Simple sequence repeats: genetic modulators of brain function and behavior

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.

[1]  M. Burmeister,et al.  Meta‐analysis of the association between a serotonin transporter promoter polymorphism (5‐HTTLPR) and anxiety‐related personality traits , 2004, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[2]  M. Munafo,et al.  Does measurement instrument moderate the association between the serotonin transporter gene and anxiety-related personality traits? A meta-analysis , 2005, Molecular Psychiatry.

[3]  K. Sobczak,et al.  Patterns of CAG repeat interruptions in SCA1 and SCA2 genes in relation to repeat instability , 2004, Human mutation.

[4]  E. Nevo,et al.  Sequence polymorphism of candidate behavioural genes in Drosophila melanogaster flies from ‘Evolution canyon’ , 2005, Molecular ecology.

[5]  S. Rusconi,et al.  Transcriptional activation modulated by homopolymeric glutamine and proline stretches. , 1994, Science.

[6]  Kenny Q. Ye,et al.  Positive association of schizophrenia to JARID2 gene , 2007, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[7]  S. Karlin,et al.  Amino acid runs in eukaryotic proteomes and disease associations , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[8]  S. Faraone,et al.  Meta‐analysis of the association between two polymorphisms in the serotonin transporter gene and affective disorders , 2005, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[9]  A. Hannan,et al.  Dynamic mutations as digital genetic modulators of brain development, function and dysfunction , 2007, BioEssays : news and reviews in molecular, cellular and developmental biology.

[10]  S. Israel,et al.  Individual differences in allocation of funds in the dictator game associated with length of the arginine vasopressin 1a receptor RS3 promoter region and correlation between RS3 length and hippocampal mRNA , 2008, Genes, brain, and behavior.

[11]  M. Rosbash,et al.  Molecular coevolution within a Drosophila clock gene. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[12]  M. Delatycki,et al.  Friedreich ataxia—update on pathogenesis and possible therapies , 2004, Neurogenetics.

[13]  C. E. Pearson,et al.  Effect of CAT or AGG Interruptions and CpG Methylation on Nucleosome Assembly upon Trinucleotide Repeats on Spinocerebellar Ataxia, Type 1 and Fragile X Syndrome* , 2005, Journal of Biological Chemistry.

[14]  Fred H. Gage,et al.  Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition , 2005, Nature.

[15]  L. Andersson,et al.  A frameshift mutation in MC1R and a high frequency of somatic reversions cause black spotting in pigs. , 2001, Genetics.

[16]  L. Excoffier,et al.  Mammalian monogamy is not controlled by a single gene. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[17]  I. Craig,et al.  Functional polymorphisms in dopamine and serotonin pathway genes , 2006, Human mutation.

[18]  Y. Kashi,et al.  Simple sequence repeats as advantageous mutators in evolution. , 2006, Trends in genetics : TIG.

[19]  A. Hannan,et al.  Molecular mechanisms mediating pathological plasticity in Huntington's disease and Alzheimer's disease , 2007, Journal of neurochemistry.

[20]  H. Heinze,et al.  The Dopaminergic Midbrain Participates in Human Episodic Memory Formation: Evidence from Genetic Imaging , 2006, The Journal of Neuroscience.

[21]  Y. Kashi,et al.  Mutability and evolvability: Indirect selection for mutability , 2007, Heredity.

[22]  C. Kyriacou,et al.  Clines in clock genes: fine-tuning circadian rhythms to the environment. , 2008, Trends in genetics : TIG.

[23]  Kristine Coleman,et al.  Anxious Behavior and Fenfluramine-Induced Prolactin Secretion in Young Rhesus Macaques with Different Alleles of the Serotonin Reuptake Transporter Polymorphism (5HTTLPR) , 2004, Behavior genetics.

[24]  K. Lesch,et al.  Serotonin transporter gene polymorphism, differential early rearing, and behavior in rhesus monkey neonates , 2002, Molecular Psychiatry.

[25]  E. Trifonov,et al.  The multiple codes of nucleotide sequences , 1989 .

[26]  P. Hagerman,et al.  Recent advances in fragile X: a model for autism and neurodegeneration , 2005, Current opinion in psychiatry.

[27]  S. Wasser.  Evolutionary Theory and Processes: Modern Perspectives , 1999, Springer Netherlands.

[28]  T. Insel,et al.  Increased affiliative response to vasopressin in mice expressing the V1a receptor from a monogamous vole , 1999, Nature.

[29]  Harry T Orr,et al.  Trinucleotide repeat disorders. , 2007, Annual review of neuroscience.

[30]  K. Lesch,et al.  Association of Anxiety-Related Traits with a Polymorphism in the Serotonin Transporter Gene Regulatory Region , 1996, Science.

[31]  T. Arendt,et al.  Aneuploidy and DNA Replication in the Normal Human Brain and Alzheimer's Disease , 2007, The Journal of Neuroscience.

[32]  D. Murphy,et al.  Population and familial association between the D4 dopamine receptor gene and measures of Novelty Seeking , 1996, Nature Genetics.

[33]  Yechezkel Kashi,et al.  Evolutionary tuning knobs , 1997 .

[34]  M. Hayden,et al.  Somatic and gonadal mosaicism of the Huntington disease gene CAG repeat in brain and sperm , 1994, Nature Genetics.

[35]  Larry J Young,et al.  Microsatellite Instability Generates Diversity in Brain and Sociobehavioral Traits , 2005, Science.

[36]  L. Caporale,et al.  Natural selection and the emergence of a mutation phenotype: an update of the evolutionary synthesis considering mechanisms that affect genome variation. , 2003, Annual review of microbiology.

[37]  D. Nelson,et al.  Interruptions in the expanded ATTCT repeat of spinocerebellar ataxia type 10: repeat purity as a disease modifier? , 2006, American journal of human genetics.

[38]  G. Breen,et al.  Differential Regulation of the Serotonin Transporter Gene by Lithium Is Mediated by Transcription Factors, CCCTC Binding Protein and Y-Box Binding Protein 1, through the Polymorphic Intron 2 Variable Number Tandem Repeat , 2007, The Journal of Neuroscience.

[39]  A. Neugut,et al.  Genetic Risk Factors , 2003 .

[40]  Mark F Bear,et al.  The mGluR theory of fragile X mental retardation , 2004, Trends in Neurosciences.

[41]  R. Manchester,et al.  A radio pulsar with an 8.5-second period that challenges emission models , 1999, Nature.

[42]  R. Ebstein,et al.  Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of Novelty Seeking , 1996, Nature Genetics.

[43]  I. V. Kovtun,et al.  Features of trinucleotide repeat instability in vivo , 2008, Cell Research.

[44]  C. Ross,et al.  A repeat expansion in the gene encoding junctophilin-3 is associated with Huntington disease–like 2 , 2001, Nature Genetics.

[45]  Robert I. Richards,et al.  Simple repeat DNA is not replicated simply , 1994, Nature Genetics.

[46]  L. Caporale.  The implicit genome , 2006 .

[47]  Takanori Yamagata,et al.  Large expansion of the ATTCT pentanucleotide repeat in spinocerebellar ataxia type 10 , 2000, Nature Genetics.

[48]  S. Warren,et al.  Transcription, translation and fragile X syndrome. , 2006, Current opinion in genetics & development.

[49]  F. Hazama,et al.  Somatic mosaicism of CAG repeat in dentatorubral-pallidoluysian atrophy (DRPLA). , 1995, Human molecular genetics.

[50]  J. Rommens,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 , 1997, Nature Genetics.

[51]  G. Sobue,et al.  Tissue-specific somatic mosaicism in spinal and bulbar muscular atrophy is dependent on CAG-repeat length and androgen receptor--gene expression level. , 1999, American journal of human genetics.

[52]  S. Tapscott,et al.  Myotonic dystrophy: emerging mechanisms for DM1 and DM2. , 2007, Biochimica et biophysica acta.

[53]  Thomas Elbert,et al.  A deletion variant of the α2b-adrenoceptor is related to emotional memory in Europeans and Africans , 2007, Nature Neuroscience.

[54]  K. Lesch,et al.  Early experience and serotonin transporter gene variation interact to influence primate CNS function , 2002, Molecular Psychiatry.

[55]  Y. Kashi,et al.  Simple sequence repeats as a source of quantitative genetic variation. , 1997, Trends in genetics : TIG.

[56]  L. A. Sawyer,et al.  Natural variation in a Drosophila clock gene and temperature compensation. , 1997, Science.

[57]  S. Choudhry,et al.  CAG repeat instability at SCA2 locus: anchoring CAA interruptions and linked single nucleotide polymorphisms. , 2001, Human molecular genetics.

[58]  D. Comings.  Polygenic inheritance and micro/minisatellites , 1998, Molecular Psychiatry.

[59]  P. Detloff,et al.  DNA instability in postmitotic neurons , 2008, Proceedings of the National Academy of Sciences.

[60]  H. Garner,et al.  Molecular origins of rapid and continuous morphological evolution , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[61]  H. Hamada,et al.  Enhanced gene expression by the poly(dT-dG).poly(dC-dA) sequence , 1984, Molecular and cellular biology.

[62]  B. Kempenaers,et al.  Avian Clock gene polymorphism: evidence for a latitudinal cline in allele frequencies , 2007, Molecular ecology.

[63]  D. Loesch,et al.  Molecular and cognitive predictors of the continuum of autistic behaviours in fragile X , 2007, Neuroscience & Biobehavioral Reviews.

[64]  A. Messer,et al.  Msh2 deficiency prevents in vivo somatic instability of the CAG repeat in Huntington disease transgenic mice , 1999, Nature Genetics.

[65]  D. King,et al.  Variation and Fidelity: The Evolution of Simple Sequence Repeats as Functional Elements in Adjustable Genes , 1999 .

[66]  M. MacDonald,et al.  Huntington's disease: seeing the pathogenic process through a genetic lens. , 2006, Trends in biochemical sciences.

[67]  J. Manning,et al.  The androgen receptor gene: a major modifier of speed of neuronal transmission and intelligence? , 2007, Medical hypotheses.

[68]  H. Ellegren.  Microsatellites: simple sequences with complex evolution , 2004, Nature Reviews Genetics.

[69]  J. Swanson,et al.  Association of the dopamine transporter (DAT1) 10/10-repeat genotype with ADHD symptoms and response inhibition in a general population sample , 2005, Molecular Psychiatry.

[70]  T. Bird,et al.  An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8) , 1999, Nature Genetics.

[71]  G. Sobue,et al.  Differential pattern in tissue-specific somatic mosaicism of expanded CAG trinucleotide repeat in dentatorubral-pallidoluysian atrophy, Machado-Joseph disease, and X-linked recessive spinal and bulbar muscular atrophy , 1996, Journal of the Neurological Sciences.

[72]  A. Caspi,et al.  Influence of Life Stress on Depression: Moderation by a Polymorphism in the 5-HTT Gene , 2003, Science.

[73]  V. Morell.  The puzzle of the triple repeats. , 1993, Science.

[74]  M. Krawczak,et al.  Natal Dispersal in Rhesus Macaques Is Related to Serotonin Transporter Gene Promoter Variation , 2000, Behavior genetics.

[75]  Melvin G McInnis,et al.  Expansion of a novel CAG trinucleotide repeat in the 5′ region of PPP2R2B is associated with SCA12 , 1999, Nature Genetics.