Advanced search
Publication Cover
Expert Opinion on Drug Metabolism & Toxicology Volume 12, 2016 - Issue 2
Submit an article Journal homepage
671
Views
19
CrossRef citations to date
0
Altmetric
Reviews

Structural variants can be more informative for disease diagnostics, prognostics and translation than current SNP mapping and exon sequencing

Allen D. RosesDepartment of Neurology and Neurosciences, Duke University, Durham, NC, USA;Zinfandel Pharmaceuticals, Chapel Hill, NC, USACorrespondence[email protected]
View further author information
,
P. Anthony AkkariShiraz Pharmaceuticals, Inc, Chapel Hill, NC, USAView further author information
,
Ornit Chiba-FalekDepartment of Neurology, Duke University, Durham, NC, USAView further author information
,
Michael W. LutzDepartment of Neurology, Duke University, Durham, NC, USAView further author information
,
William Kirby GottschalkDepartment of Neurology, Duke University, Durham, NC, USAView further author information
,
Ann Marie SaundersDepartment of Neurology, Duke University, Durham, NC, USAView further author information
,
Bob SaulPolymorphic DNA, Alameda, CA, USAView further author information
,
Scott SundsethCaberner Pharmaceuticals, Inc, Chapel Hill, NC, USAView further author information
&
Daniel BurnsZinfandel Pharmaceuticals, Inc, Raleigh-Durham, NC, USAView further author information
 show all
Pages 135-147 | Received 31 Jul 2015, Accepted 14 Dec 2015, Published online: 02 Feb 2016

References

  • Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers
  • Frazer KA, Murray SS, Schork NJ, et al. Human genetic variation and its contribution to complex traits. Nat Rev Genet. 2009;10:241–251.
  • Sinden R, Potaman V, Oussatcheva E, et al. Triplet repeat DNA structures and human genetic disease: dynamic mutations from dynamic DNA. J Biosci. 2002;27:53–65.
  • Lee DY, McMurray CT. Trinucleotide expansion in disease: why is there a length threshold? Curr Opin Genet Dev. 2014;26:131–140.
  • Mahadevan M, Tsilfidis C, Sabourin L, et al. Myotonic dystrophy mutation: an unstable CTG repeat in the 3’ untranslated region of the gene. Science. 1992;255:1253–1255.
  • Budworth H, McMurray CT. A brief history of triplet repeat diseases. Methods Mol. Biol. 2013;1010:3–17. doi:10.1007/978-1-62703-411-1_1.
  • Corder E, Saunders A, Strittmatter W, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261:921–923.

•• First demonstration of relationship of APOE genotypes to age of AD onset distributions.

  • Grant SFA, Thorleifsson G, Reynisdottir I, et al Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet. 2006;38:320–323.
  • Saunders AM, Roses AD. Apolipoprotein E4 allele frequency, ischemic cerebrovascular disease, and Alzheimer’s disease. Stroke. 1993;24:1416–1417.

•• First report of APOE4 association to sporadic Alzhimer’s disease.

  • Roses AD, Lutz MW, Amrine-Madsen H, et al. A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer’s disease. Pharmacogenomics J. 2010;10:375–384.

•• First application of human genome phylogenetics to discover a single locus with highly variable poly-Ts associated with compound genotype associations with age of onset of AD.

  • Crenshaw DG, Gottschalk WK, Lutz MW, et al. Using genetics to enable studies on the prevention of Alzheimer’s disease. Clin Pharmacol Ther. 2013;93:177–185.

•• Phase III pharmacogenetic-assisted clinical trial to qualify a genetic algorithm and test the effect of low dose pioglitazone to delay the onset of mild cognitive impairment due to AD.

  • Kim DH, Yeo SH, Park JM, et al. Genetic markers for diagnosis and pathogenesis of Alzheimer’s disease. Gene. 2014;545:185–193.
  • Bardel C, Danjean V, Hugot JP, et al. On the use of haplotype phylogeny to detect disease susceptibility loci. BMC Genet. 2005;6:24.
  • Durrant C, Zondervan KT, Cardon LR, et al. Linkage disequilibrium mapping via cladistic analysis of single-nucleotide polymorphism haplotypes. Am J Hum Genet. 2004;75:35–43.
  • Morris RW, Kaplan NL. On the advantage of haplotype analysis in the presence of multiple disease susceptibility alleles. Genet Epidemiol. 2002;23:221–233.
  • Seltman H, Roeder K, Devlin B. Evolutionary-based association analysis using haplotype data. Genet Epidemiol. 2003;25:48–58.
  • Pendleton M, Sebra R, Pang AW, et al. Assembly and diploid architecture of an individual human genome via single-molecule technologies. Nat Methods advance online publication. 2015; doi:10.1038/nmeth.3454.
  • Ait-Yahya-Graison E, Necsulea A, Reymond A RNA-seq transcriptome profiling uncovers how structural variants influence alternative splicing. presented at the 63rd Annual Meeting of The American Society of Human Genetics; 2013; Boston (MA).

• Early report of SVs influencing alternative splicing of mRNA.

  • Chang S, Ma TR, Miranda RD, et al. Lipid- and receptor-binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity. Proc Natl Acad Sci U S A. 2005;102:18694–18699.

•• Effect of apolipoprotein E isoforms on mitochondrial functions: binding and dynamic effects.

• Brief overview of pre-mRNA splicing machinery.

  • Pedrotti S, Cooper TA. In Brief: (mis)splicing in disease. J Pathol. 2014;233(1):1–3.
  • Kalsotra A, Singh RK, Gurha P, et al. The Mef2 transcription network is disrupted in heart tissue, dramatically altering miRNA and mRNA expression myotonic dystrophy. Cell Rep. 2014 Jan 30;6(2):336–345. Epub 2014 Jan 9. doi:10.1016/j.celrep.2013.12.025.

•• Illustrates a pathogenic mechanism of mRNA and miRNA in tissues from myotonic muscular dystrophy.

  • Linnertz C, Anderson L, Gottschalk W, et al. The cis-regulatory effect of an Alzheimer’s disease-associated poly-T locus on expression of TOMM40 and apolipoprotein E genes. Alzheimer’s & Dementia. 2014;10:541–551.

• Direct effect of SVs on the mRNA expression in AD.

  • Lutz MW, Saul R, Linnertz C, et al. A CT-rich haplotype in intron 4 of SNCA confers risk for Lewy body pathology in Alzheimer’s disease and affects SNCA expression. Alzheimer’s & Dementia. 2015. doi:10.1016/j.jalz.2015.05.011.

• Second example of SVs associated with a variably expressed neuropathology in AD.

  • Strittmatter WJ, Saunders AM, Schmechel D, et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A. 1993; 90:1977–1981.

• Early clear demonstration of apoE4 association with increased amyloid plaques.

  • Strittmatter WJ, Saunders AM, Goedert M, et al. Isoform-specific interactions of apolipoprotein E with microtubule-associated protein tau: implications for Alzheimer disease. Proc Natl Acad Sci U S A. 1994;91:11183–11186.
  • Matsui T, Ingelsson M, Fukumoto H, et al. Expression of APP pathway mRNAs and proteins in Alzheimer’s disease. Brain Res. 2007;1161:116–123.
  • Zarow C, Victoroff J. Increased apolipoprotein E mRNA in the hippocampus in Alzheimer disease and in rats after entorhinal cortex lesioning. Exp Neurol. 1998;149:79–86.
  • Chiba-Falek O, Lopez GJ, Nussbaum RL. Levels of alpha-synuclein mRNA in sporadic Parkinson disease patients. Mov Disord. 2006;21:1703–1708.
  • Grundemann J, Schlaudraff F, Haeckel O, et al. Elevated alpha-synuclein mRNA levels in individual UV-laser-microdissected dopaminergic substantia nigra neurons in idiopathic Parkinson’s disease. Nucleic Acids Res. 2008;36:e38.
  • Akai J, Kimura A, Hata R-I. Transcriptional regulation of the human type I collagen α2 (COL1A2) gene by the combination of two dinucleotide repeats. Gene. 1999;239:65–73.
  • Chiba-Falek O, Nussbaum RL. Effect of allelic variation at the NACP–Rep1 repeat upstream of the α-synuclein gene (SNCA) on transcription in a cell culture luciferase reporter system. Hum Mol Genet. 2001;10:3101–3109.
  • Okladnova O, Syagailo YV, Tranitz M, et al. A promoter-associated polymorphic repeat modulatesPAX-6Expression in human brain. Biochem Biophys Res Commun. 1998;248:402–405.
  • Peters DG, Kassam A, Jean PLS, et al. Functional polymorphism in the matrix metalloproteinase-9 promoter as a potential risk factor for intracranial aneurysm. Stroke. 1999;30:2612–2616.
  • Searle S, Blackwell JM. Evidence for a functional repeat polymorphism in the promoter of the human NRAMP1 gene that correlates with autoimmune versus infectious disease susceptibility. J Med Genet. 1999;36:295–299.
  • Shimajiri S, Arima N, Tanimoto A, et al. Shortened microsatellite d (CA) 21 sequence down-regulates promoter activity of matrix metalloproteinase 9 gene. FEBS Letters. 1999;455:70–74.
  • Maraganore DM, De Andrade M, Elbaz A, et al. Collaborative analysis of α-synuclein gene promoter variability and Parkinson disease. Jama. 2006;296:661–670.
  • Farrer M, Maraganore DM, Lockhart P, et al. Alpha-synuclein gene haplotypes are associated with Parkinson’s disease. Hum Mol Genet. 2001;10:1847–1851.
  • Izumi Y, Morino H, Oda M, et al. Genetic studies in Parkinson’s disease with an α-synuclein/NACP gene polymorphism in Japan. Neurosci Lett. 2001;300:125–127.
  • Krüger R, Menezes Vieira‐Saecker AM, Kuhn W, et al. Increased susceptibility to sporadic Parkinson’s disease by a certain combined α‐synuclein/apolipoprotein E genotype. Ann Neurol. 1999;45:611–617.
  • Tan E, Matsuura T, Nagamitsu S, et al/ Polymorphism of NACP-Rep1 in Parkinson’s disease: an etiologic link with essential tremor? Neurology. 2000;54:1195–1198.
  • Chiba-Falek O, Kowalak JA, Smulson ME, et al. Regulation of α-synuclein expression by poly (ADP ribose) polymerase-1 (PARP-1) binding to the NACP-Rep1 polymorphic site upstream of the SNCA gene. Am J Hum Genet. 2005;76:478–492.
  • Chiba-Falek O, Touchman JW, Nussbaum RL. Functional analysis of intra-allelic variation at NACP-Rep1 in the α-synuclein gene. Hum Genet. 2003;113:426–431.
  • Cronin KD, Ge D, Manninger P, et al. Expansion of the Parkinson disease-associated SNCA-Rep1 allele upregulates human α-synuclein in transgenic mouse brain. Hum Mol Genet. 2009;18:3274–3285.
  • Linnertz C, Saucier L, Ge D, et al. Genetic regulation of alpha-synuclein mRNA expression in various human brain tissues. PLoS One. 2009;4:e7480.
  • Barmada SJ, Ju S, Arjun A, et al. Amelioration of toxicity in neuronal models of amyotrophic lateral sclerosis by hUPF1. Proc Natl Acad Sci. 2015;112:7821–7826.
  • Pokrishevsky E, Grad LI, Yousefi M, et al. Aberrant localization of FUS and TDP43 is associated with misfolding of SOD1 in amyotrophic lateral sclerosis. PLoS One. 2012;7:e35050.
  • Kwiatkowski TJ Jr., Bosco DA, LeClerc AL, et al. Mutations in the FUS/TLS Gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science. 2009;323:1205–1208.
  • Onodera O, Ishihara T, Shiga A, et al. Minor splicing pathway is not minor any more: implications for the pathogenesis of motor neuron diseases. Neuropathology. 2014;34:99–107.

•• Demonstration of increased mRNA species and suggestion of splicing pathway involvement in ALS.

  • Bose JK, Wang IF, Hung L, et al. TDP-43 overexpression enhances exon 7 inclusion during the survival of motor neuron pre-mRNA splicing. J Biol Chem. 2008;283:28852–28859.
  • Lee EB, Lee VM-Y, Trojanowski JQ. Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration. Nat Rev Neurosci. 2012;13:38–50.

• Excellent review of TDP-43 mediated neurodegeneration.

  • Ysla RM, Wilson GM, Brewer G. Assays of adenylate uridylate-rich element-mediated mRNA decay in cells. Methods Enzymol. 2008;449:47–71.
  • Velde CV, Miller TM, Cashman NR, et al. Selective association of misfolded ALS-linked mutant SOD1 with the cytoplasmic face of mitochondria. Proc Natl Acad Sci. 2008;105:4022–4027.
  • Israelson A, Arbel N, Da Cruz S, et al. Misfolded mutant SOD1 directly inhibits VDAC1 conductance in a mouse model of inherited ALS. Neuron. 2010;67:575–587.
  • Mackenzie IR, Rademakers R, Neumann M. TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol. 2010;9:995–1007.
  • Huang C, Zhou H, Tong J, et al. FUS transgenic rats develop the phenotypes of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. PLoS Genet. 2011;7:e1002011.
  • Xu Y-F, Gendron TF, Zhang Y-J, et al. Wild-type human TDP-43 expression causes TDP-43 phosphorylation, mitochondrial aggregation, motor deficits, and early mortality in transgenic mice. J Neurosci. 2010;30:10851–10859.
  • Chain FJ, Feulner PG. Ecological and evolutionary implications of genomic structural variations. Front Genet. 2014;5:326.
  • Keane TM, Wong K, Adams DJ, et al. Structural variation in mouse genomes. Front Genet. 2014;5:192.
  • Weischenfeldt J, Symmons O, Spitz F, et al. Phenotypic impact of genomic structural variation: insights from and for human disease. Nat Rev Genet. 2013;14:125–138.
  • Haraksingh RR, Snyder MP. Impacts of variation in the human genome on gene regulation. J Mol Biol. 2013;425:3970–3977.
  • Hefferon TW, Groman JD, Yurk CE, et al. A variable dinucleotide repeat in the CFTR gene contributes to phenotype diversity by forming RNA secondary structures that alter splicing. Proc Natl Acad Sci U S A. 2004;101:3504–3509.
  • Groman JD, Hefferon TW, Casals T, et al. Cutting, variation in a repeat sequence determines whether a common variant of the cystic fibrosis transmembrane conductance regulator gene is pathogenic or benign. Am J Hum Genet. 2004;74:176–179.
  • Pinto M, Moraes CT. Mitochondrial genome changes and neurodegenerative diseases. Biochim Biophys Acta (BBA) Molecular Basis Disease. 2014;1842:1198–1207.
  • Li H, Wetten S, Li L, et al. Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease. Arch Neurol. 2008;65:45–53.
  • Linnertz C, Saunders AM, Lutz MW, et al. Characterization of the poly-T variant in the TOMM40 gene in diverse populations. PLoS One. 2012;7:e30994.

• Illustrates high variability of the poly-T allele frequencies in different ethnic groups.

  • Roses AD, Lutz MW, Saunders AM, et al. African-American TOMM40’523-APOE haplotypes are admixture of West African and Caucasian alleles. Alzheimers Dement. 2014;10:592–601.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Order Reprints Request Corporate Permissions

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

Request Academic Permissions

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.

Related research

People also read lists articles that other readers of this article have read.

Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine.

Cited by lists all citing articles based on Crossref citations.
Articles with the Crossref icon will open in a new tab.