Evolution of Simple Repeats in DNA and Their Relation to Human Disease

including a coding region confined to a single exon and largely composed of short tandem repeats, different in each gene. The evolutionary history of the epidermal differentiation complex might therefore be as follows. The coding region of the ancestral gene was first gener-Philippe Djian CNRS (Centre de Recherche sur l'Endocrinologie Molé culaire et le Dé veloppement) 9, rue Jules Hetzel 92190 Meudon-Bellevue France ated by duplications of CAG. The whole ancestral gene was then duplicated several times. The coding regions of the duplicates were subsequently diverged from each other by nucleotide substitutions, before being further expanded by duplications of short repeats. Diseases of Although simple repeats compose a substantial fraction polyglutamine may be viewed as an aberrant conse-of the eukaryotic genome, their significance has not quence of a normal evolutionary process, which has been understood. The high level of polymorphism of presumably acted on the genes for involucrin and GRP1 micro-and minisatellites has mostly been used for prac-at the initial stages of extension of the coding region tical purposes, such as positional cloning of genes asso-(Green and Djian, 1998). ciated with diseases, forensic medicine, and phyloge-netic studies. The discovery that a number of human diseases are the direct consequence of excessive dupli-Do Polyaminoacid Sequences, and Particularly Those Associated with Human Disease, cations of trinucleotide repeats, similar to microsatel-lites but located within genes, has completely changed Serve Any Function? This is a much debated question, and in many cases, the picture. Every aspect of the biology of simple repeats is now the object of intensive study. Much of the EMBO such a function seems improbable. As mentioned by David Rubinsztein (Cambridge) and John Hancock (Lon-workshop on " Trinucleotide Expansion Diseases in the Context of Micro-and Minisatellite Evolution " held at don), the size of the polyglutamine in proteins potentially able to cause human disease varies greatly within the Hammersmith Hospital in London (April 1–3, 1998) was concentrated on three questions: What is the evolution-normal human population and between species: the mouse may contain only two glutamines at a site where ary significance of simple repeats, and particularly of polyaminoacids, in proteins? What are the mechanisms the human contains over twenty. Even more compelling were examples in insects provided by Diethard Tautz of the instability of simple repeats? How does the presence of an excessive number of triplets in transcribed (Munich). The knirps gene of Drosophila contains a CAG (gln) repeat. In …

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