Expanding Mutations/Genetic Anticipation

Abstract

Expanding or dynamic mutations are caused by the abnormal expansion of simple repetitive sequences, which are scattered throughout the genome. The phenotypic effects will depend on the localization of the unstable sequence (exonic, intronic, in the promoter or intergenic region), on the size of the expansion, on the lack of interruptions and on the sequence of the repeat unit, which may favour the formation of secondary structures. More than 20 genetic disorders due to expanding (or ‘dynamic’) mutations have been reported to date.

Keywords: simple repetitive sequences; trinucleotide repeats; dynamic mutations; genetic anticipation; chromosomal instability

Figure 1.

Expansion disorders due to SRS outside coding sequences.

Figure 2.

Expansion disorders due to SRS encoding polyglutamine (poly‐Q) tracts.

Figure 3.

Expansion disorders due to SRS encoding polyalanine (poly‐A) tracts.

Figure 4.

Slipped strand mispairing and small expansions/deletions.

Figure 5.

Multiple slippage events and larger expansions.

close

References

Amiel J, Trochet D, Clément‐Ziza M, Munnich A and Lyonnet S (2004) Polyalanine expansions in human. Human Molecular Genetics 13: R235–R243.

Andres AM, Soldevila M and Lao O (2004) Comparative genetics of functional trinucleotide tandem repeats in humans and apes. Journal of Molecular Evolution 59: 329–339.

Harley HG, Brook JD and Rundle SA (1992) Expansion of an unstable DNA region and phenotypic variation in myotonic dystrophy. Nature 355: 545–546.

Huang H, Winter EE, Wang H et al. (2004) Evolutionary conservation and selection of human disease gene orthologs in the rat and mouse genomes. Genome Biology 5: R47.

International Human Genome Sequencing Consortium (2001) Initial sequencing and analysis of the human genome. Nature 409: 860–921.

Kunkel TA (1993) Slippery DNA and disease. Nature 365: 207–208.

Mewborn SK, Lese Martin C and Ledbetter DH (2005) The dynamic nature and evolutionary history of subtelomeric and pericentromeric regions. Cytogenetic and Genome Research 108: 22–25.

Michalik A and van Broeckhoven C (2003) Pathogenesis of polyglutamine disorders: aggregation revisited. Human Molecular Genetics 12: R173–R186.

Richard GF and Paques F (2000) Mini‐ and microsatellite expansions: the recombination connection. EMBO Reports 1: 122–126.

Schloetterer C and Tautz D (1992) Slippage synthesis of simple sequence DNA. Nucleic Acids Research 20: 211–215.

Sinden RR, Potaman VN, Oussatcheva EA et al. (2002) Triplet repeat DNA structures and human genetic disease: dynamic mutations from dynamic DNA. Journal of Biosciences 27: 53–65.

Subramanian S, Mishra RK and Singh L (2003a) Genome‐wide analysis of microsatellite repeats in humans: their abundance and density in specific genomic regions. Genome Biology 4: R13.

Subramanian S, Madgula VM, George R et al. (2003b) Triplet repeats in human genome: distribution and their association with genes and other genomic regions. Bioinformatics 19: 549–552.

Verkerk AJMH, Pieretti M, Sutcliffe JS et al. (1991) 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.

Weber JL and Wong C (1993) Mutation of human short tandem repeats. Human Molecular Genetics 2: 1123–1128.

Further Reading

Cummings CJ and Zoghbi HY (2000) Fourteen and counting: unraveling trinucleotide repeat diseases. Human Molecular Genetics 9: 909–916.

Parniewski P and Staczek P (2003) Molecular Mechanisms of TRS Instability. Georgetown, TX: Landes Bioscience.

http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=eurekah.chapter.13297.

Richards RI (2001) Dynamic mutations: a decade of unstable expanded repeats in human genetic disease. Human Molecular Genetics 10: 2187–2194.

Web pages on DNA repeat sequences and disease by the Neuromuscular Disease Center of the Washington University, St Louis, MO, USA. http://www.neuro.wustl.edu/neuromuscular/mother/dnarep.htm.

Web site of the Simple Sequence Repeat Database for the Human Genome, maintained at the Centre for Cellular and Molecular Biology (CCMB), Hyderabad, India. http://www.ccmb.res.in/ssr/.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Chiurazzi, Pietro, and Oostra, Ben A(Jan 2006) Expanding Mutations/Genetic Anticipation. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0001463]