DOCSLIB.ORG

A Genome-Wide Association Study Identifies Genetic Variants

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Genome-Wide Association Study Identifies Genetic Variants www.nature.com/scientificreports OPEN A Genome-Wide Association Study Identifies Genetic Variants Associated with Mathematics Received: 16 May 2016 Accepted: 06 December 2016 Ability Published: 03 February 2017 Huan Chen1,2,*, Xiao-hong Gu3,*, Yuxi Zhou4,5,*, Zeng Ge4,5,*, Bin Wang4,5, Wai Ting Siok6, Guoqing Wang4,5, Michael Huen7, Yuyang Jiang8, Li-Hai Tan1,9 & Yimin Sun4,5,8,10 Mathematics ability is a complex cognitive trait with polygenic heritability. Genome-wide association study (GWAS) has been an effective approach to investigate genetic components underlying mathematic ability. Although previous studies reported several candidate genetic variants, none of them exceeded genome-wide significant threshold in general populations. Herein, we performed GWAS in Chinese elementary school students to identify potential genetic variants associated with mathematics ability. The discovery stage included 494 and 504 individuals from two independent cohorts respectively. The replication stage included another cohort of 599 individuals. In total, 28 of 81 candidate SNPs that met validation criteria were further replicated. Combined meta-analysis of three cohorts identified four SNPs (rs1012694, rs11743006, rs17778739 and rs17777541) ofSPOCK1 gene showing association with mathematics ability (minimum p value 5.67 × 10−10, maximum β −2.43). The SPOCK1 gene is located on chromosome 5q31.2 and encodes a highly conserved glycoprotein testican-1 which was associated with tumor progression and prognosis as well as neurogenesis. This is the first study to report genome-wide significant association of individual SNPs with mathematics ability in general populations. Our preliminary results further supported the role of SPOCK1 during neurodevelopment. The genetic complexities underlying mathematics ability might contribute to explain the basis of human cognition and intelligence at genetic level. Mathematics serves as a fundamental instrument in modern society as it plays an important role in many fields including science, engineering, and economics. It also used as a key index of human intelligence. Exceptional mathematics ability was frequently observed among genius from many domains. Meanwhile, dyscalculia, char- acterized by impaired number processing skills, is a specific developmental disorder of mathematics ability that affects approximately 3 to 6% of children1. Childhood mathematics ability was associated with adult socioeco- nomic status and quality of life2. Understanding mathematics ability is an essential step to improve children’s numeracy skills and academic achievements and could also provide novel insights into human brain functions. Mathematics ability is a complex trait that involves neurological and cognitive development as well as postnatal education and training. In particular, it is estimated that considerable proportion of variation in mathematic ability could be explained by genetic factors. 1Center for Neurogenetics, Shenzhen Institute of Neuroscience, Shenzhen, 518057, China. 2State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, 102206, China. 3Department of Healthy Management, Research Institute of Surgery, DaPing Hospital, Third Military Medical University, Chongqing, 400042, China. 4CapitalBio eHealth Science & Technology (Beijing) Co., Ltd., Beijing, 102206, China. 5National Engineering Research Center for Beijing Biochip Technology, Beijing, 102206, China. 6Department of Linguistics, The University of Hong Kong, Hong Kong, China. 7Department of Anatomy, The University of Hong Kong, Hong Kong, China. 8The State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen, 518055, China. 9School of Biomedical Engineering, Shenzhen University Health Science Center, Shenzhen, 518060, China. 10Department of Biomedical Engineering, Medical Systems Biology Research Center, Tsinghua University School of Medicine, Beijing, 100084, China. *These authors contributed equally to this work. Correspondence and requests for materials should be addressed to L.H.T. (email: [email protected]) or Y.S. (email: [email protected]) SCIENTIFIC REPORTS | 7:40365 | DOI: 10.1038/srep40365 1 www.nature.com/scientificreports/ GWAS Liangshan Dongming Replication Cao Variables (n = 494) (n = 504) (n = 599) Grade 2 98 (19.84) 98 (19.44) 121 (20.20) 3 103 (20.85) 101 (20.04) 134 (22.37) 4 122 (24.70) 102 (20.24) 136 (22.70) 5 82 (16.60) 99 (19.64) 108 (18.03) 6 89 (18.02) 104 (20.63) 100 (16.69) Sex Male 213 (43.12) 202 (40.08) 283 (47.25) Female 281 (56.88) 302 (59.92) 316 (52.75) Age, year 9.79 ± 1.39 9.51 ± 1.44 9.40 ± 1.45 Math score* 97 (93,99) 91 (83, 95) 95 (89,98) Table 1. Basic characteristics of three populations. *Full score is 100. Data are expressed as number of participants (percentage), mean ±​ SD or median (Q1, Q3). Math score* <80 80–90 ≥90 P value Grade 2 12 (6.22) 35 (12.15) 275 (24.64) 3 38 (19.69) 91 (31.60) 221 (19.80) 4 44 (22.80) 47 (16.32) 261 (23.39) < 0.001 5 43 (22.28) 70 (24.31) 172 (15.41) 6 56 (29.02) 45 (15.63) 187 (16.76) Sex Male 77 (39.90) 125 (43.40) 506 (45.34) 0.28 Female 116 (60.10) 163 (56.60) 610 (54.66) Region Liangshan 16 (8.29) 49 (17.01) 429 (38.44) Dongming 92 (47.67) 149 (51.74) 263 (23.57) < 0.001 Cao 85 (44.04) 90 (31.25) 424 (37.99) Raven score** 45.76 ± 5.63 45.13 ± 5.75 46.69 ± 5.67 < 0.001 Table 2. Breakdown of math score in all participants. Data are expressed as number of participants (percentage) or mean ± SD. *Full math score is 100. **Full Raven score is 60. Recent years, genome-wide association study (GWAS) has been widely applied to investigate genetic com- ponents underlying complex traits3. The first GWAS of mathematics ability was performed among children with high and low mathematics ability respectively and nominated top-performing SNPs for subsequent validation in a large sample of individuals spanning the entire distribution of mathematical ability4. The study did not observe any SNPs alone showing genome-wide significant association with mathematic ability but hypothesized that genetic contribution to mathematics ability might be explained by multiple quantitative trait locus (QTLs) of small effect4. Indeed, the top 10 candidate SNPs only accounted for 2.9% of phenotypic variance in mathematics ability4. The second GWAS of mathematics ability used children’s verbal ability as control and then divided them into groups of high and low mathematic ability5. Candidate SNPs from the discovery stage were individually genotyped for validation but none of them exceeded threshold of genome-wide significance5. In the meantime, another GWAS in monozygotic and dizygotic twin pairs also observed a number of SNPs showing signals of asso- ciations with mathematic ability, but none of them achieved genome-wide significant level6. To date, none of studies has identified genome-wide significant association with mathematics ability in general populations due to small effects of common variants. However, research with specific populations might increase statistical power to detect significant association as it was reported that prevalence of mathematic disability was higher among children with neurodevelopmental disorders such as reading disability, attention-deficit/hyperac- tivity disorder (ADHD) and autism7,8. The GWAS performed in German dyslexic children identified rs133885 as a genome-wide significant SNP associated with mathematics ability9. This variant is a coding variant of MYO18B and is associated with intraparietal sulcus morphology9. However, a recent replication study of rs133885 failed to find its association with mathematics ability in either dyslexic or general populations10. Previous GWAS of mathematic ability is mainly performed in Western populations of which genetic back- grounds are substantially different to Chinese populations. In the present study, we performed GWAS of mathe- matic ability in the Han Chinese elementary school students through QTL-based approach. In total, we identified SCIENTIFIC REPORTS | 7:40365 | DOI: 10.1038/srep40365 2 www.nature.com/scientificreports/ Figure 1. Manhattan plot of –log10 (P values) of meta-analysis result from the additive model after adjustment for sex, age, school and nominal significant principal components in GWAS in Liangshan and Dongming population. The genome-wide threshold for significant (P =​ 5 ×​ 10−8) and suggestive (P =​ 1 ×​ 10−5) association are indicated by the horizontal blue and red lines, respectively. 81 SNPs in meta-analysis had P value <​ 1 ×​ 10−5, of which 28 met the criteria for further replication. The symbol for the gene where the significant SNPs are in combined meta-analysis is shown in italics. four SNPs exceeding genome-wide significant threshold which is the first time to report genome-wide significant association of individual SNPs with mathematics ability in general populations. Our results provide novel evi- dence to explain genetic complexities underlying mathematic ability and the basis of human intelligence at the genetic level. Results In the initial discovery phase, we performed a GWAS scan in two cohorts of Liangshan and Dongming (Supplementary Figure S1; Table 1). Breakdown of math scores according to grades, sex and regions of all par- ticipants were presented in Table 2. After quality control, about 1.1 million autosomal SNPs were analyzed (see Methods) in 998 samples (494 from the Liangshan cohort and 504 from the Dongming cohort). We per- formed linear regression in each cohort with adjustment for age, sex, school and top ten significant principal components of the corresponding cohort to test the additive effect of minor alleles of each SNP. In total, 13082 and 11170 SNPs with P-value less than 0.01 were identified in Liangshan and Dongming cohort respectively (Supplementary Figure S2). Results of the two discovery cohorts were combined by meta-analysis and 81 SNPs with P-value less than 1 ×​ 10−5 were identified (Fig. 1). Finally, 28 SNPs met the criteria selection for subsequent replication stage (see Methods; Table 3). The 28 SNPs met the replication criteria were evaluated in an independent cohort (Cao, Table 4).
Load more

Recommended publications
  • PARSANA-DISSERTATION-2020.Pdf
    DECIPHERING TRANSCRIPTIONAL PATTERNS OF GENE REGULATION: A COMPUTATIONAL APPROACH by Princy Parsana A dissertation submitted to The Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland July, 2020 © 2020 Princy Parsana All rights reserved Abstract With rapid advancements in sequencing technology, we now have the ability to sequence the entire human genome, and to quantify expression of tens of thousands of genes from hundreds of individuals. This provides an extraordinary opportunity to learn phenotype relevant genomic patterns that can improve our understanding of molecular and cellular processes underlying a trait. The high dimensional nature of genomic data presents a range of computational and statistical challenges. This dissertation presents a compilation of projects that were driven by the motivation to efficiently capture gene regulatory patterns in the human transcriptome, while addressing statistical and computational challenges that accompany this data. We attempt to address two major difficulties in this domain: a) artifacts and noise in transcriptomic data, andb) limited statistical power. First, we present our work on investigating the effect of artifactual variation in gene expression data and its impact on trans-eQTL discovery. Here we performed an in-depth analysis of diverse pre-recorded covariates and latent confounders to understand their contribution to heterogeneity in gene expression measurements. Next, we discovered 673 trans-eQTLs across 16 human tissues using v6 data from the Genotype Tissue Expression (GTEx) project. Finally, we characterized two trait-associated trans-eQTLs; one in Skeletal Muscle and another in Thyroid. Second, we present a principal component based residualization method to correct gene expression measurements prior to reconstruction of co-expression networks.
    [Show full text]
  • Mouse Spock1 Knockout Project (CRISPR/Cas9)
    https://www.alphaknockout.com Mouse Spock1 Knockout Project (CRISPR/Cas9) Objective: To create a Spock1 knockout Mouse model (C57BL/6J) by CRISPR/Cas-mediated genome engineering. Strategy summary: The Spock1 gene (NCBI Reference Sequence: NM_009262 ; Ensembl: ENSMUSG00000056222 ) is located on Mouse chromosome 13. 12 exons are identified, with the ATG start codon in exon 2 and the TAG stop codon in exon 12 (Transcript: ENSMUST00000185502). Exon 5 will be selected as target site. Cas9 and gRNA will be co-injected into fertilized eggs for KO Mouse production. The pups will be genotyped by PCR followed by sequencing analysis. Note: Mice homozygous for a targeted null mutation display no obvious morphological or behavioral abnormalities, are fertile, and have normal life spans. Adult homozygotes exhibit normal brain morphology and EEG recordings. Exon 5 starts from about 18.25% of the coding region. Exon 5 covers 8.67% of the coding region. The size of effective KO region: ~115 bp. The KO region does not have any other known gene. Page 1 of 8 https://www.alphaknockout.com Overview of the Targeting Strategy Wildtype allele gRNA region 5' gRNA region 3' 1 5 12 Legends Exon of mouse Spock1 Knockout region Page 2 of 8 https://www.alphaknockout.com Overview of the Dot Plot (up) Window size: 15 bp Forward Reverse Complement Sequence 12 Note: The 2000 bp section upstream of Exon 5 is aligned with itself to determine if there are tandem repeats. Tandem repeats are found in the dot plot matrix. The gRNA site is selected outside of these tandem repeats.
    [Show full text]
  • Association Weight Matrix for the Genetic Dissection of Puberty in Beef Cattle
    Association weight matrix for the genetic dissection of puberty in beef cattle Marina R. S. Fortesa,b,c, Antonio Revertera,b, Yuandan Zhanga,d, Eliza Collisa,b, Shivashankar H. Nagarajb,NickN.Jonssona,c,e, Kishore C. Prayagaa,b,1, Wes Barrisa,b, and Rachel J. Hawkena,b,2 aCooperative Research Centre for Beef Genetic Technologies; bCommonwealth Scientific and Industrial Research Organization, division of Livestock Industries, Queensland Bioscience Precinct, Brisbane QLD 4067, Australia; cThe University of Queensland, School of Veterinary Science, Gatton QLD 4343, Australia; dAnimal Genetics and Breeding Unit, University of New England, Armidale NSW 2351, Australia; and eFaculty of Veterinary Medicine, University of Glasgow, Glasgow G61 1QH, United Kingdom Edited by George Seidel, Colorado State University, Fort Collins, CO, and approved June 21, 2010 (received for review February 23, 2010) We describe a systems biology approach for the genetic dissection tional data on traits related to puberty are available. For example, of complex traits based on applying gene network theory to the re- weight and condition score are often measured on occasions sults from genome-wide associations. The associations of single- throughout an animal’s development. Hence, understanding ge- nucleotide polymorphisms (SNP) that were individually associated netics of cattle puberty and its biology serves two purposes: as with a primary phenotype of interest, age at puberty in our study, a strategy to develop efficient livestock resources and as a model were explored across 22 related traits. Genomic regions were sur- for human biology. veyed for genes harboring the selected SNP. As a result, an asso- The focus of this work is to demonstrate a unique systems ap- ciation weight matrix (AWM) was constructed with as many rows proach, which we call an association weight matrix (AWM), ap- as genes and as many columns as traits.
    [Show full text]
  • Downloaded from Refseq Database ( Duct Development (After E7.5), in Which Both Ducts Re
    Roly et al. BMC Genomics (2020) 21:688 https://doi.org/10.1186/s12864-020-07106-8 RESEARCH ARTICLE Open Access Transcriptional landscape of the embryonic chicken Müllerian duct Zahida Yesmin Roly, Rasoul Godini, Martin A. Estermann, Andrew T. Major, Roger Pocock and Craig A. Smith* Abstract Background: Müllerian ducts are paired embryonic tubes that give rise to the female reproductive tract in vertebrates. Many disorders of female reproduction can be attributed to anomalies of Müllerian duct development. However, the molecular genetics of Müllerian duct formation is poorly understood and most disorders of duct development have unknown etiology. In this study, we describe for the first time the transcriptional landscape of the embryonic Müllerian duct, using the chicken embryo as a model system. RNA sequencing was conducted at 1 day intervals during duct formation to identify developmentally-regulated genes, validated by in situ hybridization. Results: This analysis detected hundreds of genes specifically up-regulated during duct morphogenesis. Gene ontology and pathway analysis revealed enrichment for developmental pathways associated with cell adhesion, cell migration and proliferation, ERK and WNT signaling, and, interestingly, axonal guidance. The latter included factors linked to neuronal cell migration or axonal outgrowth, such as Ephrin B2, netrin receptor, SLIT1 and class A semaphorins. A number of transcriptional modules were identified that centred around key hub genes specifying matrix-associated signaling factors; SPOCK1, HTRA3 and ADGRD1. Several novel regulators of the WNT and TFG-β signaling pathway were identified in Müllerian ducts, including APCDD1 and DKK1, BMP3 and TGFBI.A number of novel transcription factors were also identified, including OSR1, FOXE1, PRICKLE1, TSHZ3 and SMARCA2.
    [Show full text]
  • Molecular and Cytogenetic Analysis of the Spreading of X Inactivation in a Girl with Microcephaly, Mild Dysmorphic Features and T(X;5)(Q22.1;Q31.1)
    European Journal of Human Genetics (2008) 16, 897–905 & 2008 Nature Publishing Group All rights reserved 1018-4813/08 $30.00 www.nature.com/ejhg ARTICLE Molecular and cytogenetic analysis of the spreading of X inactivation in a girl with microcephaly, mild dysmorphic features and t(X;5)(q22.1;q31.1) Roberto Giorda*,1,7, M Clara Bonaglia2,7, Greta Milani1, Anna Baroncini3, Francesca Spada3, Silvana Beri1, Giorgia Menozzi4, Marianna Rusconi1 and Orsetta Zuffardi5,6 1Molecular Biology Laboratory, ‘E. Medea’ Scientific Institute, Bosisio Parini, Lecco, Italy; 2Cytogenetics Laboratory, ‘E. Medea’ Scientific Institute, Bosisio Parini, Lecco, Italy; 3UO Genetica Medica, AUSL Imola, Imola, Italy; 4Bioinformatic Laboratory, ‘E. Medea’ Scientific Institute, Bosisio Parini, Lecco, Italy; 5Biologia Generale e Genetica Medica, Universita` di Pavia, Pavia, Italy; 6IRCCS Policlinico San Matteo, Pavia, Italy X chromosome inactivation involves initiation, propagation, and maintenance of gene inactivation. Studies of replication pattern and timing in X;autosome translocations have suggested that X inactivation may spread to autosomal DNA. To examine this phenomenon at the molecular level, we have tested the transcriptional activity of a number of chromosome 5 loci in a female subject with microcephaly, mild dysmorphic features and 46,X,der(X)t(X;5)(q22.1;q31.1) karyotype. RT-PCR analysis of 20 transcribed sequences spanning 5q31.1-qter revealed that nine of them were not expressed in somatic cell hybrid clones carrying the translocated chromosome. However, eight genes were expressed and therefore escaped inactivation. This direct expression test demonstrates that spreading of inactivation from the X chromosome to the adjoining autosomal DNA was incomplete and ‘patchy’.
    [Show full text]
  • View Board for Human Subjects Research
    BMC Medical Genetics BioMed Central G4Research article Open Access Expression profiling of clonal lymphocyte cell cultures from Rett syndrome patients Ivan J Delgado1,4, Dong Sun Kim1,5, Karen N Thatcher2, Janine M LaSalle2 and Ignatia B Van den Veyver*1,3 Address: 1Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX, USA, 2Medical Microbiology and Immunology and Rowe Program in Human Genetics, School of Medicine, University of California, Davis, CA, USA, 3Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA, 4Senior Scientist, Identigene Inc., 5615 Kirby, Suite 800 Houston, TX 77005, USA and 5Assistant Professor, Department of Anatomy, School of Medicine, Kyungpook National University, South Korea Email: Ivan J Delgado - [email protected]; Dong Sun Kim - [email protected]; Karen N Thatcher - [email protected]; Janine M LaSalle - [email protected]; Ignatia B Van den Veyver* - [email protected] * Corresponding author Published: 21 July 2006 Received: 25 October 2005 Accepted: 21 July 2006 BMC Medical Genetics 2006, 7:61 doi:10.1186/1471-2350-7-61 This article is available from: http://www.biomedcentral.com/1471-2350/7/61 © 2006 Delgado 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: More than 85% of Rett syndrome (RTT) patients have heterozygous mutations in the X-linked MECP2 gene which encodes methyl-CpG-binding protein 2, a transcriptional repressor that binds methylated CpG sites.
    [Show full text]
  • NIH Public Access Author Manuscript Neuroscience
    NIH Public Access Author Manuscript Neuroscience. Author manuscript; available in PMC 2008 May 9. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Neuroscience. 2007 November 9; 149(3): 561±572. Mesencephalic Dopamine Neuron Number and Tyrosine Hydroxylase Content: Genetic Control and Candidate Genes Csaba Vadasz1,4, John F. Smiley2, Khadija Figarsky1,2, Mariko Saito1,4, Reka Toth1, Beatrix M. Gyetvai1, Melinda Oros1, Krisztina K. Kovacs1, Panaiyur Mohan3, and Ray Wang1 1Laboratory of Neurobehavior Genetics, Nathan Kline Institute, Office of Mental Health, State of New York, Orangeburg, NY 10962 2Laboratory of Neuroanatomy, Nathan Kline Institute, Office of Mental Health, State of New York, Orangeburg, NY 10962 3Center for Dementia Research, Nathan Kline Institute, Office of Mental Health, State of New York, Orangeburg, NY 10962 4Department of Psychiatry, New York University, School of Medicine, New York, NY 10055 Abstract The mesotelencephalic dopamine system shows substantial genetic variation which fundamentally affects normal and pathological behaviors related to motor function, motivation, and learning. Our earlier radioenzyme assay studies demonstrated significantly higher activity of tyrosine hydroxylase (TH), the first and rate limiting enzyme in the biosynthesis of catecholamine neurotransmitters, in the substantia nigra – ventral tegmental area of BALB/cJ mice in comparison with that of C57BL/ 6ByJ mice. Here, using quantitative immunoblotting and immunocytochemistry, we tested the hypothesis that mesencephalic TH protein content and number of nigral TH-positive neurons show strain-dependent differences in C57BL/6ByJ and BALB/cJ parallel to those observed in the TH activity studies. Immunoblotting experiments detected significantly higher mesencephalic TH protein content in BALB/cJ in comparison to C57BL/6ByJ (p<0.05).
    [Show full text]
  • Fine Mapping of a Linkage Peak with Integration of Lipid Traits Identifies
    Nolan et al. BMC Genetics 2012, 13:12 http://www.biomedcentral.com/1471-2156/13/12 RESEARCHARTICLE Open Access Fine mapping of a linkage peak with integration of lipid traits identifies novel coronary artery disease genes on chromosome 5 Daniel K Nolan1, Beth Sutton1, Carol Haynes1, Jessica Johnson1, Jacqueline Sebek1, Elaine Dowdy1, David Crosslin1, David Crossman4, Michael H Sketch Jr2, Christopher B Granger2, David Seo3, Pascal Goldschmidt-Clermont3, William E Kraus2, Simon G Gregory1,2, Elizabeth R Hauser1,2 and Svati H Shah1,2* Abstract Background: Coronary artery disease (CAD), and one of its intermediate risk factors, dyslipidemia, possess a demonstrable genetic component, although the genetic architecture is incompletely defined. We previously reported a linkage peak on chromosome 5q31-33 for early-onset CAD where the strength of evidence for linkage was increased in families with higher mean low density lipoprotein-cholesterol (LDL-C). Therefore, we sought to fine-map the peak using association mapping of LDL-C as an intermediate disease-related trait to further define the etiology of this linkage peak. The study populations consisted of 1908 individuals from the CATHGEN biorepository of patients undergoing cardiac catheterization; 254 families (N = 827 individuals) from the GENECARD familial study of early-onset CAD; and 162 aorta samples harvested from deceased donors. Linkage disequilibrium-tagged SNPs were selected with an average of one SNP per 20 kb for 126.6-160.2 MB (region of highest linkage) and less dense spacing (one SNP per 50 kb) for the flanking regions (117.7-126.6 and 160.2-167.5 MB) and genotyped on all samples using a custom Illumina array.
    [Show full text]
  • Association Weight Matrix for the Genetic Dissection of Puberty in Beef Cattle
    Association weight matrix for the genetic dissection of puberty in beef cattle Marina R. S. Fortesa,b,c, Antonio Revertera,b, Yuandan Zhanga,d, Eliza Collisa,b, Shivashankar H. Nagarajb,NickN.Jonssona,c,e, Kishore C. Prayagaa,b,1, Wes Barrisa,b, and Rachel J. Hawkena,b,2 aCooperative Research Centre for Beef Genetic Technologies; bCommonwealth Scientific and Industrial Research Organization, division of Livestock Industries, Queensland Bioscience Precinct, Brisbane QLD 4067, Australia; cThe University of Queensland, School of Veterinary Science, Gatton QLD 4343, Australia; dAnimal Genetics and Breeding Unit, University of New England, Armidale NSW 2351, Australia; and eFaculty of Veterinary Medicine, University of Glasgow, Glasgow G61 1QH, United Kingdom Edited by George Seidel, Colorado State University, Fort Collins, CO, and approved June 21, 2010 (received for review February 23, 2010) We describe a systems biology approach for the genetic dissection tional data on traits related to puberty are available. For example, of complex traits based on applying gene network theory to the re- weight and condition score are often measured on occasions sults from genome-wide associations. The associations of single- throughout an animal’s development. Hence, understanding ge- nucleotide polymorphisms (SNP) that were individually associated netics of cattle puberty and its biology serves two purposes: as with a primary phenotype of interest, age at puberty in our study, a strategy to develop efficient livestock resources and as a model were explored across 22 related traits. Genomic regions were sur- for human biology. veyed for genes harboring the selected SNP. As a result, an asso- The focus of this work is to demonstrate a unique systems ap- ciation weight matrix (AWM) was constructed with as many rows proach, which we call an association weight matrix (AWM), ap- as genes and as many columns as traits.
    [Show full text]
  • The Pdx1 Bound Swi/Snf Chromatin Remodeling Complex Regulates Pancreatic Progenitor Cell Proliferation and Mature Islet Β Cell
    Page 1 of 125 Diabetes The Pdx1 bound Swi/Snf chromatin remodeling complex regulates pancreatic progenitor cell proliferation and mature islet β cell function Jason M. Spaeth1,2, Jin-Hua Liu1, Daniel Peters3, Min Guo1, Anna B. Osipovich1, Fardin Mohammadi3, Nilotpal Roy4, Anil Bhushan4, Mark A. Magnuson1, Matthias Hebrok4, Christopher V. E. Wright3, Roland Stein1,5 1 Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 2 Present address: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 3 Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 4 Diabetes Center, Department of Medicine, UCSF, San Francisco, California 5 Corresponding author: [email protected]; (615)322-7026 1 Diabetes Publish Ahead of Print, published online June 14, 2019 Diabetes Page 2 of 125 Abstract Transcription factors positively and/or negatively impact gene expression by recruiting coregulatory factors, which interact through protein-protein binding. Here we demonstrate that mouse pancreas size and islet β cell function are controlled by the ATP-dependent Swi/Snf chromatin remodeling coregulatory complex that physically associates with Pdx1, a diabetes- linked transcription factor essential to pancreatic morphogenesis and adult islet-cell function and maintenance. Early embryonic deletion of just the Swi/Snf Brg1 ATPase subunit reduced multipotent pancreatic progenitor cell proliferation and resulted in pancreas hypoplasia. In contrast, removal of both Swi/Snf ATPase subunits, Brg1 and Brm, was necessary to compromise adult islet β cell activity, which included whole animal glucose intolerance, hyperglycemia and impaired insulin secretion. Notably, lineage-tracing analysis revealed Swi/Snf-deficient β cells lost the ability to produce the mRNAs for insulin and other key metabolic genes without effecting the expression of many essential islet-enriched transcription factors.
    [Show full text]
  • DNA Methylation Heterogeneity Patterns in Breast Cancer Cell Lines
    DNA Methylation Heterogeneity Patterns in Breast Cancer Cell Lines The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Sun, Shuying, Sunny Tian, Karina Bertelsmann, Linda Yu, and Shuying Sun. “DNA Methylation Heterogeneity Patterns in Breast Cancer Cell Lines.” Cancer Informatics (September 2016): 1. © 2016 the authors, publisher and licensee Libertas Academica Limited As Published http://dx.doi.org/10.4137/cin.s40300 Publisher Libertas Academica, Ltd. Version Final published version Citable link http://hdl.handle.net/1721.1/108129 Terms of Use Creative Commons Attribution-NonCommercial 3.0 Unported Detailed Terms https://creativecommons.org/licenses/by-nc/3.0/ DNA Methylation Heterogeneity Patterns in Breast Cancer Cell Lines Sunny Tian1, Karina Bertelsmann2, Linda Yu3 and Shuying Sun4 1Massachusetts Institute of Technology, Cambridge, MA, USA. 2Clear Creek High School, League City, TX, USA. 3St. John’s School, Houston, TX, USA. 4Department of Mathematics, Texas State University, San Marcos, TX, USA. Supplementary Issue: Computer Simulation, Bioinformatics, and Statistical Analysis of Cancer Data and Processes (A) ABSTR ACT: Heterogeneous DNA methylation patterns are linked to tumor growth. In order to study DNA methylation heterogeneity patterns for breast cancer cell lines, we comparatively study four metrics: variance, I2 statistic, entropy, and methylation state. Using the categorical metric methylation state, we select the two most heterogeneous states to identify genes that directly affect tumor suppressor genes and high- or moderate-risk breast cancer genes. Utilizing the Gene Set Enrichment Analysis software and the ConsensusPath Database visualization tool, we generate integrated gene networks to study biological relations of heterogeneous genes.
    [Show full text]
  • A Network Inference Approach to Understanding Musculoskeletal
    A NETWORK INFERENCE APPROACH TO UNDERSTANDING MUSCULOSKELETAL DISORDERS by NIL TURAN A thesis submitted to The University of Birmingham for the degree of Doctor of Philosophy College of Life and Environmental Sciences School of Biosciences The University of Birmingham June 2013 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. ABSTRACT Musculoskeletal disorders are among the most important health problem affecting the quality of life and contributing to a high burden on healthcare systems worldwide. Understanding the molecular mechanisms underlying these disorders is crucial for the development of efficient treatments. In this thesis, musculoskeletal disorders including muscle wasting, bone loss and cartilage deformation have been studied using systems biology approaches. Muscle wasting occurring as a systemic effect in COPD patients has been investigated with an integrative network inference approach. This work has lead to a model describing the relationship between muscle molecular and physiological response to training and systemic inflammatory mediators. This model has shown for the first time that oxygen dependent changes in the expression of epigenetic modifiers and not chronic inflammation may be causally linked to muscle dysfunction.
    [Show full text]