DUPLICATION OF A GENE-RICH CLUSTER BETWEEN 16P11.1 AND XQ28 - A NOVELPERICENTROMERIC-DIRECTED MECHANISM FOR PARALOGOUS GENOME EVOLUTION

We have identified a 26.5 kb gene-rich duplication shared by human Xq2 8 and 16p11.1. Complete comparative sequence analysis of cosmids from both loci has revealed identical Xq28 and 16p11.1 genomic structures f or both the human creatine transporter gene (SLC6A8) and five exons of the CDM gene (DXS1357E), Overall nucleotide similarity within the dup lication was found to be 94.6%, suggesting that this interchromosomal duplication occurred within recent evolutionary time (7-10 mya). Based on comparisons between genomic and cDNA sequence, both the Xq28 creat ine transporter and DXS1357E genes are transcriptionally active. Predi cted translation of exons and RT-PCR analysis reveal that chromosome 1 6 paralogs likely represent pseudogenes. Comparative fluorescent in si te hybridization (FISH) analyses of chromosomes from various primates indicate that this gene-rich segment has undergone several duplication s, In gorilla and chimpanzee, multiple pericentromeric localizations o n a variety of chromosomes were found using probes from the duplicated region. In other species, such as the orangutan and gibbon, FISH sign als were only identified at the distal end of the X chromosome, sugges ting that the Xq28 locus represents the ancestral copy. Sequencing of the 16p11.1/Xq28 duplication breakpoints has revealed the presence of repetitive immunoglobulin-like CAGGG pentamer sequences at or near the paralogy boundaries. The mobilization and dispersal of this gene-rich 27 kb element to the pericentromeric regions of primate chromosomes d efines an unprecedented form of recent genome evolution and a novel me chanism for the generation of genetic diversity among closely related species.