A large proportion of the human genome consists of the repeatome, repetitive DNA sequences that are present in either tandem or interspersed configurations.
There are over 1 million distinct tandem repeats in the human genome, many of which are highly polymorphic.
Tandem repeat expansions cause dozens of Mendelian tandem repeat disorders, including fragile X syndrome, Huntington disease, various ataxias and a major subset of amyotrophic lateral sclerosis and frontotemporal dementia cases.
Tandem repeats occur across a range of genic and intergenic locations and can thus affect the structure and function of DNA, RNA and proteins, with a range of molecular and cellular consequences.
Tandem repeats generally mutate more rapidly than single nucleotides and may contribute to the missing heritability observed in genome-wide association studies of complex polygenic diseases and traits.
The systematic genome-wide investigation of tandem repeats is required to fully understand their roles in organismal development and function and in health and disease, including their somatic mutability, epigenetic modulation and evolutionary origins.
Accumulating evidence suggests that many classes of DNA repeats exhibit attributes that distinguish them from other genetic variants, including the fact that they are more liable to mutation; this enables them to mediate genetic plasticity. The expansion of tandem repeats, particularly of short tandem repeats, can cause a range of disorders (including Huntington disease, various ataxias, motor neuron disease, frontotemporal dementia, fragile X syndrome and other neurological disorders), and emerging data suggest that tandem repeat polymorphisms (TRPs) can also regulate gene expression in healthy individuals. TRPs in human genomes may also contribute to the missing heritability of polygenic disorders. A better understanding of tandem repeats and their associated repeatome, as well as their capacity for genetic plasticity via both germline and somatic mutations, is needed to transform our understanding of the role of TRPs in health and disease.
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Hannan, A. J. Tandem repeat polymorphisms: mediators of genetic plasticity, modulators of biological diversity and dynamic sources of disease susceptibility. Adv. Exp. Med. Biol. 769, 1–9 (2012).
Liang, K. C., Tseng, J. T., Tsai, S. J. & Sun, H. S. Characterization and distribution of repetitive elements in association with genes in the human genome. Comput. Biol. Chem. 57, 29–38 (2015).
Fondon, J. W., Hammock, E. A., Hannan, A. J. & King, D. G. Simple sequence repeats: genetic modulators of brain function and behavior. Trends Neurosci. 31, 328–334 (2008).
Press, M. O., Carlson, K. D. & Queitsch, C. The overdue promise of short tandem repeat variation for heritability. Trends Genet. 30, 504–512 (2014).
Faux, N. Single amino acid and trinucleotide repeats: function and evolution. Adv. Exp. Med. Biol. 769, 26–40 (2012).
Subramanian, S., Mishra, R. K. & Singh, L. Genome-wide analysis of microsatellite repeats in humans: their abundance and density in specific genomic regions. Genome Biol. 4, R13 (2003).
Gymrek, M. et al. Abundant contribution of short tandem repeats to gene expression variation in humans. Nat. Genet. 48, 22–29 (2016). This study provides striking evidence that short tandem repeats are key regulators of gene expression in humans. Although the data are from lymphocytes, the implication is that this is likely to occur in other cell types as well.
Quilez, J. et al. Polymorphic tandem repeats within gene promoters act as modifiers of gene expression and DNA methylation in humans. Nucleic Acids Res. 44, 3750–3762 (2016). This study is a key demonstration that tandem repeats are important regulators of human gene expression and associated DNA methylation. Together with reference 7, it provides genome-wide evidence for a crucial role of tandem repeats as 'tuning knobs' that regulate gene expression.
Dejesus-Hernandez, M. et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-Linked FTD and ALS. Neuron 72, 245–256 (2011).
Renton, A. E. et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72, 257–268 (2011). This study and that described in reference 9 are the first demonstration that this GGGGCC hexanucleotide repeat expansion is a major genetic contributor to both ALS and FTD.
López Castel, A., Cleary, J. D. & Pearson, C. E. Repeat instability as the basis for human diseases and as a potential target for therapy. Nat. Rev. Mol. Cell. Biol. 11, 165–170 (2010).
La Spada, A. R. & Taylor, J. P. Repeat expansion disease: progress and puzzles in disease pathogenesis. Nat. Rev. Genet. 11, 247–258 (2010).
Orr, H. T. Polyglutamine neurodegeneration: expanded glutamines enhance native functions. Curr. Opin. Genet. Dev. 22, 251–255 (2012).
Huntington's Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72, 971–983 (1993).
Mo, C., Hannan, A. J. & Renoir, T. Environmental factors as modulators of neurodegeneration: insights from gene-environment interactions in Huntington's disease. Neurosci. Biobehav. Rev. 52, 178–192 (2015).
Genetic Modifiers of Huntington's Disease (GeM-HD) Consortium. Identification of genetic factors that modify clinical onset of Huntington's disease. Cell 162, 516–526 (2014).
Bates, G. P. et al. Huntington disease. Nat. Rev. Dis. Primers 1, 15005 (2015).
La Spada, A. R., Wilson, E. M., Lubahn, D. B., Harding, A. E. & Fischbeck, K. H. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352, 77–79 (1991).
Rüb, U. et al. Clinical features, neurogenetics and neuropathology of the polyglutamine spinocerebellar ataxias type 1, 2, 3, 6 and 7. Prog. Neurobiol. 104, 38–66 (2013).
Wilburn, B. et al. An antisense CAG repeat transcript at JPH3 locus mediates expanded polyglutamine protein toxicity in Huntington's disease-like 2 mice. Neuron 70, 427–440 (2011).
Moseley, M. L. et al. Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8. Nat. Genet. 38, 758–769 (2006).
Zu, T. et al. Non-ATG-initiated translation directed by microsatellite expansions. Proc. Natl Acad. Sci. USA 108, 260–265 (2011). This study describes the first description of RAN translation that does not require ATG initiation and that can produce amino acid repeat peptides that may contribute to dysfunction in various tandem repeat disorders.
Pearson, C. E. Repeat associated non-ATG translation initiation: one DNA, two transcripts, seven reading frames, potentially nine toxic entities! PLOS Genet. 7, e1002018 (2011).
Cleary, J. D. & Ranum, L. P. New developments in RAN translation: insights from multiple diseases. Curr. Opin. Genet. Dev. 44, 125–134 (2017).
Nopoulos, P., Epping, E. A., Wassink, T., Schlaggar, B. L. & Perlmutter, J. Correlation of CAG repeat length between the maternal and paternal allele of the Huntingtin gene: evidence for assortative mating. Behav. Brain Funct. 7, 45 (2011).
Rubinsztein, D. C., Amos, B. & Cooper, G. Microsatellite and trinucleotide-repeat evolution: evidence for mutational bias and different rates of evolution in different lineages. Phil. Trans. R. Soc. 354, 1095–1099 (1999).
Mühlau, M. et al. Variation within the Huntington's disease gene influences normal brain structure. PLOS ONE 7, e29809 (2012).
Lee, J. K. et al. Sex-specific effects of the Huntington gene on normal neurodevelopment. J. Neurosci. Res. 95, 398–408 (2017).
Zheng, S. et al. Deletion of the huntingtin polyglutamine stretch enhances neuronal autophagy and longevity in mice. PLOS Genet. 6, e1000838 (2010).
Perlis, R. H. et al. Prevalence of incompletely penetrant Huntington's disease alleles among individuals with major depressive disorder. Am. J. Psychiatry 167, 574–579 (2010).
Gardiner, S. L. et al. Huntingtin gene repeat size variations affect risk of lifetime depression. Transl Psychiatry 7, 1277 (2017).
Du, X., Pang, T. Y. & Hannan, A. J. A tale of two maladies? Pathogenesis of depression with and without the Huntington's disease gene mutation. Front. Neurol. 4, 81 (2013).
Gardiner, S. L. et al. Large normal-range TBP and ATXN7 CAG repeat lengths are associated with increased lifetime risk of depression. Transl Psychiatry 7, e1143 (2017).
Shoubridge, C. & Gecz, J. Polyalanine tract disorders and neurocognitive phenotypes. Adv. Exp. Med. Biol. 769, 185–203 (2012).
Hughes, J. N. & Thomas, P. Q. Molecular pathology of polyalanine expansion disorders: new perspectives from mouse models. Methods Mol. Biol. 1017, 135–151 (2013).
Fondon, J. W. & Garner, H. R. Molecular origins of rapid and continuous morphological evolution. Proc. Natl Acad. Sci. USA 101, 18058–18063 (2004). This study provides evidence that tandem repeats and their encoded polyalanine tracts in proteins are implicated in the development, evolution and morphology of dogs.
Nasrallah, M. P. et al. Differential effects of a polyalanine tract expansion in Arx on neural development and gene expression. Hum. Mol. Genet. 21, 1090–1098 (2012).
Polling, S. et al. Polyalanine expansions drive a shift into α-helical clusters without amyloid-fibril formation. Nat. Struct. Mol. Biol. 22, 1008–1015 (2015).
Campuzano, V. et al. Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 271, 1423–1427 (1996).
Evans-Galea, M. V., Lockhart, P. J., Galea, C. A., Hannan, A. J. & Delatycki, M. B. Beyond loss of frataxin: the complex molecular pathology of Friedreich ataxia. Discov. Med. 17, 25–35 (2014).
Matsuura, T. et al. Large expansion of the ATTCT pentanucleotide repeat in spinocerebellar ataxia type 10. Nat. Genet. 26, 191–194 (2000).
Evans-Galea, M. V., Hannan, A. J., Carrodus, N., Delatycki, M. B. & Saffery, R. Epigenetic modifications in trinucleotide repeat diseases. Trends Mol. Med. 19, 655–663 (2013).
Kremer, E. J. et al. Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n. Science 252, 1711–1714 (1991).
Verkerk, A. J. et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65, 905–914 (1991).
Sutcliffe, J. S. et al. DNA methylation represses FMR-1 transcription in fragile X syndrome. Hum. Mol. Genet. 1, 397–400 (1992).
Hagerman, R. J. et al. Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology 57, 127–130 (2001).
Loesch, D. & Hagerman, R. Unstable mutations in the FMR1 gene and the phenotypes. Adv. Exp. Med. Biol. 769, 78–114 (2012).
Gecz, J., Gedeon, A. K., Sutherland, G. R. & Mulley, J. C. Identification of the gene FMR2, associated with FRAXE mental retardation. Nat. Genet. 13, 105–108 (1996).
Gu, Y., Shen, Y., Gibbs, R. A. & Nelson, D. L. Identification of FMR2, a novel gene associated with the FRAXE CCG repeat and CpG island. Nat. Genet. 13, 109–113 (1996).
Ciesiolka, A., Jazurek, M., Drazkowska, K. & Krzyzosiak, W. J. Structural characteristics of simple RNA repeats associated with disease and their deleterious protein interactions. Front. Cell. Neurosci. 11, 97 (2017).
Fu, Y. H. et al. An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science 255, 1256–1258 (1992).
Liquori, C. L. et al. Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science 293, 864–867 (2001).
Zu, T. et al. RAN translation regulated by muscleblind proteins in myotonic dystrophy type 2. Neuron 95, 1292–1305.e5 (2017).
Hannan, A. J. (ed.) Tandem Repeat Polymorphisms: Genetic Plasticity, Neural Diversity and Disease Vol. 769, 208 (Springer-Verlag, 2012).
Van Eyk, C. L. & Richards, R. I. Dynamic mutations: where are we now? Adv. Exp. Med. Biol. 769, 55–77 (2012).
Batra, R., Charizanis, K. & Swanson, M. S. Partners in crime: bidirectional transcription in unstable microsatellite disease. Hum. Mol. Genet. 19, R77–R82 (2010).
Haeusler, A. R., Donnelly, C. J. & Rothstein, J. D. The expanding biology of the C9orf72 nucleotide repeat expansion in neurodegenerative disease. Nat. Rev. Neurosci. 17, 383–395 (2016).
Elden, A. C. et al. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466, 1069–1075 (2010).
Daoud, H. et al. Association of long ATXN2 CAG repeat sizes with increased risk of amyotrophic lateral sclerosis. Arch. Neurol. 68, 739–742 (2011).
van Blitterswijk, M. et al. Ataxin-2 as potential disease modifier in C9ORF72 expansion carriers. Neurobiol. Aging 35, 2421.e13–2421.e17 (2014).
Majounie, E. et al. Repeat expansion in C9ORF72 in Alzheimer's disease. N. Engl. J. Med. 366, 283–284 (2012).
Zu, T. et al. RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. Proc. Natl Acad. Sci. USA 110, E4968–E4977 (2013).
Kobayashi, H. et al. Expansion of intronic GGCCTG hexanucleotide repeat in NOP56 causes SCA36, a type of spinocerebellar ataxia accompanied by motor neuron involvement. Am. J. Hum. Genet. 89, 121–130 (2011).
Lafrenière, R. G. et al. Unstable insertion in the 5′ flanking region of the cystatin B gene is the most common mutation in progressive myoclonus epilepsy type 1, EPM1. Nat. Genet. 15, 298–302 (1997).
Virtaneva, K. et al. Unstable minisatellite expansion causing recessively inherited myoclonus epilepsy, EPM1. Nat. Genet. 15, 393–396 (1997).
Hause, R. J., Pritchard, C. C., Shendure, J. & Salipante, S. J. Classification and characterization of microsatellite instability across 18 cancer types. Nat. Med. 22, 1342–1350 (2016). This study demonstrates that tandem repeat instability, particularly that of STRs, is a major contributor to a variety of different cancers. This finding provides insights into the extent of somatic instability of tandem repeats and is a major incentive to improve sequencing and bioinformatics approaches to capture all tandem repeat mutations in oncological disorders, which may provide novel therapeutic targets.
Gebhardt, F., Zänker, K. S. & Brandt, B. Modulation of epidermal growth factor receptor gene transcription by a polymorphic dinucleotide repeat in intron 1. J. Biol. Chem. 274, 13176–13180 (1999).
Shimajiri, S. et al. Shortened microsatellite d(CA)21 sequence down-regulates promoter activity of matrix metalloproteinase 9 gene. FEBS Lett. 455, 70–74 (1999).
Contente, A., Dittmer, A., Koch, M. C., Roth, J. & Dobbelstein, M. A polymorphic microsatellite that mediates induction of PIG3 by p53. Nat. Genet. 30, 315–320 (2002).
King, D. G. Evolution of simple sequence repeats as mutable sites. Adv. Exp. Med. Biol. 769, 10–25 (2012).
Sawaya, S. et al. Microsatellite tandem repeats are abundant in human promoters and are associated with regulatory elements. PLOS ONE 8, e54710 (2013).
Sawaya, S. M., Bagshaw, A. T., Buschiazzo, E. & Gemmel, N. J. Promoter microsatellites as modulators of human gene expression. Adv. Exp. Med. Biol. 769, 41–44 (2012).
Hsieh, T. Y. et al. Molecular pathogenesis of Gilbert's syndrome: decreased TATA-binding protein binding affinity of UGT1A1 gene promoter. Pharmacogenet. Genomics 17, 229–236 (2007).
Borel, C. et al. Tandem repeat sequence variation as causative cis-eQTLs for protein-coding gene expression variation: the case of CSTB. Hum. Mutat. 33, 1302–1309 (2012).
Rockman, M. V. & Wray, G. A. Abundant raw material for cis-regulatory evolution in humans. Mol. Biol. Evol. 19, 1991–2004 (2002).
Rothenburg, S., Koch-Nolte, F., Rich, A. & Haag, F. A polymorphic dinucleotide repeat in the rat nucleolin gene forms Z-DNA and inhibits promoter activity. Proc. Natl Acad. Sci. USA 98, 8985–8990 (2001).
Stöger, R., Kajimura, T. M., Brown, W. T. & Laird, C. D. Epigenetic variation illustrated by DNA methylation patterns of the fragile-X gene FMR1. Hum. Mol. Genet. 6, 1791–1801 (1997).
Gymrek, M., Golan, D., Rosset, S. & Erlich, Y. lobSTR: a short tandem repeat profiler for personal genomes. Genome Res. 22, 1154–1162 (2012).
Hannan, A. J. Tandem repeat polymorphisms: modulators of disease susceptibility and candidates for 'missing heritability'. Trends Genet. 26, 59–65 (2010). This article includes the first proposal that tandem repeats, and their polymorphic variants, can help explain the missing heritability associated with complex polygenic disorders. It also proposes key roles of somatic tandem repeat variability and predicts a new era of tandem repeat associations in human genetics.
Hefferon, T. W., Groman, J. D., Yurk, C. E. & Cutting, G. R. A variable dinucleotide repeat in the CFTR gene contributes to phenotype diversity by forming RNA secondary structures that alter splicing. Proc. Natl Acad. Sci. USA 101, 3504–3509 (2004).
Hui, J. et al. Intronic CA-repeat and CA-rich elements: a new class of regulators of mammalian alternative splicing. EMBO J. 24, 1988–1998 (2005).
Santos-Pereira, J. M. & Aguilera, A. R loops: new modulators of genome dynamics and function. Nat. Rev. Genet. 16, 583–597 (2015).
Schmidt, M. H. & Pearson, C. E. Disease-associated repeat instability and mismatch repair. DNA Repair 38, 117–126 (2016).
Jain, A. & Vale, R. D. RNA phase transitions in repeat expansion disorders. Nature 546, 243–247 (2017).
Schaefer, M. H., Wanker, E. E. & Andrade-Navarro, M. A. Evolution and function of CAG/polyglutamine repeats in protein-protein interaction networks. Nucleic Acids Res. 40, 4273–4287 (2012).
Pellegrini, M. Tandem repeats in proteins: prediction algorithms and biological role. Front. Bioeng. Biotechnol. 3, 143 (2015).
Kumar, A. S., Sowpati, D. T. & Mishra, R. K. Single amino acid repeats in the proteome world: structural, functional, and evolutionary insights. PLOS ONE 11, e0166854 (2016).
Willems, T. et al. Population-scale sequencing data enable precise estimates of Y-STR mutation rates. Am. J. Hum. Genet. 98, 919–933 (2016).
O'Dushlaine, C. T. & Shields, D. C. Marked variation in predicted and observed variability of tandem repeat loci across the human genome. BMC Genomics 9, 175 (2008).
Payseur, B. A., Jing, P. & Haasl, R. J. A genomic portrait of human microsatellite variation. Mol. Biol. Evol. 28, 303–312 (2011).
McIver, L. J., Fondon, J. W., Skinner, M. A. & Garner, H. R. Evaluation of microsatellite variation in the 1000 Genomes Project pilot studies is indicative of the quality and utility of the raw data and alignments. Genomics 97, 193–199 (2011).
McIver, L. J., McCormick, J. F., Martin, A., Fondon, J. W. & Garner, H. R. Population-scale analysis of human microsatellites reveals novel sources of exonic variation. Gene 516, 328–334 (2013).
Willems, T. et al. The landscape of human STR variation. Genome Res. 24, 1894–1904 (2014).
Mallick, S. et al. The Simons Genome Diversity Project: 300 genomes from 142 diverse populations. Nature 538, 201–206 (2016).
Nithianantharajah, J. & Hannan, A. J. Dynamic mutations as digital genetic modulators of brain development, function and dysfunction. Bioessays 29, 525–535 (2007). This paper proposes that tandem repeats serve novel functions in evolution, ontology, neural development and disease. It is the first proposal of a key role of somatic tandem repeat variability in development, particularly that of the brain and associated aspects of behaviour and cognition.
Verstrepen, K. J., Jansen, A., Lewitter, F. & Fink, G. R. Intragenic tandem repeats generate functional variability. Nat. Genet. 37, 986–990 (2005).
Hammock, E. A. & Young, L. J. Microsatellite instability generates diversity in brain and sociobehavioral traits. Science 308, 1630–1634 (2005). The authors of this study demonstrate that a specific short tandem repeat can regulate neural systems underlying social behaviour using monogamous and polygamous voles as model species.
Matsushima, N. et al. Flexible structures and ligand interactions of tandem repeats consisting of proline, glycine, asparagine, serine, and/or threonine rich oligopeptides in proteins. Curr. Protein Pept. Sci. 9, 591–610 (2008).
Van Eyk, C. L., McLeod, C. J., O'Keefe, L. V. & Richards, R. I. Comparative toxicity of polyglutamine, polyalanine and polyleucine tracts in Drosophila models of expanded repeat disease. Hum. Mol. Genet. 21, 536–547 (2012).
Gonitel, R. et al. DNA instability in postmitotic neurons. Proc. Natl Acad. Sci. USA 105, 3467–3472 (2008).
McMurray, C. T. Mechanisms of trinucleotide repeat instability during human development. Nat. Rev. Genet. 11, 786–799 (2010).
Lee, J. M., Pinto, R. M., Gillis, T., St Claire, J. C. & Wheeler, V. C. Quantification of age-dependent somatic CAG repeat instability in Hdh CAG knock-in mice reveals different expansion dynamics in striatum and liver. PLOS ONE 6, e23647 (2011).
Lokanga, R. A. et al. Somatic expansion in mouse and human carriers of fragile X premutation alleles. Hum. Mutat. 34, 157–166 (2013).
Richardson, S. R., Morell, S. & Faulkner, G. J. L1 retrotransposons and somatic mosaicism in the brain. Annu. Rev. Genet. 48, 1–27 (2014).
Dion, V., Lin, Y., Hubert, L., Waterland, R. A. & Wilson, J. H. Dnmt1 deficiency promotes CAG repeat expansion in the mouse germline. Hum. Mol. Genet. 17, 1306–1317 (2008).
Libby, R. T. et al. CTCF cis-regulates trinucleotide repeat instability in an epigenetic manner: a novel basis for mutational hot spot determination. PLOS Genet. 4, e1000257 (2008).
Slean, M. M., Panigrahi, G. B., Ranum, L. P. & Pearson, C. E. Mutagenic roles of DNA “repair” proteins in antibody diversity and disease-associated trinucleotide repeat instability. DNA Repair 7, 1135–1154 (2008).
Fonville, N. C., Ward, R. M. & Mittelman, D. Stress-induced modulators of repeat instability and genome evolution. J. Mol. Microbiol. Biotechnol. 21, 36–44 (2011).
Chatterjee, N., Lin, Y., Santillan, B. A., Yotnda, P. & Wilson, J. H. Environmental stress induces trinucleotide repeat mutagenesis in human cells. Proc. Natl Acad. Sci. USA 112, 3764–3769 (2015).
Greene, E., Mahishi, L., Entezam, A., Kumari, D. & Usdin, K. Repeat-induced epigenetic changes in intron 1 of the frataxin gene and its consequences in Friedreich ataxia. Nucleic Acids Res. 35, 3383–3390 (2007).
Ruan, H., Wang, Y. H. Friedrich's ataxia GAA.TTC duplex and GAA.GAA.TTC triplex structures exclude nucleosome assembly. J. Mol. Biol. 383, 292–300 (2008).
Evans-Galea, M. V. et al. FXN methylation predicts expression and clinical outcome in Friedreich ataxia. Ann. Neurol. 71, 487–497 (2012).
Colak, D. et al. Promoter-bound trinucleotide repeat mRNA drives epigenetic silencing in fragile X syndrome. Science 343, 1002–1005 (2014).
Pretto, D. I. et al. CGG allele size somatic mosaicism and methylation in FMR1 premutation alleles. J. Med. Genet. 51, 309–318 (2014).
Eichler, E. E. et al. Missing heritability and strategies for finding the underlying causes of complex disease. Nat. Rev. Genet. 11, 446–450 (2010).
Gymrek, M. A genomic view of short tandem repeats. Curr. Opin. Genet. Dev. 44, 9–16 (2017).
Cerasa, A. et al. MAO A VNTR polymorphism and amygdala volume in healthy subjects. Psychiatry Res. 191, 87–91 (2011).
Grube, S. et al. A CAG repeat polymorphism of KCNN3 predicts SK3 channel function and cognitive performance in schizophrenia. EMBO Mol. Med. 3, 309–319 (2011).
Kopf, J. et al. NOS1 ex1f-VNTR polymorphism influences prefrontal brain oxygenation during a working memory task. Neuroimage 57, 1617–1623 (2011).
Squitieri, F., Esmaeilzadeh, M., Ciarmiello, A. & Jankovic, J. Caudate glucose hypometabolism in a subject carrying an unstable allele of intermediate CAG(33) repeat length in the Huntington's disease gene. Mov. Disord. 26, 925–927 (2011).
Sonuga-Barke, E. J. et al. A functional variant of the serotonin transporter gene (SLC6A4) moderates impulsive choice in attention-deficit/hyperactivity disorder boys and siblings. Biol. Psychiatry 70, 230–236 (2011).
Van Holstein, M. et al. Human cognitive flexibility depends on dopamine D2 receptor signaling. Psychopharmacology 218, 567–578 (2011).
Simmons, Z. L. & Roney, J. R. Variation in CAG repeat length of the androgen receptor gene predicts variables associated with intrasexual competitiveness in human males. Horm. Behav. 60, 306–312 (2011).
Abshire, M. Y. et al. Role of androgen receptor CAG repeat polymorphism length in hypothalamic progesterone sensitivity in hyperandrogenic adolescent girls. Endocrine 41, 156–158 (2012).
Shumay, E. et al. Repeat variation in the human PER2 gene as a new genetic marker associated with cocaine addiction and brain dopamine D2 receptor availability. Transl Psychiatry 2, e86 (2012).
Zilles, D. et al. Genetic polymorphisms of 5-HTT and DAT but not COMT differentially affect verbal and visuospatial working memory functioning. Eur. Arch. Psychiatry Clin. Neurosci. 262, 667–676 (2012).
Eisenegger, C. et al. DAT1 polymorphism determines L-DOPA effects on learning about others' prosociality. PLOS ONE 8, e67820 (2013).
Bagshaw, A. T., Horwood, L. J., Fergusson, D. M., Gemmell, N. J. & Kennedy, M. A. Microsatellite polymorphisms associated with human behavioural and psychological phenotypes including a gene-environment interaction. BMC Med. Genet. 18, 12 (2017).
McOmish, C. E., Burrows, E. L. & Hannan, A. J. Identifying novel interventional strategies for psychiatric disorders: integrating genomics, 'enviromics' and gene-environment interactions in valid preclinical models. Br. J. Pharmacol. 171, 4719–4728 (2014).
Zavodna, M., Bagshaw, A., Brauning, R. & Gemmell, N. J. The accuracy, feasibility and challenges of sequencing short tandem repeats using next-generation sequencing platforms. PLOS ONE 9, e113862 (2014).
Sawaya, S., Boocock, J., Black, M. A. & Gemmell, N. J. Exploring possible DNA structures in real-time polymerase kinetics using Pacific Biosciences sequencer data. BMC Bioinformatics 16, 21 (2015).
Carlson, K. D. et al. MIPSTR: a method for multiplex genotyping of germline and somatic STR variation across many individuals. Genome Res. 25, 750–761 (2015).
Kristmundsdóttir, S., Sigurpálsdóttir, B. D., Kehr, B. & Halldórsson, B. V. popSTR: population-scale detection of STR variants. Bioinformatics 33, 4041–4048 (2016).
Willems, T. et al. Genome-wide profiling of heritable and de novo STR variations. Nat. Methods 14, 590–592 (2017).
Highnam, G. et al. Accurate human microsatellite genotypes from high-throughput resequencing data using informed error profiles. Nucleic Acids Res. 41, e32 (2013).
Cao, M. D. et al. Inferring short tandem repeat variation from paired-end short reads. Nucleic Acids Res. 42, e16 (2014).
Fungtammasan, A. et al. Accurate typing of short tandem repeats from genome-wide sequencing data and its applications. Genome Res. 25, 736–749 (2015).
Anisimova, M., Pecerska, J. & Schaper, E. Statistical approaches to detecting and analyzing tandem repeats in genomic sequences. Front. Bioeng. Biotechnol. 3, 31 (2015).
Gelfand, Y., Hernandez, Y., Loving, J. & Benson, G. VNTRseek-a computational tool to detect tandem repeat variants in high-throughput sequencing data. Nucleic Acids Res. 42, 8884–8894 (2014).
Sun, J. X. et al. A direct characterization of human mutation based on microsatellites. Nat. Genet. 44, 1161–1165 (2012).
Fondon, J. W., Martin, A., Richards, S., Gibbs, R. A. & Mittelman, D. Analysis of microsatellite variation in Drosophila melanogaster with population-scale genome sequencing. PLOS ONE 7, e33036 (2012).
Ananda, G. et al. Microsatellite interruptions stabilize primate genomes and exist as population-specific single nucleotide polymorphisms within individual human genomes. PLOS Genet. 10, e1004498 (2014).
Bilgin Sonay, T. et al. Tandem repeat variation in human and great ape populations and its impact on gene expression divergence. Genome Res. 25, 1591–1599 (2015).
Abe, H. & Gemmell, N. J. Evolutionary footprints of short tandem repeats in avian promoters. Sci. Rep. 6, 19421 (2016).
Shimada, M. K. et al. Selection pressure on human STR loci and its relevance in repeat expansion disease. Mol. Genet. Genomics 291, 1851–1869 (2016).
Wray, N. R. et al. Research review: polygenic methods and their application to psychiatric traits. J. Child. Psychol. Psychiatry 55, 1068–1087 (2014).
Sackton, T. B. & Hartl, D. L. Genotypic context and epistasis in individuals and populations. Cell 166, 279–287 (2016).
Guilmatre, A., Highnam, G., Borel, C., Mittelman, D. & Sharp, A. J. Rapid multiplexed genotyping of simple tandem repeats using capture and high-throughput sequencing. Hum. Mutat. 34, 1304–1311 (2013).
Duitama, J. et al. Large-scale analysis of tandem repeat variability in the human genome. Nucleic Acids Res. 42, 5728–5741 (2014).
Hatters, D. M. & Hannan, A. J. (eds) Tandem Repeats in Genes, Proteins and Disease: Methods and Protocols Vol. 1017, 258 (Humana Press, 2013).
The author thanks C. Pearson for comments on an early outline of the manuscript and past and present members of the Hannan laboratory for useful discussions. Apologies to the authors of the many excellent relevant articles that could not be cited and discussed due to space constraints. The author is supported by a Principal Research Fellowship and Project Grants from the National Health and Medical Research Council (NHMRC), as well as the Australian Research Council (ARC) and DHB Foundation, Equity Trustees.
The author declares no competing financial interests.
- Genome-wide association studies
(GWAS). Studies that have been used extensively since the development of microchips that assay single nucleotide polymorphisms (SNPs) across the genome. These studies examine the association of particular polymorphisms and their linked genes with traits and disorders.
The entire collection of repetitive DNA sequences within a whole genome. Subsets of the repeatome can be transcribed and translated, producing equivalent RNA and protein repeatomes within the transcriptome and proteome.
- Short interspersed nuclear elements
(SINEs). A major class of interspersed repetitive DNA, with each element consisting of approximately 100–700 bp of DNA. SINEs are retrotransposons and are thus able to amplify themselves within genomes, usually via RNA intermediates and reverse transcription.
- Alu repeats
Primate-specific SINEs that constitute the most abundant transposable elements in the human genome, which contains over 1 million Alu elements. Alu elements are retrotransposons consisting of interspersed repetitive DNA segments approximately 300 bp in length that constitute over 10% of the human genome.
- Long interspersed nuclear elements
(LINEs). Another major class of interspersed repetitive DNA. They consist of elements approximately 7,000 bp in length. LINEs constitute over 20% of the human genome and are transcriptionally and translationally active (encoding a reverse transcriptase), with recent evidence suggesting that they have evolved roles, including somatic mutation affecting brain development and function.
- Tandem repeat disorders
(TRDs). Disorders caused by mutation of a tandem repeat sequence. These are usually Mendelian disorders with dominant or recessive inheritance patterns, although tandem repeats are increasingly being found to contribute to additional disorders with non-Mendelian inheritance patterns.
A repeating sequence of amino acids encoded by a trinucleotide repeat. For example, a CAG repeat encodes a polyglutamine homopeptide and when the expansion of this homopeptide occurs in the huntingtin protein, it causes Huntington disease.
- Repeat-associated non-ATG translation
(RAN translation). Type of translation of a peptide from a tandem repeat that occurs in the absence of an ATG start codon. The resultant peptides, consisting of repeating amino acid sequences, have been shown to exert toxic effects in specific human diseases.
- Somatic mutations
Changes in the DNA sequence that occur in somatic (non-germline) cells after conception, either during development or in adulthood. The gene mutation can occur either during mitosis (somatic cell division) or in non-dividing cells.
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Hannan, A. Tandem repeats mediating genetic plasticity in health and disease. Nat Rev Genet 19, 286–298 (2018). https://doi.org/10.1038/nrg.2017.115
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