Review
Simple sequence repeats: genetic modulators of brain function and behavior

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Simple sequence repeats (SSRs), sometimes described as genetic ‘stutters,’ are DNA tracts in which a short base-pair motif is repeated several to many times in tandem (e.g. CAGCAGCAG). These sequences experience frequent mutations that alter the number of repeats. Because SSRs are commonly located in promoters, untranslated regions and even coding sequences, such mutations can directly influence almost any aspect of gene function. Mutational expansion of certain triplet repeats is responsible for several hereditary neurodegenerative disorders, but SSR alleles can also contribute to normal variation in brain and behavioral traits. Here we review studies implicating SSRs not just in disease but also in circadian rhythmicity, sociosexual interaction, aggression, cognition and personality. SSRs can affect neuronal differentiation, brain development and even behavioral evolution.

Introduction

In the early 1990s, the neuroscience community was surprised by reports that Huntington's disease, fragile X syndrome and several other hereditary neurological disorders all shared a common cause in the form of mutational expansion of triplet repeat DNA sequences within genes 1, 2. As one researcher was quoted in Science[3], ‘No one expected that DNA sequences could be so unstable or behave as these do.’ Nevertheless, DNA researchers have long known that simple sequence repeats (SSRs; also called microsatellites and minisatellites) have a propensity for ‘slippage mutations,’ which increase or decrease the number of repeats without otherwise altering the sequence 4, 5. SSRs based on various motifs are extremely numerous in eukaryotic genomes; many human genes possess multiple SSRs. The abundant polymorphism which results from repeat slippage has become the basis for DNA fingerprinting, lineage analysis and gene mapping. Yet this very mutability, together with the seeming lack of information content in such repetitive genetic ‘stutters,’ once appeared to preclude any possibility of critical function for SSRs. Indeed, much of the literature on SSR polymorphism has assumed (and continues to assume; see e.g. Ref. [6]) that SSRs are genetic ‘junk,’ supplying only ‘neutral’ variation with no appreciable effect on phenotype.

As we review here, however, abundant evidence warrants some skepticism toward any presumption of neutrality for SSR alleles 7, 8, 9, 10, 11, 12, 13, 14, 15. Repeat-expansion diseases have highlighted the occurrence of repetitive sequences at sites where slippage mutations can have dramatic consequences. But many other examples of repeat-number effects have come to light since Hamada and colleagues first established that altering the number of repeating dinucleotides could affect gene activity [7]. By now, SSR sequences are widely recognized for a remarkable set of characteristics (reviewed in Refs 10, 11, 12, 13, 14, 15):

  • slippage mutations, occurring at rates that can be as high as 10−2 per cell division at a single SSR locus, yield abundant repeat-number variation at innumerable SSR sites;

  • SSR slippage mutations are readily reversible, unlike single nucleotide substitutions;

  • SSR mutability is a function of locus-specific properties including motif length, total number of repeats, inclusion of variant motifs and flanking sequences;

  • repeat-number variation can affect diverse aspects of gene function including transcription rates and transcript stability, rates of protein folding and turnover, and protein–protein interactions, aggregation and subcellular location; and

  • repeat-number mutations commonly exert incremental quantitative effects, not unlike adjusting a ‘tuning knob’ [11]. They can also act reversibly to switch genes on or off.

These characteristics have prompted speculation that the mutability of SSRs could play an important and potentially beneficial role in evolution 5, 8, 9, 10, 11, 13, 14, 15, 16, 17. Thus, the triplet repeat-expansion diseases represent only the pathological extreme of a much more general mutational process, one which also contributes to normal brain function and development.

Section snippets

Repeat-expansion diseases

At least 20 different neurological disorders are caused by expanded SSRs (Table 1; reviewed in Refs 1, 2). Such diseases are frequently characterized by ‘genetic anticipation,’ a hereditary tendency toward further expansion of pathological repeat alleles in each generation, leading to earlier onset and accelerated disease progression in subsequent generations.

Huntington's disease (HD) exemplifies neurodegenerative repeat-expansion diseases caused by an expanded protein-coding repeat. The

Effects of SSR variation on behavior

Although extreme repeat expansion is deleterious, studies of many different organisms provide evidence that nonpathogenic SSR polymorphism contributes to normal quantitative genetic variation in traits ranging from yeast cell adhesion to dog skeletal morphology 10, 14, 15. Among the best-studied examples of relationships among phenotype, molecular function and SSR polymorphism are three genes influencing animal behavior. One of these, the period (per) gene of Drosophila melanogaster,

Potential significance of mitotic SSR mutation for brain development

Somatic mosaicism is a common feature of several of the neurodegenerative repeat-expansion diseases 40, 41, 42, 43. For example, as seen in spinocerebellar ataxia 2 (a classic triplet repeat disease caused by expanded CAG-encoded polyglutamine tracts), pathologically expanded repeats can expand further during development to create a mosaic of cells with differing repeat lengths. Awareness of this role for mitotic repeat expansion was prompted by the discovery of individuals who possessed

Conclusion

SSR mutability provides an abundant source of genetic variation. Most genes, including many involved with brain activity, are associated with one and often several polymorphic SSRs located in sites where repeat-number variation could affect gene function 1, 9, 10, 11, 12, 13, 14, 15. A decade ago David Comings [12] wrote, ‘Our initial assumption was that like the neutral or silent single base pair polymorphisms [SNPs], the micro/minisatellite alleles would be in linkage disequilibrium with

Acknowledgements

J.W.F. is supported by the Sara and Frank McKnight Fellowship in Biochemistry. E.A.D.H. would like to acknowledge recent support from NIH F31MH67397, NIH T32MH65215 and NIH T32MH075883. A.J.H. is supported by the NHMRC (Australia), a Pfizer Australia Research Fellowship and the Lord Mayor's Charitable Fund (Eldon and Anne Foote Trust). The authors are aware of no actual or potential conflict of interest related to this work.

Glossary

Allele
a distinct form of DNA sequence at a particular chromosomal locus, differing in base-pair sequence from other alleles at that locus.
Coding sequences
those portions of genes (exons) that are translated into proteins. In conventional usage, all other sequences, whether or not they have a function, are ‘noncoding.’
Gene
a tract of DNA consisting not only of coding sequences but also introns and associated noncoding upstream and downstream regulatory elements.
Linkage analysis
localization of

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