COMPARATIVE-STUDY OF THE GENOMIC ORGANIZATION OF DNA REPEATS WITHIN THE 5'-FLANKING REGION OF THE NATURAL RESISTANCE-ASSOCIATED MACROPHAGE PROTEIN GENE (NRAMP1) BETWEEN HUMANS AND GREAT APES

The human NRAMP1 gene located on Chromosome (Chr) region 2q35 is a can didate gene for increased risk of infection by several intracellular m acrophage parasites, including M. tuberculosis and M, leprae. In searc h for a possible mutational hot spot, we have analyzed a 3.5-kb region 5' to NRAMP1 that is highly enriched for DNA repeat sequences. The re peat sequences could be grouped into one Mer element and six Alu eleme nts, representing five Alu subfamilies, that had integrated in the sam e DNA region during successive rounds of Alu retropositional activity. Comparative sequence analysis of the Alu cluster region in humans, ch impanzee (Pan paniscus), and gorilla (Gorilla gorilla) revealed only m odest sequence variability and failed to detect any evidence for genom ic instability of the highly repetitive DNA region. These results show that sequence length variants in the Alu-flanking regions as well as nucleotide substitutions are the most common genomic variations even i n a region of extreme Alu-clustering. Moreover, the high degree of seq uence conservation among three primate species argues against the Alu cluster being the site of frequent genomic rearrangements or other fre quent genetic events that might influence NRAMP1 expression.