TRANSCRIPTOME 2002: From Functional Genomics to Systems
Comparative and Functional Analysis of Cardiovascular-Related Genes
Len A. Pennacchio1, Michael Olivier2, Jaroslav A. Hubacek3, Jonathan C. Cohen3, Ronald M. Krauss1, and Edward M. Rubin1, 1Genome Sciences Department, Lawrence Berkeley National Laboratory, Berkeley, CA, 2Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI, 3Center for Human Nutrition and McDermott, Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX
Cardiovascular diseases represent the leading cause of death in Western society. It has been well established that both genetic and environmental factors contribute to the pathophysiology of these disorders. To better understand genes important in cardiovascular biology, we are performing comparative sequence analysis of ~200 cardiovascular-related genes in numerous vertebrate species. We will describe numerous computational tools and databases we have constructed to exploit this information. As an example of this analysis, we will discuss the apolipoprotein gene cluster on human chromosome 11q23 (APOA1/C3/A4) which is known to influence a variety of plasma lipid parameters and atherosclerosis susceptibility in humans. To facilitate the identification of evolutionarily conserved sequences with potential function near this cluster, we determined the sequence of ~200 kilobasepairs (kbp) of orthologous mouse, rabbit, and chicken DNA and compared these sequences to human. The presence of a stretch of inter-species sequence conservation approximately 30 kbp proximal to the APOA1/C3/A4 gene cluster, led us to an interval that upon further analysis was shown to encode a new member (APOA5) of the chromosome 11 apolipoprotein gene cluster. We find that APOA5 is expressed primarily in liver tissue and encodes a secreted protein that dramatically impacts plasma triglyceride levels in humans and mice. Specifically, mice over-expressing a human APOA5 transgene display a 70% decrease in plasma triglyceride concentrations, while oppositely, mice lacking Apoa5 have a 400% increase in this lipid parameter. These findings in mice suggested that alterations in APOA5 could also influence human plasma lipid levels. To explore this possibility, we identified several single nucleotide polymorphisms (SNPs) in the human APOA5 gene and determined their distribution in two independent patient populations. Through this analysis, we found a significant association between several polymorphisms and abnormal triglyceride levels in both independent studies. These findings in humans and mice illustrate the utility of comparative sequence analysis to prioritize regions of the genome for further study and suggest an important physiological role for apoAV in affecting plasma levels of triglyceride, a major risk factor for heart disease in humans.
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