POSITIONALLY CLONED HUMAN-DISEASE GENES - PATTERNS OF EVOLUTIONARY CONSERVATION AND FUNCTIONAL MOTIFS

Positional cloning has already produced the sequences of more than 70 human genes associated with specific diseases, In addition to their me dical importance, these genes are of interest as a set of human genes isolated solely on the basis of the phenotypic effect of the respectiv e mutations, We analyzed the protein sequences encoded by the position ally cloned disease genes using an iterative strategy combining severa l sensitive computer methods, Comparisons to complete sequence databas es and to separate databases of nematode, yeast, and bacterial protein s showed that for most of the disease gene products, statistically sig nificant sequence similarities are detectable in each of the model org anisms, Only the nematode genome encodes apparent orthologs with conse rved domain architecture for the majority of the disease genes, In yea st and bacterial homologs, domain organization is typically not conser ved, and sequence similarity is limited to individual domains, General ly, human genes complement mutations only in orthologous yeast genes, Most of the positionally cloned genes encode large proteins with sever al globular and nonglobular domains, the functions of some or all of w hich are not known. We detected conserved domains and motifs not descr ibed previously in a number of proteins encoded by disease genes and p redicted functions for some of them, These predictions include an ATP- binding domain in the product of hereditary nonpolyposis colon cancer gene (a MutL homolog), which is conserved in the HS90 family of chaper one proteins, type II DNA topoisomerases, and histidine kinases, and a nuclease domain homologous to bacterial RNase D and the 3'-5' exonucl ease domain of DNA polymerase I in the Werner syndrome gene product.