International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


POSTER 9 - LINKING MAMMALIAN GENOME EVOLUTIONARY INSTABILITY TO HUMAN CANCER DEVELOPMENT AND PROGRESSION

Zhao S, Delcher D, Shetty J

The Institute For Genomic Research, 9712 Medical Center Drive,, Rockville, MD, United States

Using paired-end sequences from bacterial artificial chromosomes (BACs), we have constructed high-resolution synteny and rearrangement breakpoint maps among human, mouse and rat genomes.  This not only has allowed us to achieve several novel discoveries about mammalian genome evolution, but also provides a unique resource to study human cancer development and progression. 

As closely related species, mouse and rat share the majority of the breakpoints and often have the same types of rearrangements, when compared to the human genome.  However, the breakpoints not shared between them indicate that mouse rearrangements are more often inter-chromosomal, whereas intra-chromosomal rearrangements are more prominent in rat.  Centromeres may have played a significant role in reorganizing a number of chromosomes in all three species. 

Among the >300 syntenic blocks identified, are segments of over 40Mb without any detected interspecies rearrangements, as well as regions with frequently broken synteny and extensive rearrangements.  Computer simulation of the syntenic block length distribution supports the fragile breakage model but not the random breakage model for mammalian genome evolution, indicating that mammalian genomes consist of evolutionary stable and unstable regions.

Statistical analyses indicate that many human cancer-associated genome lesions are directly linked to evolutionary genome instability.  By examining the genomic locations of ~50 genome wide recurrent chromosomal aberrations with their associated genes identified from the Mitelman Database at http://cgap.nci.nih.gov/Chromosomes/RecurrentAberrations, we have found that over 95% of these lesions fall in the evolutionarily unstable sites.  This is consistent with a previous study that examined the relationship between evolutionary breakpoints among primates and chromosomal defects in human cancer.  These analyses indicate that the evolutionarily unstable regions should become logical targets for research on the origins of human malignancy.  We are currently studying the linkage between evolutionary genome instability and colon tumorigenesis.

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