Large scale duplication of genetic material is a major force driving the evolution of genetic diversity. Gene duplication and subsequent divergence have been instrumental in the creation of new genes with specialized functional roles, a process that has been important for the creation of evolutionary diversity and speciation. The accumulating sequence of the human genome has revealed a class of genomic duplications that are chromosome-specific. Interestingly, these chromosome-specific sequence duplications or low copy repeats (LCRs) have been implicated in a number of human genetic disorders that are associated with recurrent genomic rearrangements. It has been proposed that illegitimate recombination facilitated by the highly homologous duplicated sequences give rise to deletions, duplications and inversions. Chromosome-specific LCRs on human chromosome 22q11 have been implicated in various constitutional rearrangements leading to genetic disease. Although the human 22q11 LCRs have been sequenced, very little is known about their evolution and amplification in the genome. Comparative analysis of the mouse genome has revealed an absence of LCRs at the orthologous loci. Examination of the 22q11 LCRs in non-human primates suggests that they have originated and evolved during primate evolution. We wish to investigate the mechanism responsible for chromosome-specific duplications and their role in the evolution of the primate genome. Toward this goal, we propose a comparative analysis of the organization and structure of the 22q11 LCRs in humans and non-human primates. We will analyze the 22q11 LCRs in various non-human primates at the chromosomal, gross structural and nucleotide sequence levels. The evolutionary analysis of the primate-specific 22q11 LCRs provide a unique opportunity to investigate the molecular mechanism underlying this form of genome evolution. We will also test the hypothesis that the processes responsible for the origin and spread of the chromosome-specific duplications are ongoing and may have resulted in genomic variability within the human population. We will perform a population-based analysis to look for genetic polymorphism in the structural organization of 22q11 LCRs within various human population groups. This will allow us to assess the involvement of LCRs in creating genetic variation that may lead to the genomic instability associated with human genetic disorders. Thus, the 22q11 LCRs provide a model system with which to gain a better understanding of the evolution of the human genome.
