DOCSLIB.ORG

Mapping DNA Structural Variation in Dogs

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Mapping DNA Structural Variation in Dogs Downloaded from genome.cshlp.org on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press Resource Mapping DNA structural variation in dogs Wei-Kang Chen,1,4 Joshua D. Swartz,1,4,5 Laura J. Rush,2 and Carlos E. Alvarez1,3,6 1Center for Molecular and Human Genetics, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio 43205, USA; 2Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210, USA; 3Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio 43210, USA DNA structural variation (SV) comprises a major portion of genetic diversity, but its biological impact is unclear. We propose that the genetic history and extraordinary phenotypic variation of dogs make them an ideal mammal in which to study the effects of SV on biology and disease. The hundreds of existing dog breeds were created by selection of extreme morphological and behavioral traits. And along with those traits, each breed carries increased risk for different diseases. We used array CGH to create the first map of DNA copy number variation (CNV) or SV in dogs. The extent of this variation, and some of the gene classes affected, are similar to those of mice and humans. Most canine CNVs affect genes, including disease and candidate disease genes, and are thus likely to be functional. We identified many CNVs that may be breed or breed class specific. Cluster analysis of CNV regions showed that dog breeds tend to group according to breed classes. Our combined findings suggest many CNVs are (1) in linkage disequilibrium with flanking sequence, and (2) associated with breed-specific traits. We discuss how a catalog of structural variation in dogs will accelerate the iden- tification of the genetic basis of canine traits and diseases, beginning with the use of whole genome association and candidate-CNV/gene approaches. [Supplemental material is available online at www.genome.org.] Recent findings revealed that DNA structural variation (SV) is tory elements (for reviews, see Lupski and Stankiewicz 2005; common in normal rodents (Graubert et al. 2007; Guryev et al. Reymond et al. 2007). 2008) and primates (Iafrate et al. 2004; Sebat et al. 2007; Lee et al. Disease relevance of DNA copy number alteration was already 2008; for review, see Freeman et al. 2006). The term SV and its appreciated from recurrent deletions of tumor suppressors (e.g., subset of copy number variation (CNV), refer to alterations from 1 TP53 and RB1) and amplifications of oncogenes (e.g., MYC and kb to multi-Mb. The development of high-resolution array com- EGFR) in cancer. However, since the recent discovery of CNV in parative genome hybridization (aCGH) allowed the genome-wide germline DNA, several affected genes were shown to be associated discovery of submicroscopic copy number changes (Ishkanian with disease: CCL3L1 with HIV/AIDS, FCGR3 with glomerulone- et al. 2004). More recently, other approaches have allowed other phritis, DEFB2 with Crohn’s, C4A/C4B with lupus, and PRSS1 with types of SV (e.g., inversions) and polymorphisms to be surveyed. pancreatitis (Gonzalez et al. 2005; Aitman et al. 2006; Fellermann For example, high-density single nucleotide polymorphism (SNP) et al. 2006; Le Marechal et al. 2006; Fanciulli et al. 2007; Yang et al. platforms can allow detection of subsets of SNPs and SVs (Conrad 2007). CNV also provides material and mechanism for creating et al. 2006; McCarroll et al. 2006). Most recently, paired end new genes. CNV thus accounts for a great deal of the genetic approaches have evolved to yield massive numbers of new SVs at variation in animals and humans. For example, it was recently ultra-high resolution (although requiring significant cost and ef- shown that the CNV landscape in flies is under natural selection fort) (Tuzun et al. 2005; Korbel et al. 2007). (Emerson et al. 2008). Little is known about CNV in mammalian Many human CNVs appear to be old because they are in evolution, as only Euarchontoglires—the clade of primates and linkage disequilibrium with nearby genetic markers (Hinds et al. rodents—has been surveyed for CNV. 2006). Others are recent or recurrent. Notably, CNVs are enriched Dogs have extraordinary advantages as animal models in regions that are rearrangement hotspots, such as those rich in (Lindblad-Toh et al. 2005): (1) they are numerous, (2) they share segmental duplications (or ‘‘low copy repeats’’) (Sharp et al. 2005). many diseases that are similar to those of humans, (3) they have In humans, more than 5000 CNVs have been identified in normal a greater than fivefold reduced lifespan compared to humans, (4) individuals, and at least several hundred are common in the they often have a high level of health care, and (5) live in an en- population (Redon et al. 2006; Korbel et al. 2007; Wong et al. 2007; vironment that is very similar to that of their owners. Humans are Kidd et al. 2008). Most known CNVs span genes and appear likely more closely related to mice than dogs (divergence times of 80 to affect genetic networks. Thus, while SNPs and point mutations million years ago [Mya] and 90 Mya, respectively). However, dogs are more frequent, CNVs seem more likely to have an impact on share ;650 Mb of ancestral sequence that is absent in mice, and phenotype. CNVs can have various effects, including changes in the sequence divergence rate of dogs is half that of mice (Lindblad- gene expression levels, disruption of gene dosage, unmasking of Toh et al. 2005). This suggests that a subset of human biology is recessive alleles or regulatory polymorphisms, and loss of regula- more similar to that of dogs versus mice. But the main advantage of canine models is their evolutionary history. Largely based on 20 yr of studying dog and pigeon breeding, Darwin (1859) began 4Co-first authors. 5Present address: Department of Chemistry, Vanderbilt University, On the Origin of Species by saying that variation under domestication Station B 351822, Nashville, TN 37235, USA. is the best clue to understanding evolution. He believed that 6 Corresponding author. selection is the most important aspect of evolution, and that it E-mail [email protected]; fax (614) 722-2817. Article published online before print. Article and publication date are at is exaggerated in domestication. In many cases, it also offers http://www.genome.org/cgi/doi/10.1101/gr.083741.108. documentation of parental breeds (or subspecies), of the selection 19:00–00 Ó2009 by Cold Spring Harbor Laboratory Press; ISSN 1088-9051/09; www.genome.org Genome Research 1 www.genome.org Downloaded from genome.cshlp.org on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press Chen et al. began our study by conducting aCGH on the well-characterized OSW T-cell lymphoma cell line from an Airedale Terrier (Kisseberth et al. 2007; Supplemental Table S1). The aCGH reference DNA for this hybridization—and for all others reported here—was from a pedigreed Boxer. Notably, OSW was previously analyzed on a low resolution BAC array, and several copy number alterations were validated (Kisseberth et al. 2007). Each spot of such BAC arrays is comprised of many fragments 0.5–2 kb in size, but our spots cor- respond to single unique-sequence oligos. We thus consider these two platforms to cross-validate each other (as essentially different methodologies). This comparison also confirmed the mapping of the arrayed oligos. (In depth analysis and discussion of the exten- sive copy number alteration present in this single lymphoma cell line are outside the scope of this work, and will be included in a second publication.) Figure 1 compares the linearized whole ge- nome karyogram of OSW to that of a normal dog (Rottweiler), and shows a close up of all of chr 11. There is very strong correlation between the published low resolution BAC aCGH results and our largest alterations. This is most apparent for the copy number gain of nearly all of chr 13 and the one copy loss of almost all of chr 22 (cf. Fig. 1 in this study with Fig. 3 of Kisseberth et al. 2007). Figure 1. Whole-genome DNA copy number quantification of the OSW Kisseberth et al. (2007) additionally confirmed the DNA copy dog lymphoma cell line by aCGH. DNA was cohybridized with a reference number changes of four genes within alterations detected in both pedigreed Boxer (in two colors) to an oligo array with <5 kb mean studies (P16, MYC, RB1, PTEN). Beyond validating our methods, we spacing. Copy number is shown as log2 ratios, with gains above the also identified alterations previously implicated in canine lym- midline and losses below. The top panel shows the linearized whole- phoma, such as the whole chromosome amplification of chr 13 genome copy number of a normal Rottweiler and the middle panel that of OSW. (There is no Y chromosome data, and the last segment before the (containing MYC) and loss of chr 11 and regions of chr 22 (con- X is the unmapped genome assembly.) Note the complete or nearly taining RB1) and chr 26 (containing PTEN) (Hahn et al. 1994; complete gain of chr 13 and losses of chr 22 and chr 32. The bottom Thomas et al. 2003; Modiano et al. 2007). The copy number alter- panel shows all of OSW chr 11, with seven large single-copy losses and ation of some of those regions/genes, and others, are known to be one small two-copy loss. The P16 tumor suppressor gene lies within the two-copy loss region. associated with human lymphoma (e.g., P16 loss and MYC gain). Finally, we also identified novel candidate cancer genes (e.g., see SLITRK1 below).
Load more

Recommended publications
  • Old Data and Friends Improve with Age: Advancements with the Updated Tools of Genenetwork
    bioRxiv preprint doi: https://doi.org/10.1101/2021.05.24.445383; this version posted May 25, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Old data and friends improve with age: Advancements with the updated tools of GeneNetwork Alisha Chunduri1, David G. Ashbrook2 1Department of Biotechnology, Chaitanya Bharathi Institute of Technology, Hyderabad 500075, India 2Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA Abstract Understanding gene-by-environment interactions is important across biology, particularly behaviour. Families of isogenic strains are excellently placed, as the same genome can be tested in multiple environments. The BXD’s recent expansion to 140 strains makes them the largest family of murine isogenic genomes, and therefore give great power to detect QTL. Indefinite reproducible genometypes can be leveraged; old data can be reanalysed with emerging tools to produce novel biological insights. To highlight the importance of reanalyses, we obtained drug- and behavioural-phenotypes from Philip et al. 2010, and reanalysed their data with new genotypes from sequencing, and new models (GEMMA and R/qtl2). We discover QTL on chromosomes 3, 5, 9, 11, and 14, not found in the original study. We narrowed down the candidate genes based on their ability to alter gene expression and/or protein function, using cis-eQTL analysis, and variants predicted to be deleterious. Co-expression analysis (‘gene friends’) and human PheWAS were used to further narrow candidates.
    [Show full text]
  • Slitrks Control Excitatory and Inhibitory Synapse Formation with LAR
    Slitrks control excitatory and inhibitory synapse SEE COMMENTARY formation with LAR receptor protein tyrosine phosphatases Yeong Shin Yima,1, Younghee Kwonb,1, Jungyong Namc, Hong In Yoona, Kangduk Leeb, Dong Goo Kima, Eunjoon Kimc, Chul Hoon Kima,2, and Jaewon Kob,2 aDepartment of Pharmacology, Brain Research Institute, Brain Korea 21 Project for Medical Science, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 120-752, Korea; bDepartment of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea; and cCenter for Synaptic Brain Dysfunctions, Institute for Basic Science, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea Edited by Thomas C. Südhof, Stanford University School of Medicine, Stanford, CA, and approved December 26, 2012 (received for review June 11, 2012) The balance between excitatory and inhibitory synaptic inputs, share a similar domain organization comprising three Ig domains which is governed by multiple synapse organizers, controls neural and four to eight fibronectin type III repeats. LAR-RPTP family circuit functions and behaviors. Slit- and Trk-like proteins (Slitrks) are members are evolutionarily conserved and are functionally required a family of synapse organizers, whose emerging synaptic roles are for axon guidance and synapse formation (15). Recent studies have incompletely understood. Here, we report that Slitrks are enriched shown that netrin-G ligand-3 (NGL-3), neurotrophin receptor ty- in postsynaptic densities in rat brains. Overexpression of Slitrks rosine kinase C (TrkC), and IL-1 receptor accessory protein-like 1 promoted synapse formation, whereas RNAi-mediated knock- (IL1RAPL1) bind to all three LAR-RPTP family members or dis- down of Slitrks decreased synapse density.
    [Show full text]
  • Novel Candidate Genes of Thyroid Tumourigenesis Identified in Trk-T1 Transgenic Mice
    Endocrine-Related Cancer (2012) 19 409–421 Novel candidate genes of thyroid tumourigenesis identified in Trk-T1 transgenic mice Katrin-Janine Heiliger*, Julia Hess*, Donata Vitagliano1, Paolo Salerno1, Herbert Braselmann, Giuliana Salvatore 2, Clara Ugolini 3, Isolde Summerer 4, Tatjana Bogdanova5, Kristian Unger 6, Gerry Thomas6, Massimo Santoro1 and Horst Zitzelsberger Research Unit of Radiation Cytogenetics, Helmholtz Zentrum Mu¨nchen, Ingolsta¨dter Landstr. 1, 85764 Neuherberg, Germany 1Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Universita` Federico II, Naples 80131, Italy 2Dipartimento di Studi delle Istituzioni e dei Sistemi Territoriali, Universita` ‘Parthenope’, Naples 80133, Italy 3Division of Pathology, Department of Surgery, University of Pisa, 56100 Pisa, Italy 4Institute of Radiation Biology, Helmholtz Zentrum Mu¨nchen, 85764 Neuherberg, Germany 5Institute of Endocrinology and Metabolism, Academy of Medical Sciences of the Ukraine, 254114 Kiev, Ukraine 6Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London W12 0HS, UK (Correspondence should be addressed to H Zitzelsberger; Email: [email protected]) *(K-J Heiliger and J Hess contributed equally to this work) Abstract For an identification of novel candidate genes in thyroid tumourigenesis, we have investigated gene copy number changes in a Trk-T1 transgenic mouse model of thyroid neoplasia. For this aim, 30 thyroid tumours from Trk-T1 transgenics were investigated by comparative genomic hybridisation. Recurrent gene copy number alterations were identified and genes located in the altered chromosomal regions were analysed by Gene Ontology term enrichment analysis in order to reveal gene functions potentially associated with thyroid tumourigenesis. In thyroid neoplasms from Trk-T1 mice, a recurrent gain on chromosomal bands 1C4–E2.3 (10.0% of cases), and losses on 3H1–H3 (13.3%), 4D2.3–E2 (43.3%) and 14E4–E5 (6.7%) were identified.
    [Show full text]
  • Investigating Seven Recently Identified Genes in 100 Iranian Families with Autosomal Recessive Non-Syndromic Hearing Loss
    Iranian Rehabilitation Journal, Vol. 13, Issue 3, Autumn 2015 Original Article Investigating Seven Recently Identified Genes in 100 Iranian Families with Autosomal Recessive Non-syndromic Hearing Loss Reihaneh Hadji Alikhani; Fatemeh Ostaresh; Mojgan Babanejad Nilofar Bazazzadegan; Hossein Najmabadi*; Kimia Kahrizi Genetic Research Center University of Social Welfare and Rehabilitation Sciences, Tehran, Iran Objectives: Hearing loss (HL) is the most common sensory disorder, and affects 1 in 1000 newborns. About 50% of HL is due to genetics and 70% of them are non-syndromic with a recessive pattern of inheritance. Up to now, more than 50 genes have been detected which are responsible for autosomal recessive non-syndromic hearing loss, (ARNSHL). In Iran, HL is one of the most common disabilities due to consanguineous marriages. The aim was to investigate the prevalence of three new ARHL genes (GJB4, GJC3, and SLITRK6) reported in neighboring countries among Iranian families with ARNSHL. Methods: One hundred unrelated families with at least two affected siblings in consanguineous marriage, who were negative for GJB2 gene mutations, were selected. By using three STR markers for each gene, homozygosity mapping was performed. Results: Two families showed linkage to GJB4, six families were linked to GJC3 and only one family linked to SLITRK6. The samples of these families who showed linkage were sent for Sanger sequencing to detect the causative mutations. However, after analyzing the sequencing results, no mutation could be detected in either of the families. Molecular analysis for these nine families is underway in order to determine the pathogenic mutations using whole exome sequencing. Discussion: These data demonstrate a very low prevalence of mutation in these three genes (GJB4, GJC3, and SLITRK6) in the Iranian population, since no mutation was detected in our study group of 100 families.
    [Show full text]
  • Viewed and Published Immediately Upon Acceptance Cited in Pubmed and Archived on Pubmed Central Yours — You Keep the Copyright
    BMC Genomics BioMed Central Research article Open Access Differential gene expression in ADAM10 and mutant ADAM10 transgenic mice Claudia Prinzen1, Dietrich Trümbach2, Wolfgang Wurst2, Kristina Endres1, Rolf Postina1 and Falk Fahrenholz*1 Address: 1Johannes Gutenberg-University, Institute of Biochemistry, Mainz, Johann-Joachim-Becherweg 30, 55128 Mainz, Germany and 2Helmholtz Zentrum München – German Research Center for Environmental Health, Institute for Developmental Genetics, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany Email: Claudia Prinzen - [email protected]; Dietrich Trümbach - [email protected]; Wolfgang Wurst - [email protected]; Kristina Endres - [email protected]; Rolf Postina - [email protected]; Falk Fahrenholz* - [email protected] * Corresponding author Published: 5 February 2009 Received: 19 June 2008 Accepted: 5 February 2009 BMC Genomics 2009, 10:66 doi:10.1186/1471-2164-10-66 This article is available from: http://www.biomedcentral.com/1471-2164/10/66 © 2009 Prinzen et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: In a transgenic mouse model of Alzheimer disease (AD), cleavage of the amyloid precursor protein (APP) by the α-secretase ADAM10 prevented amyloid plaque formation, and alleviated cognitive deficits. Furthermore, ADAM10 overexpression increased the cortical synaptogenesis. These results suggest that upregulation of ADAM10 in the brain has beneficial effects on AD pathology. Results: To assess the influence of ADAM10 on the gene expression profile in the brain, we performed a microarray analysis using RNA isolated from brains of five months old mice overexpressing either the α-secretase ADAM10, or a dominant-negative mutant (dn) of this enzyme.
    [Show full text]
  • Identification of Novel Genes in Human Airway Epithelial Cells Associated with Chronic Obstructive Pulmonary Disease (COPD) Usin
    www.nature.com/scientificreports OPEN Identifcation of Novel Genes in Human Airway Epithelial Cells associated with Chronic Obstructive Received: 6 July 2018 Accepted: 7 October 2018 Pulmonary Disease (COPD) using Published: xx xx xxxx Machine-Based Learning Algorithms Shayan Mostafaei1, Anoshirvan Kazemnejad1, Sadegh Azimzadeh Jamalkandi2, Soroush Amirhashchi 3, Seamas C. Donnelly4,5, Michelle E. Armstrong4 & Mohammad Doroudian4 The aim of this project was to identify candidate novel therapeutic targets to facilitate the treatment of COPD using machine-based learning (ML) algorithms and penalized regression models. In this study, 59 healthy smokers, 53 healthy non-smokers and 21 COPD smokers (9 GOLD stage I and 12 GOLD stage II) were included (n = 133). 20,097 probes were generated from a small airway epithelium (SAE) microarray dataset obtained from these subjects previously. Subsequently, the association between gene expression levels and smoking and COPD, respectively, was assessed using: AdaBoost Classifcation Trees, Decision Tree, Gradient Boosting Machines, Naive Bayes, Neural Network, Random Forest, Support Vector Machine and adaptive LASSO, Elastic-Net, and Ridge logistic regression analyses. Using this methodology, we identifed 44 candidate genes, 27 of these genes had been previously been reported as important factors in the pathogenesis of COPD or regulation of lung function. Here, we also identifed 17 genes, which have not been previously identifed to be associated with the pathogenesis of COPD or the regulation of lung function. The most signifcantly regulated of these genes included: PRKAR2B, GAD1, LINC00930 and SLITRK6. These novel genes may provide the basis for the future development of novel therapeutics in COPD and its associated morbidities.
    [Show full text]
  • Supplemental Figure and Table Legends
    Supplemental figure and table legends Supplementary Figure 1: KIAA1841 is well conserved among vertebrates. NCBI HomoloGene pairwise alignment scores of human KIAA1841 sequence compared to other vertebrate orthologs. Supplementary Figure 2: µ-germline transcripts (GLT) and AID mRNA expression are not affected by overexpression of KIAA1841. Splenic B cells were isolated from wild-type mice, and transduced with retroviral vector control (pMIG) or a vector expressing KIAA1841. Levels of µ-GLT and AID mRNA were determined at 72h post-infection by RT-qPCR, and normalized to -actin mRNA and the pMIG control. The mean of three independent experiments +/- SD is shown. NS, p = not significant, p 0.05, two-tailed paired student’s t-test. Supplementary Figure 3: Overexpression of untagged and Xpress-tagged KIAA1841 does not affect cell proliferation. Splenic B cells were isolated from wild-type mice, stimulated with LPS+IL4, and transduced with retroviral vector control (pMIG) or a vector expressing KIAA1841 or Xpress (Xp)-tagged KIAA1841. Cells are labeled with seminaphthorhodafluor (SNARF) cell tracking dye and SNARF intensity was measured at 0h, 24h, and 48h after retroviral infection. Histograms of transduced cells (GFP+) for pMIG control, KIAA1841 and Xp-KIAA1841 were superimposed at each time point. Three independent retroviral infection experiments are shown. Supplementary Figure 4: Sequence alignment of the putative SANT domain of KIAA1841 with the SANT domain of SWI3. Alignment was performed using ClustalOmega; *, conserved residue, :, strongly similar residues, ., weakly similar residues. Numbers indicate amino acid residues in each sequence. Helix 3, which has been reported to be important for the chromatin remodeling function of SWI3 (Boyer et.
    [Show full text]
  • Taqman® Human Protein Kinase Array
    TaqMan® Gene Signature Arrays TaqMan® Human Protein Kinase Array This array is part of a collection of TaqMan® Gene Signature these kinases are from receptor protein-tyrosine kinase (RPTK) Arrays that enable analysis of hundreds of TaqMan® Gene families: EGFR, InsulinR, PDGFR, VEGFR, FGFR, CCK, NGFR, Expression Assays on a micro fluidic card with minimal effort. HGFR, EPHR, AXL, TIE, RYK, DDR, RET, ROS, LTK, ROR and MUSK. The remaining 15 kinases are Ser/Thr kinases from the Protein kinases are one of the largest families of genes in kinase families: CAMKL, IRAK, Lmr, RIPK and STKR. eukaryotes. They belong to one superfamily containing a eukaryotic protein kinase catalytic domain. The ability of kinases We have also selected assays for 26 non-kinase genes in the to reversibly phosphorylate and regulate protein function Human Protein Kinase Array. These genes are involved in signal has been a subject of intense investigation. Kinases are transduction and mediate protein-protein interaction, transcrip- responsible for most of the signal transduction in eukaryotic tional regulation, neural development and cell adhesion. cells, affecting cellular processes including metabolism, References: angiogenesis, hemopoiesis, apoptosis, transcription and Manning, G., Whyte, D.B., Martinez, R., Hunter, T., and differentiation. Protein kinases are also involved in functioning Sudarsanam, S. 2002. The Protein Kinase Complement of the of the nervous and immune systems, in physiologic responses Human Genome. Science 298:1912–34. and in development. Imbalances in signal transduction due to accumulation of mutations or genetic alterations have Blume-Jensen, P. and Hunter, T. 2001. Oncogenic kinase been shown to result in malignant transformation.
    [Show full text]
  • Prediction of Human Disease Genes by Human-Mouse Conserved Coexpression Analysis
    Prediction of Human Disease Genes by Human-Mouse Conserved Coexpression Analysis Ugo Ala1., Rosario Michael Piro1., Elena Grassi1, Christian Damasco1, Lorenzo Silengo1, Martin Oti2, Paolo Provero1*, Ferdinando Di Cunto1* 1 Molecular Biotechnology Center, Department of Genetics, Biology and Biochemistry, University of Turin, Turin, Italy, 2 Department of Human Genetics and Centre for Molecular and Biomolecular Informatics, University Medical Centre Nijmegen, Nijmegen, The Netherlands Abstract Background: Even in the post-genomic era, the identification of candidate genes within loci associated with human genetic diseases is a very demanding task, because the critical region may typically contain hundreds of positional candidates. Since genes implicated in similar phenotypes tend to share very similar expression profiles, high throughput gene expression data may represent a very important resource to identify the best candidates for sequencing. However, so far, gene coexpression has not been used very successfully to prioritize positional candidates. Methodology/Principal Findings: We show that it is possible to reliably identify disease-relevant relationships among genes from massive microarray datasets by concentrating only on genes sharing similar expression profiles in both human and mouse. Moreover, we show systematically that the integration of human-mouse conserved coexpression with a phenotype similarity map allows the efficient identification of disease genes in large genomic regions. Finally, using this approach on 850 OMIM loci characterized by an unknown molecular basis, we propose high-probability candidates for 81 genetic diseases. Conclusion: Our results demonstrate that conserved coexpression, even at the human-mouse phylogenetic distance, represents a very strong criterion to predict disease-relevant relationships among human genes. Citation: Ala U, Piro RM, Grassi E, Damasco C, Silengo L, et al.
    [Show full text]
  • SLITRK6 Mutations Cause Myopia and Deafness in Humans and Mice
    SLITRK6 mutations cause myopia and deafness in humans and mice Mustafa Tekin, … , Jun Aruga, Andrew H. Crosby J Clin Invest. 2013;123(5):2094-2102. https://doi.org/10.1172/JCI65853. Research Article Ophthalmology Myopia is by far the most common human eye disorder that is known to have a clear, albeit poorly defined, heritable component. In this study, we describe an autosomal-recessive syndrome characterized by high myopia and sensorineural deafness. Our molecular investigation in 3 families led to the identification of 3 homozygous nonsense mutations (p.R181X, p.S297X, and p.Q414X) in SLIT and NTRK-like family, member 6 (SLITRK6), a leucine-rich repeat domain transmembrane protein. All 3 mutant SLITRK6 proteins displayed defective cell surface localization. High-resolution MRI of WT and Slitrk6-deficient mouse eyes revealed axial length increase in the mutant (the endophenotype of myopia). Additionally, mutant mice exhibited auditory function deficits that mirrored the human phenotype. Histological investigation of WT and Slitrk6-deficient mouse retinas in postnatal development indicated a delay in synaptogenesis inS litrk6-deficient animals. Taken together, our results showed that SLITRK6 plays a crucial role in the development of normal hearing as well as vision in humans and in mice and that its disruption leads to a syndrome characterized by severe myopia and deafness. Find the latest version: https://jci.me/65853/pdf Research article SLITRK6 mutations cause myopia and deafness in humans and mice Mustafa Tekin,1,2 Barry A. Chioza,3 Yoshifumi Matsumoto,4 Oscar Diaz-Horta,1 Harold E. Cross,5 Duygu Duman,2 Haris Kokotas,6 Heather L.
    [Show full text]
  • Heterogeneity Between Primary Colon Carcinoma and Paired Lymphatic and Hepatic Metastases
    MOLECULAR MEDICINE REPORTS 6: 1057-1068, 2012 Heterogeneity between primary colon carcinoma and paired lymphatic and hepatic metastases HUANRONG LAN1, KETAO JIN2,3, BOJIAN XIE4, NA HAN5, BINBIN CUI2, FEILIN CAO2 and LISONG TENG3 Departments of 1Gynecology and Obstetrics, and 2Surgical Oncology, Taizhou Hospital, Wenzhou Medical College, Linhai, Zhejiang; 3Department of Surgical Oncology, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang; 4Department of Surgical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang; 5Cancer Chemotherapy Center, Zhejiang Cancer Hospital, Zhejiang University of Chinese Medicine, Hangzhou, Zhejiang, P.R. China Received January 26, 2012; Accepted May 8, 2012 DOI: 10.3892/mmr.2012.1051 Abstract. Heterogeneity is one of the recognized characteris- Introduction tics of human tumors, and occurs on multiple levels in a wide range of tumors. A number of studies have focused on the Intratumor heterogeneity is one of the recognized charac- heterogeneity found in primary tumors and related metastases teristics of human tumors, which occurs on multiple levels, with the consideration that the evaluation of metastatic rather including genetic, protein and macroscopic, in a wide range than primary sites could be of clinical relevance. Numerous of tumors, including breast, colorectal cancer (CRC), non- studies have demonstrated particularly high rates of hetero- small cell lung cancer (NSCLC), prostate, ovarian, pancreatic, geneity between primary colorectal tumors and their paired gastric, brain and renal clear cell carcinoma (1). Over the past lymphatic and hepatic metastases. It has also been proposed decade, a number of studies have focused on the heterogeneity that the heterogeneity between primary colon carcinomas and found in primary tumors and related metastases with the their paired lymphatic and hepatic metastases may result in consideration that the evaluation of metastatic rather than different responses to anticancer therapies.
    [Show full text]
  • Results to Test Classic Anthropological Hypotheses: Human Third Molar Agenesis and the ‘Probable Mutation Effect’ Alexis Sullivan [email protected]
    Wayne State University Human Biology Open Access Pre-Prints WSU Press 9-1-2016 Extending genome-wide association study (GWAS) results to test classic anthropological hypotheses: Human third molar agenesis and the ‘probable mutation effect’ Alexis Sullivan [email protected] Adrijana Vukelic [email protected] Jacob Cohen [email protected] George (PJ) Perry Pennsylvania State University, [email protected] Recommended Citation Sullivan, Alexis; Vukelic, Adrijana; Cohen, Jacob; and Perry, George (PJ), "Extending genome-wide association study (GWAS) results to test classic anthropological hypotheses: Human third molar agenesis and the ‘probable mutation effect’" (2016). Human Biology Open Access Pre-Prints. 116. http://digitalcommons.wayne.edu/humbiol_preprints/116 This Open Access Preprint is brought to you for free and open access by the WSU Press at DigitalCommons@WayneState. It has been accepted for inclusion in Human Biology Open Access Pre-Prints by an authorized administrator of DigitalCommons@WayneState. Invited Commentary Extending genome-wide association study (GWAS) results to test classic anthropological hypotheses: Human third molar agenesis and the ‘probable mutation effect’ Adrijana Vukelic1,2, Jacob A. Cohen2, Alexis P. Sullivan2, George H. Perry1,2 1 Department of Anthropology, Pennsylvania State University, University Park, PA 16802 2 Department of Biology, Pennsylvania State University, University Park, PA 16802 Date Submitted: May 10 2016 Date Accepted: Feb 24 2017 Running title: Human M3 agenesis evolutionary genetics Keywords: Anthropometric traits; evolutionary genomics; Human dental formula evolution; wisdom tooth Corresponding author: George H. Perry 513 Carpenter Building Pennsylvania State University University Park, PA 16802 USA E-mail: [email protected] Phone: +1-814-863-7654 Pre-print version.
    [Show full text]