This proposal seeks to identify regions of the genome undergoing somatic selection in aging F1 hybrid mice. Current theories on the role of stem cells in aging suggest that genomic instability is a major contributor to dysfunction in this cellular compartment and contributes to age related phenotypes. Our preliminary data supports this hypothesis and identifies regions of the genome that display repeated instability, suggesting these sites may be under selective pressure. To test this hypothesis, we propose to study age related genetic changes occurring in adult neural stem cells and to define genes that are important in stem cell survival on the basis of somatic selection. Clonally derived stem cells from young and old mice will be evaluated for genomic instability. A survey of genomic instability will be assessed using SNP specific PCR on C57BI/6 x DBA/2 F1 hybrids. Polymorphisms present in F1 mice between long- and short-lived strains may identify gene variants which have differential effects on stem cell survival in aging animals. Those regions of the genome undergoing consistent allelic loss of one strain will be defined to map and identify genes present in the deleted region. ? ?