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GeneNetwork: A Toolbox for Systems Genetics

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Systems Genetics

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1488))

Abstract

The goal of systems genetics is to understand the impact of genetic variation across all levels of biological organization, from mRNAs, proteins, and metabolites, to higher-order physiological and behavioral traits. This approach requires the accumulation and integration of many types of data, and also requires the use of many types of statistical tools to extract relevant patterns of covariation and causal relations as a function of genetics, environment, stage, and treatment. In this protocol we explain how to use the GeneNetwork web service, a powerful and free online resource for systems genetics. We provide workflows and methods to navigate massive multiscalar data sets and we explain how to use an extensive systems genetics toolkit for analysis and synthesis. Finally, we provide two detailed case studies that take advantage of human and mouse cohorts to evaluate linkage between gene variants, addiction, and aging.

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References

  1. Manly KF, Olson JM (1999) Overview of QTL mapping software and introduction to map manager QT. Mamm Genome 10(4):327–334

    Article  CAS  PubMed  Google Scholar 

  2. Williams RW (1994) The portable dictionary of the mouse genome: a personal database for gene mapping and molecular biology. Mamm Genome 5(6):372–375

    Article  CAS  PubMed  Google Scholar 

  3. Chesler EJ, Lu L, Shou S, Qu Y, Gu J, Wang J, Hsu HC, Mountz JD, Baldwin NE, Langston MA, Threadgill DW, Manly KF, Williams RW (2005) Complex trait analysis of gene expression uncovers polygenic and pleiotropic networks that modulate nervous system function. Nat Genet 37(3):233–242. doi:10.1038/ng1518

    Article  CAS  PubMed  Google Scholar 

  4. Andreux PA, Williams EG, Koutnikova H, Houtkooper RH, Champy MF, Henry H, Schoonjans K, Williams RW, Auwerx J (2012) Systems genetics of metabolism: the use of the BXD murine reference panel for multiscalar integration of traits. Cell 150(6):1287–1299. doi:10.1016/j.cell.2012.08.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chesler EJ, Wang J, Lu L, Qu Y, Manly KF, Williams RW (2003) Genetic correlates of gene expression in recombinant inbred strains: a relational model system to explore neurobehavioral phenotypes. Neuroinformatics 1(4):343–357. doi:10.1385/NI:1:4:343

    Article  PubMed  Google Scholar 

  6. Wang J, Williams RW, Manly KF (2003) WebQTL: web-based complex trait analysis. Neuroinformatics 1(4):299–308. doi:10.1385/NI:1:4:299

    Article  PubMed  Google Scholar 

  7. Li Z, Mulligan MK, Wang X, Miles MF, Lu L, Williams RW (2010) A transposon in comt generates mRNA variants and causes widespread expression and behavioral differences among mice. PLoS One 5(8):e12181. doi:10.1371/journal.pone.0012181

    Article  PubMed  PubMed Central  Google Scholar 

  8. Williams EG, Mouchiroud L, Frochaux M, Pandey A, Andreux PA, Deplancke B, Auwerx J (2014) An evolutionarily conserved role for the aryl hydrocarbon receptor in the regulation of movement. PLoS Genet 10(9):e1004673. doi:10.1371/journal.pgen.1004673

    Article  PubMed  PubMed Central  Google Scholar 

  9. Wang X, MK M, Pandey A, Williams EG, Mozhui K et al (2016) Joint mouse-human phenome-wide association to test gene function and disease risk. Nat Commun 7:10464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chesler EJ, Lu L, Wang J, Williams RW, Manly KF (2004) WebQTL: rapid exploratory analysis of gene expression and genetic networks for brain and behavior. Nat Neurosci 7(5):485–486. doi:10.1038/nn0504-485

    Article  CAS  PubMed  Google Scholar 

  11. Peirce JL, Lu L, Gu J, Silver LM, Williams RW (2004) A new set of BXD recombinant inbred lines from advanced intercross populations in mice. BMC Genet 5:7. doi:10.1186/1471-2156-5-7

    Article  PubMed  PubMed Central  Google Scholar 

  12. Taylor BA, Heiniger HJ, Meier H (1973) Genetic analysis of resistance to cadmium-induced testicular damage in mice. Proc Soc Exp Biol Med 143(3):629–633

    Article  CAS  PubMed  Google Scholar 

  13. Alberts R, Schughart K (2010) QTLminer: identifying genes regulating quantitative traits. BMC Bioinformatics 11:516. doi:10.1186/1471-2105-11-5161471-2105-11-516

    Article  PubMed  PubMed Central  Google Scholar 

  14. Overall RW, Kempermann G, Peirce J, Lu L, Goldowitz D, Gage FH, Goodwin S, Smit AB, Airey DC, Rosen GD, Schalkwyk LC, Sutter TR, Nowakowski RS, Whatley S, Williams RW (2009) Genetics of the hippocampal transcriptome in mouse: a systematic survey and online neurogenomics resource. Front Neurosci 3:55. doi:10.3389/neuro.15.003.2009

    PubMed  PubMed Central  Google Scholar 

  15. Wang XS, Agarwala R, Capra JA, Chen ZG, Church DM, Ciobanu DC, Li ZS, Lu L, Mozhui K, Mulligan MK, Nelson SF, Pollard KS, Taylor WL, Thomason DB, Williams RW (2010) High-throughput sequencing of the DBA/2J mouse genome. BMC Bioinformatics 11:O7. doi:10.1186/1471-2105-11-S4-O7

  16. Bottomly D, Walter NA, Hunter JE, Darakjian P, Kawane S, Buck KJ, Searles RP, Mooney M, McWeeney SK, Hitzemann R (2011) Evaluating gene expression in C57BL/6J and DBA/2J mouse striatum using RNA-Seq and microarrays. PLoS One 6(3):e17820. doi:10.1371/journal.pone.0017820

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ciobanu DC, Lu L, Mozhui K, Wang X, Jagalur M, Morris JA, Taylor WL, Dietz K, Simon P, Williams RW (2010) Detection, validation, and downstream analysis of allelic variation in gene expression. Genetics 184(1):119–128. doi:10.1534/genetics.109.107474, doi:genetics.109.107474 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Homayouni R, Heinrich K, Wei L, Berry MW (2005) Gene clustering by latent semantic indexing of MEDLINE abstracts. Bioinformatics 21(1):104–115. doi:10.1093/bioinformatics/bth464

    Article  CAS  PubMed  Google Scholar 

  19. Williams RW, Mulligan MK (2012) Genetic and molecular network analysis of behavior. Int Rev Neurobiol 104:135–157. doi:10.1016/B978-0-12-398323-7.00006-9

    Article  PubMed  PubMed Central  Google Scholar 

  20. Schadt EE, Molony C, Chudin E, Hao K, Yang X, Lum PY, Kasarskis A, Zhang B, Wang S, Suver C, Zhu J, Millstein J, Sieberts S, Lamb J, GuhaThakurta D, Derry J, Storey JD, Avila-Campillo I, Kruger MJ, Johnson JM, Rohl CA, van Nas A, Mehrabian M, Drake TA, Lusis AJ, Smith RC, Guengerich FP, Strom SC, Schuetz E, Rushmore TH, Ulrich R (2008) Mapping the genetic architecture of gene expression in human liver. PLoS Biol 6(5):e107. doi:10.1371/journal.pbio.0060107

    Article  PubMed  PubMed Central  Google Scholar 

  21. Yang X, Zhang B, Molony C, Chudin E, Hao K, Zhu J, Gaedigk A, Suver C, Zhong H, Leeder JS, Guengerich FP, Strom SC, Schuetz E, Rushmore TH, Ulrich RG, Slatter JG, Schadt EE, Kasarskis A, Lum PY (2010) Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver. Genome Res 20(8):1020–1036. doi:10.1101/gr.103341.109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Houtkooper RH, Mouchiroud L, Ryu D, Moullan N, Katsyuba E, Knott G, Williams RW, Auwerx J (2013) Mitonuclear protein imbalance as a conserved longevity mechanism. Nature 497(7450):451–457. doi:10.1038/nature12188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81(3):559–575. doi:10.1086/519795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Langfelder P, Horvath S (2008) WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics 9:559. doi:10.1186/1471-2105-9-559

    Article  PubMed  PubMed Central  Google Scholar 

  25. GTEx Consortium (2015) Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 348(6235):648–660. doi:10.1126/science.1262110

    Article  PubMed Central  Google Scholar 

  26. Webster JA, Gibbs JR, Clarke J, Ray M, Zhang W, Holmans P, Rohrer K, Zhao A, Marlowe L, Kaleem M, McCorquodale DS 3rd, Cuello C, Leung D, Bryden L, Nath P, Zismann VL, Joshipura K, Huentelman MJ, Hu-Lince D, Coon KD, Craig DW, Pearson JV, NACC-Neuropathology Group, Heward CB, Reiman EM, Stephan D, Hardy J, Myers AJ (2009) Genetic control of human brain transcript expression in Alzheimer disease. American Journal of Human Genetics 84(4):445–458

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gibbs JR, van der Brug MP, Hernandez DG, Traynor BJ, Nalls MA, Lai SL, Arepalli S, Dillman A, Rafferty IP, Troncoso J, Johnson R, Zielke HR, Ferrucci L, Longo DL, Cookson MR, Singleton AB (2010) Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain. PLoS Genetics 6(5), e1000952

    Article  PubMed  PubMed Central  Google Scholar 

  28. Liang WS, Reiman EM, Valla J, Dunckley T, Beach TG, Grover A, Niedzielko TL, Schneider LE, Mastroeni D, Caselli R, Kukull W, Morris JC, Hulette CM, Schmechel D, Rogers J, Stephan DA (2008) Alzheimer’s disease is associated with reduced expression of energy metabolism genes in posterior cingulate neurons. Proc Natl Acad Sci U S A 105(11):4441–4446. doi:10.1073/pnas.0709259105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhang B, Gaiteri C, Bodea LG, Wang Z, McElwee J, Podtelezhnikov AA, Zhang C, Xie T, Tran L, Dobrin R, Fluder E, Clurman B, Melquist S, Narayanan M, Suver C, Shah H, Mahajan M, Gillis T, Mysore J, MacDonald ME, Lamb JR, Bennett DA, Molony C, Stone DJ, Gudnason V, Myers AJ, Schadt EE, Neumann H, Zhu J, Emilsson V (2013) Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease. Cell 153(3):707–720. doi:10.1016/j.cell.2013.03.030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. McClurg P, Janes J, Wu C, Delano DL, Walker JR, Batalov S, Takahashi JS, Shimomura K, Kohsaka A, Bass J, Wiltshire T, Su AI (2007) Genomewide association analysis in diverse inbred mice: power and population structure. Genetics 176(1):675–683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wang S, Yehya N, Schadt EE, Wang H, Drake TA, Lusis AJ (2006) Genetic and genomic analysis of a fat mass trait with complex inheritance reveals marked sex specificity. PLoS Genet 2(2), e15

    Article  PubMed  PubMed Central  Google Scholar 

  32. Huang GJ, Shifman S, Valdar W, Johannesson M, Yalcin B, Taylor MS, Taylor JM, Mott R, Flint J (2009) High resolution mapping of expression QTLs in heterogeneous stock mice in multiple tissues. Genome Res 19(6):1133–1140. doi:10.1101/gr.088120.108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgment

We thank Lei Yan, Arthur Centeno, and Zachary Sloan, for their many contributions to building and maintaining GN over the past decade. GN code has benefited greatly from contributions by Jintao Wang, Sam Ockman, Xiaodong Zhou, Ning Liu, and Alex G. Williams, and Drs. Rudi Alberts, Arends, Elissa J. Chesler, Kenneth Manly, Danny and Evan G. Williams. We also thank M. Trevor Houseal and Austin Kimes for their help in editing this chapter. Support for GeneNetwork has been provided by NIH grants U01AA013499, U01AA16662, U01AA014425, P20DA21131, U01CA105417, and U24 RR021760. GN is also generously supported by the UT Center for Integrative and Translational Genomics, and funds from the UT-ORNL Governor’s Chair.

Author information

Authors and Affiliations

  1. Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, 855 Monroe Ave., Suite 515, Memphis, TN, 38163, USA

    Megan K. Mulligan, Pjotr Prins & Robert W. Williams

  2. Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN, USA

    Khyobeni Mozhui & Pjotr Prins

Authors
  1. Megan K. Mulligan
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  2. Khyobeni Mozhui
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  3. Pjotr Prins
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  4. Robert W. Williams
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Corresponding author

Correspondence to Megan K. Mulligan .

Editor information

Editors and Affiliations

  1. Department of Infection Genetics, Helmholtz Centre for Infection Research & University of Veterinary Medicine Hannover, Braunschweig, Niedersachsen, Germany

    Klaus Schughart

  2. Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee, USA

    Robert W. Williams

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Mulligan, M.K., Mozhui, K., Prins, P., Williams, R.W. (2017). GeneNetwork: A Toolbox for Systems Genetics. In: Schughart, K., Williams, R. (eds) Systems Genetics. Methods in Molecular Biology, vol 1488. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-6427-7_4

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  • DOI: https://doi.org/10.1007/978-1-4939-6427-7_4

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  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-6425-3

  • Online ISBN: 978-1-4939-6427-7

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