quantify regulatory mechanisms across genetically diverse populations in increasingly realistic cell models would be highly beneficial to realize that potential. -
Indelible Markers the Recruitment of Modified Histones by the RITS Complex
RESEARCH HIGHLIGHTS IN BRIEF EPIGENETICS Argonaute slicing is required for heterochromatic silencing and spreading. HUMAN GENETICS Irvine, D. V. et al. Science 313, 1134–1137 (2006) It has been proposed that small interfering RNA (siRNA)- guided histone H3 dimethylation on lysine 9 (H3K9me2) might be caused by an interaction of siRNA with DNA and INDELible markers the recruitment of modified histones by the RITS complex. Alternatively, siRNAs might guide histone modification by Over 10 million unique SNPs, some comprised about 30% of the base-pairing with RNA. Working in fission yeast, Irvine et al. of which influence human traits and total. Another ~30% consisted of provide support for the second mechanism. They show that disease susceptibilities, have been expansions of either monomeric the endonucleolytic cleavage motif of Argonaute is required identified in the human genome. base-pair repeats or multi-base for heterochromatic silencing and for ‘slicing’ mRNAs that are Now, another type of natural genetic repeats. Approximately 40% of indels complementary to siRNAs. They also show that spreading of variation, which involves insertion included insertions of apparently ran- silencing requires read-through transcription, as well as slicing. and deletion polymorphisms (indels), dom DNA sequences. Transposons has been systematically studied and accounted for only a small proportion TECHNOLOGY mapped for the first time. (less than 1%) of the polymorphisms Trans-kingdom transposition of the maize Dissociation Understanding more about indels that were identified. element. is important because they are known Indels were spread throughout Emelyanov, A. et al. Genetics 1 September 2006 (doi:10.1534/ to contribute to human disease. -
Pervasive Indels and Their Evolutionary Dynamics After The
MBE Advance Access published April 24, 2012 Pervasive Indels and Their Evolutionary Dynamics after the Fish-Specific Genome Duplication Baocheng Guo,1,2 Ming Zou,3 and Andreas Wagner*,1,2 1Institute of Evolutionary Biology and Environmental Studies, University of Zurich, Zurich, Switzerland 2The Swiss Institute of Bioinformatics, Quartier Sorge-Batiment Genopode, Lausanne, Switzerland 3Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, People’s Republic of China *Corresponding author: E-mail: [email protected]. Associate editor: Herve´ Philippe Abstract Research article Insertions and deletions (indels) in protein-coding genes are important sources of genetic variation. Their role in creating new proteins may be especially important after gene duplication. However, little is known about how indels affect the divergence of duplicate genes. We here study thousands of duplicate genes in five fish (teleost) species with completely sequenced genomes. The ancestor of these species has been subject to a fish-specific genome duplication (FSGD) event Downloaded from that occurred approximately 350 Ma. We find that duplicate genes contain at least 25% more indels than single-copy genes. These indels accumulated preferentially in the first 40 my after the FSGD. A lack of widespread asymmetric indel accumulation indicates that both members of a duplicate gene pair typically experience relaxed selection. Strikingly, we observe a 30–80% excess of deletions over insertions that is consistent for indels of various lengths and across the five genomes. We also find that indels preferentially accumulate inside loop regions of protein secondary structure and in http://mbe.oxfordjournals.org/ regions where amino acids are exposed to solvent. -
The Origin, Evolution, and Functional Impact of Short Insertion–Deletion Variants Identified in 179 Human Genomes
Downloaded from genome.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press Research The origin, evolution, and functional impact of short insertion–deletion variants identified in 179 human genomes Stephen B. Montgomery,1,2,3,14,16 David L. Goode,3,14,15 Erika Kvikstad,4,13,14 Cornelis A. Albers,5,6 Zhengdong D. Zhang,7 Xinmeng Jasmine Mu,8 Guruprasad Ananda,9 Bryan Howie,10 Konrad J. Karczewski,3 Kevin S. Smith,2 Vanessa Anaya,2 Rhea Richardson,2 Joe Davis,3 The 1000 Genomes Pilot Project Consortium, Daniel G. MacArthur,5,11 Arend Sidow,2,3 Laurent Duret,4 Mark Gerstein,8 Kateryna D. Makova,9 Jonathan Marchini,12 Gil McVean,12,13 and Gerton Lunter13,16 1–13[Author affiliations appear at the end of the paper.] Short insertions and deletions (indels) are the second most abundant form of human genetic variation, but our un- derstanding of their origins and functional effects lags behind that of other types of variants. Using population-scale sequencing, we have identified a high-quality set of 1.6 million indels from 179 individuals representing three diverse human populations. We show that rates of indel mutagenesis are highly heterogeneous, with 43%–48% of indels occurring in 4.03% of the genome, whereas in the remaining 96% their prevalence is 16 times lower than SNPs. Polymerase slippage can explain upwards of three-fourths of all indels, with the remainder being mostly simple de- letions in complex sequence. However, insertions do occur and are significantly associated with pseudo-palindromic sequence features compatible with the fork stalling and template switching (FoSTeS) mechanism more commonly as- sociated with large structural variations. -
The Genomics Era: the Future of Genetics in Medicine - Glossary
The Genomics Era: the Future of Genetics in Medicine - Glossary The glossary below provides a list of key terms used throughout the course. You do not need to read them all now; we’ll be linking back to the main glossary step wherever these terms appear, so you may refer back to this list if you are unsure of the terminology being used. Term Definition The process of matching reads back to their original Alignment position in the reference genome. An allele is one of a number of alternative forms of the same gene or genetic locus. We inherit one copy Allele of our genetic code from our mother and one copy of our genetic code from our father. Each copy is known as an allele. Microarray based genomic comparative hybridisation. This is a technique used to detect chromosome imbalances by comparing patient and control DNA and comparing differences between the two sets. It is Array CGH a useful technique for detecting small chromosome deletions and duplications which would not have been detected with more traditional karyotyping techniques. A unit of DNA. There are four bases which form the Base cross links (or rungs) of the DNA double helix: adenine (A), thymine (T), guanine (G) and cytosine (C). Capture see Target enrichment. The process by which a cell becomes specialized in Cell differentiation order to perform a specific function. Centromere The point at which the sister chromatids are joined. #1 FutureLearn A structure located in the nucleus all living cells, comprised of DNA bound around proteins called histones. The normal number of chromosomes in each Chromosome human cell nucleus is 46 and is composed of 22 pairs of autosomes and a pair of sex chromosomes which determine gender: males have an X and a Y chromosome whilst females have two X chromosomes. -
Integrated Analysis of Gene Expression, SNP, Indel, and CNV
G C A T T A C G G C A T genes Article Integrated Analysis of Gene Expression, SNP, InDel, and CNV Identifies Candidate Avirulence Genes in Australian Isolates of the Wheat Leaf Rust Pathogen Puccinia triticina Long Song , Jing Qin Wu, Chong Mei Dong and Robert F. Park * Plant Breeding Institute, School of Life and Environmental Science, Faculty of Science, The University of Sydney, Sydney 2006, NSW, Australia; [email protected] (L.S.); [email protected] (J.Q.W.); [email protected] (C.M.D.) * Correspondence: [email protected]; Tel.: +61-2-9351-8806; Fax: +61-2-9351-8875 Received: 3 September 2020; Accepted: 18 September 2020; Published: 21 September 2020 Abstract: The leaf rust pathogen, Puccinia triticina (Pt), threatens global wheat production. The deployment of leaf rust (Lr) resistance (R) genes in wheat varieties is often followed by the development of matching virulence in Pt due to presumed changes in avirulence (Avr) genes in Pt. Identifying such Avr genes is a crucial step to understand the mechanisms of wheat-rust interactions. This study is the first to develop and apply an integrated framework of gene expression, single nucleotide polymorphism (SNP), insertion/deletion (InDel), and copy number variation (CNV) analysis in a rust fungus and identify candidate avirulence genes. Using a long-read based de novo genome assembly of an isolate of Pt (‘Pt104’) as the reference, whole-genome resequencing data of 12 Pt pathotypes derived from three lineages Pt104, Pt53, and Pt76 were analyzed. Candidate avirulence genes were identified by correlating virulence profiles with small variants (SNP and InDel) and CNV, and RNA-seq data of an additional three Pt isolates to validate expression of genes encoding secreted proteins (SPs). -
QTL Analysis Reveals Genomic Variants Linked to High-Temperature
Wang et al. Biotechnol Biofuels (2019) 12:59 https://doi.org/10.1186/s13068-019-1398-7 Biotechnology for Biofuels RESEARCH Open Access QTL analysis reveals genomic variants linked to high-temperature fermentation performance in the industrial yeast Zhen Wang1,2†, Qi Qi1,2†, Yuping Lin1*, Yufeng Guo1, Yanfang Liu1,2 and Qinhong Wang1* Abstract Background: High-temperature fermentation is desirable for the industrial production of ethanol, which requires thermotolerant yeast strains. However, yeast thermotolerance is a complicated quantitative trait. The understanding of genetic basis behind high-temperature fermentation performance is still limited. Quantitative trait locus (QTL) map- ping by pooled-segregant whole genome sequencing has been proved to be a powerful and reliable approach to identify the loci, genes and single nucleotide polymorphism (SNP) variants linked to quantitative traits of yeast. Results: One superior thermotolerant industrial strain and one inferior thermosensitive natural strain with distinct high-temperature fermentation performances were screened from 124 Saccharomyces cerevisiae strains as parent strains for crossing and segregant isolation. Based on QTL mapping by pooled-segregant whole genome sequencing as well as the subsequent reciprocal hemizygosity analysis (RHA) and allele replacement analysis, we identifed and validated total eight causative genes in four QTLs that linked to high-temperature fermentation of yeast. Interestingly, loss of heterozygosity in fve of the eight causative genes including RXT2, ECM24, CSC1, IRA2 and AVO1 exhibited posi- tive efects on high-temperature fermentation. Principal component analysis (PCA) of high-temperature fermentation data from all the RHA and allele replacement strains of those eight genes distinguished three superior parent alleles including VPS34, VID24 and DAP1 to be greatly benefcial to high-temperature fermentation in contrast to their inferior parent alleles.