..• Focuses on key aspects of TRPs in health and disease
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..• Provides a detailed discussion of repeat sequences as mutable sites providing genetic variability upon which natural selection can act
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..• Provides insights into how expanded polyalanine in specific proteins leads to developmental abnormalities and neurocognitive dysfunction
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..Tandem repeats of DNA sequences provide a unique and abundant source of genomic variability and recent evidence suggests they can modulate a range of biological processes in a wide variety of different species. These classes of repetitive DNA are variously referred to as simple sequence repeats, satellite DNA (microsatellites, minisatellites and satellites) or variable number tandem repeats. A key aspect of tandem repeats is that they represent highly polymorphic and uniquely mutable genomic components which can (depending on their sequence, length and location) affect the structure and function of DNA, RNA and protein. This book addresses the role of tandem repeat polymorphisms (TRPs) in genetic plasticity, evolution, development, biological processes, neural diversity, brain function, dysfunction and disease.
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..Expansions in tandem repeats (‘dynamic mutations’) are known to cause many disorders, which mainly affect the nervous system, including Huntington’s disease (the most common polyglutamine disorder), spinocerebellar ataxias, Kennedy’s disease (spinobulbar muscular atrophy), dentatorubral-pallidoluysian atrophy, Friedreich ataxia, polyalanine disorders, fragile X syndrome and related disorders. Whilst the plasticity of these tandem repeats occurs at the DNA level, evidence for both ‘gain of function’ and ‘loss of function’ pathogenic effects of repeat expansions (‘genetic stutters’) at RNA and protein levels is discussed using specific examples of these monogenic disorders. Furthermore, it has been proposed that TRPs could help solve the conundrum of ‘missing heritability’ produced by genome-wide association studies of various polygenic complex diseases which have only examined single nucleotide polymorphisms (SNPs). There are hundreds of thousands of unique tandem repeats in the human genome and their polymorphic distributions have the potential to greatly influence functional diversity and disease susceptibility. Recent discoveries in this expanding field are critically reviewed and discussed in a range of different chapters from leading experts in their respective fields, with a focus on the role of TRPs and their various gene products in evolution, development, diverse molecular and cellular processes, brain function and disease.
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