Trinucleotide expansion diseases in the context of micro- and minisatellite evolution, Hammersmith Hospital, April 1-3, 1998.

Abstract

In 1991, La Spada et al . and Kremer et al . showed that spinal and bulbar muscular atrophy and Fragile X syndrome are caused by expansions of CAG and CGG repeats, respectively. Since then, numerous other diseases have been found to result from a similar mechanism of expansion. Expansions have been found affecting repeats in exons, 5′ and 3′ UTRs and introns. A considerable amount of effort has been put into understanding the process of this expansion, its relationship to disease and the behaviour of these repeats within human populations—all essential prerequisites for providing effective genetic counselling, and, in the longer run, developing effective therapies. The revelation that triplet repeats can make a significant pathological impact was a surprise—since the earliest discovery of simple sequences (now generally known as microsatellites) they have been regarded as essentially neutral structures, useful as genetic markers but of no evolutionary significance beyond that. Despite (or, in part, because of) this assumed neutrality, evolutionary biologists and population geneticists had focused a considerable amount of attention on the pattern and process of repetitive sequence evolution. Much of this knowledge remains at the fringes of studies of the diseases themselves, while evolutionary biologists working on repetitive sequences are largely ignorant of the biological processes that contribute to instability in triplet repeats. The aim of this meeting was to improve the cross‐fertilization between these two, not necessarily mutually exclusive, groups of researchers. Three main strands could be discerned from the presentations. We will describe these loosely as: the genomic and evolutionary context of repeats, mechanisms of mutation at repeats and the molecular genetic basis of repeat instability. ### Genomic and evolutionary context of repeats Surveys of the frequencies and distributions of repeats in eukaryotic genomes, based on database searches, show that certain repeats are more common than others, and that those involved in triplet …