Project descriptions
Research has not yet distinguished the specific causes of mammalian aging, despite a wealth of hypotheses. The Jackson Aging Center focuses on genetic phenotypes, because gene discovery does not depend on preconceived hypotheses. Most aspects of age are almost certainly under complex genetic regulation, involving multiple genes and genetic interactions. Previously, it would have been extremely difficult to identify specific genes regulating aging phenotypes. Now, through the use of a wide variety of inbred strains including many derived from wild progenitors, a powerful tool of modern genetics, quantitative trait locus (QTL) analysis, extremely dense maps defined by SNP markers (>20,000 SNPs), and specific BAC libraries, we have the foundation needed to identify specific genes that regulate aging.
The Jackson Aging Center, when combined with The Jackson Laboratory’s preeminent role in the international Mouse Phenome Project (MPP), provides a range of new tools for defining genes important in aging. In the past, aging mice in complex crosses had to be produced and genotyped by the researcher. Now the Jackson Aging Center will provide young, middle-aged and old mice from each of 32 strains. Each strain is already genotyped to a map density of >20,000 SNPs as of May 2005, and both genetic marker densities, and numbers of strains mapped, are increasing rapidly. For 16 MPP aging strains, extensive sequence and SNP data are already available, and millions of SNPs will be genotyped for these 15 strains relative to C57BL/6J using the re-sequencing strategy.
Selected aging phenotypes will be defined accurately in each strain, by testing several individuals of each age. Computational analysis will then associate haplotypes with the phenotypes, thus mapping QTLs in silico. This is feasible because inbred mouse strains share a limited number of progenitors and therefore may be regarded as several families with shared genomic regions that are identical by descent (Wade et al, 2002). Even in wild-derived strains and stocks such as Pohn, strong QTLs occur in locations where the 2 strains have regions of DNA that came from different ancient progenitors. Computational analysis based on that fact examines the haplotype structure using densely mapped SNPs. These analyses become more powerful and precise with an increasing number of markers, which is why having >20,000 SNPs for each strain is vital.
The overall project is divided into two groups. The first group, Longitudinal analyses, focuses on the life span for each strain. In addition, selected non-invasive phenotypes, including immune aging, renal function, neuron/muscle function, etc, are also measured. The second group, Cross-sectional analyses, focuses on the lesions of aging. In addition, selected invasive phenotypes are being defined in young, middle and old aged to investigate changes with age from the DNA to the organ level. These studies include hundreds of parameters which will be analyzed to search for the genetic networks regulating aging.
