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  • Review Article
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Repeat instability: mechanisms of dynamic mutations

Key Points

  • Since the identification in 1991 of repeat instability as a disease-causing mutation, gene-specific repeat instability is now known to be the mutational cause of at least 40 neurological, neurodegenerative and neuromuscular diseases.

  • Repeat instability is a dynamic mutation and is defined by both cis-elements and trans-factors.

  • Both germline (parent-to-offspring) and tissue-specific somatic instability occurs.

  • There are unique and common effectors for the instability of different repeat sequences, although each disease or locus is unique.

  • Replication, repair and recombination contribute to repeat instability, either separately or in combination.

  • Extrapolation of repeat instability data from model systems must take into account the limitations of the model and observations from human patients.

Abstract

Disease-causing repeat instability is an important and unique form of mutation that is linked to more than 40 neurological, neurodegenerative and neuromuscular disorders. DNA repeat expansion mutations are dynamic and ongoing within tissues and across generations. The patterns of inherited and tissue-specific instability are determined by both gene-specific cis-elements and trans-acting DNA metabolic proteins. Repeat instability probably involves the formation of unusual DNA structures during DNA replication, repair and recombination. Experimental advances towards explaining the mechanisms of repeat instability have broadened our understanding of this mutational process. They have revealed surprising ways in which metabolic pathways can drive or protect from repeat instability.

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Figure 1: Unstable repeat tracts and the processes associated with repeat instability.
Figure 2: Germline and somatic instability.
Figure 3: DNA metabolic processes associated with repeat instability.
Figure 4: Mismatch repair and trinucleotide repeat instability.

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Acknowledgements

The authors wish to thank the many scientists, too numerous to list individually, for discussions and comments on this manuscript. In addition, we wish to express our gratitude to the members of the Pearson laboratory (K. Hagerman, R. Lau, M. Leonard and G. Panigrahi) for their input into the manuscript. We apologize to those authors whose work we could not cite owing to space limitations. The Pearson laboratory is supported by funding from the Muscular Dystrophy Association, USA, the Canadian Institutes of Health Research (CIHR), the Fragile X Research Foundation of Canada and the University of Toronto Deans fund. J.D.C. is supported by a CIHR doctoral research award. C.E.P. is a CIHR Scholar and Canadian Genetic Disease Network Scholar.

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DATABASES

Entrez Gene

FRAXE

FRAXF

FRA10B

FRA11A

FRA16B

OMIM

dentatorubral-pallidoluysian atrophy

dystrophia myotonica 1

dystrophia myotonica 2

facioscapulohumeral muscular dystrophy 1A

fragile X syndrome

Friedreich ataxia

Huntington disease

insulin

Machado–Joseph disease

myoclonic epilepsy of Unverricht and Lundborg

spinal and bulbar muscular atrophy

spinocerebellar ataxia 8

spinocerebellar ataxia 10

FURTHER INFORMATION

Huntington's Disease Society of America

Muscular Dystrophy Association

Neuromuscular Disease Centre DNA Repeat Sequence and Disease page

Tandemly Repeated (Satellite) DNA

The National Fragile X Foundation

The Pearson Laboratory home page

Trinucleotide Repeats at OMIM

Glossary

GENETIC ANTICIPATION

A phenomenon in which disease severity increases and/or age of onset of disease decreases from one generation to the next.

SPERMATOGONIA

The mitotically dividing stem cells of the male germ line, the descendants of which ultimately become mature sperm.

FULL MUTATION

The expanded repeat tract that is typically associated with disease. The term is often used to distinguish this event from an individual who has the shorter premutation or proto-mutation expansions that are not associated with disease.

PREMUTATION

A repeat tract of a length that rarely leads to disease symptoms. However, the possibility for further repeat-length expansion to occur on transmission is high as a result of the longer repeat length. The term applies to disorders such as Huntington disease and fragile X syndrome. The term proto-mutation applies to dystrophia myotonica 1, for which individuals might (or might not) eventually develop symptoms.

CpG ISLAND

A sequence of at least 200 bp with a greater number of CpG sites than expected for its GC content. These regions are often GC rich, associated with genes and typically undermethylated.

PARENT-OF-ORIGIN EFFECT

The increased proportion of paternal or maternal disease-causing transmission to offspring. This effect is molecularly explained by a paternal or maternal repeat-expansion bias in the germ line.

LINKAGE DISEQUILIBRIUM

A measure of genetic associations between alleles at different loci, which indicates whether allelic or marker associations on the same chromosome are more common than expected.

OKAZAKI FRAGMENT

Short DNA fragments (140 nucleotides for primates) that are produced on the lagging strand of the replication fork during discontinuous DNA replication; these fragments are eventually processed (to remove the RNA primer) and ligated to form the mature full-length lagging nascent strand.

GENE CONVERSION

A meiotic process that involves the non-reciprocal transfer of genetic information, in which one allele directs the conversion of its sister allele.

SINGLE-STRAND ANNEALING

A process that is typically initiated after a double-strand break, in which regions of ssDNA are created to allow for complementary strands of sister chromatids or homologues to anneal to each other.

XERODERMA PIGMENTOSUM

A human disease that is characterized by extraordinary sensitivity to sunlight, and is caused by a defect in the ultraviolet-mutation-repair system.

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Pearson, C., Edamura, K. & Cleary, J. Repeat instability: mechanisms of dynamic mutations. Nat Rev Genet 6, 729–742 (2005). https://doi.org/10.1038/nrg1689

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