ON SIMPLE REPETITIVE DNA-SEQUENCES AND COMPLEX DISEASES

Simple repetitive DNA sequences are abundantly interspersed in eukaryo te genomes and therefore useful in genome research and genetic fingerp rinting in plants, fungi and animals, including man. Recently, simple repeats were also identified in some prokaryotic genomes. Hence the sa me probes can be applied for multilocus DNA fingerprinting in medicall y relevant bacteria. Simple repeats including composite dinucleotide m icrosatellites are differentially represented in different compartment s of eukaryote genomes. Expanded triplet blocks in and around certain genes may, for example, cause so-called trinucleotide diseases in man. As a consequence, simple repetitive sequences should also be characte rized with respect to their influences on the DNA structure, gene expr ession, genomic (in)stability and their development on an evolutionary time scale. Here three examples of microsatellites in the human major histocompatibility complex (HLA) are investigated, a (GT)(n) microsat ellite situated 2 kb 5' off the lymphotoxin alpha (LTA) gene, a (GAA)( n) block in the 5' part of the HLA-F gene and a composite (GT),(GA), s tretch in the second intron of HLA-DRBl genes. Grossly differing mutat ion rates are evident in these elements as well as varying linkage dis equilibria. The unfolding of these simple repeats in distant human pop ulations is covered including Caucasians, Bushmen and South American I ndians. Furthermore, implications of simple repeat neighboring genes a re discussed for the multifactorial diseases multiple sclerosis (MS), rheumatoid arthritis (RA) and early onset pauciarticular arthritis (EO PA). Polymorphisms of HLA-DRBl and T cell receptor beta variable (TCRB V) genes confer susceptibility for these autoimmune diseases as demons trable by intronic simple repeat variability. Microsatellite polymorph isms within the TNF region reveal linkage disequilibria with HLA-DRBl and different promotor alleles of the TNFA gene. Disease associations with TNFA microsatellite alleles are, on the one hand, secondary to as sociations with HLA-DRBl genes (in MS) or they represent additional ri sk factors (in RA, EOPA) on the other hand. Evolutionary persistence, various structural conformations and the specific binding of nuclear p roteins to several simple repeat sequences refute the preconceptions o f biological insignificance for all of these ubiquitously interspersed elements.