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Tandem repeats mediating genetic plasticity in health and disease

Key Points

  • 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.

Abstract

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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Figure 1: Genic locations and expression products of tandem repeats causing human disorders.
Figure 2: Pathways to pathogenesis in tandem repeat disorders.
Figure 3: Tandem repeat polymorphisms as dynamic sources of phenotypic plasticity.
Figure 4: Impacts of tandem repeats on the structure and function of DNA, RNA and proteins.

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Acknowledgements

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.

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Glossary

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.

Repeatome

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.

Homopeptide

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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