New Scholar Award in Aging
Stephen Robert Wicks, Ph.D.
Boston College

Natural Sequence Variation in C. elegans: Impact on Lifespan and Aging
Lifespan is determined by variables in both the genetic and environmental dimensions. It appears, that in natural aging populations of animals, a number of genetic loci, some independent, others as interdependent pairs or even sets, contribute to the genetic lifespan potential of a given organism. Within a given species, these multiple polymorphic loci are apportioned independently throughout the population creating a continuous range of aging potentials. Mutagenesis studies in model genetic organisms such as the fruit fly Drosophila, or the nematode C. elegans have been successfully applied to identify some of these mutable loci. However, for a variety of reasons, not all loci that modulate aging will be detected by mutagenesis, and conversely, not all loci that can be mutated to modulate lifespan in the lab will impact lifespan in natural aging populations.

We are studying the contribution of naturally occurring sequence variation, present in wild isolates of the nematode Caenorhabditis elegans, on lifespan correlates. As a consequence of their reproductive strategy (hermaphrodites self fertilize and produce clonal copies of themselves), all members of a given isolate of are genetically identical; there are no polymorphisms that discriminate individual members of the isolate from one another. However, various isolates from around the world, that have been reproductively isolated from one another for evolutionary timescales, have recently been characterized. The genomes of two of these (the sequenced strain from Bristol, England and a more recent isolate from Hawaii) have been characterized in detail, and are thought to differ from each other at about 60,000 positions. Although many of these polymorphisms are trivial, in that they will not affect gene expression or peptide sequence and hence not produce any detectable phenotypic differences, the remaining polymorphisms are the essence of phenotypic variation that distinguish one strain from the other, the essence of individuality.

We are creating a set of strains derived by mating these two isolates together. Both the parental genomes are highly selected, natural isolates, successful within their ecological niches. However, the new strains derived from crossing these two isolates together, called recombinant inbred lines or RILs, are essentially patchwork mosaics of the two parental genomes, different from each parent, and different from each other. Furthermore, these strains have never existed in the natural environment, and would therefore be relatively unselected by the rigors of competitive life outside the laboratory. We would expect high variation along a given dimension such as lifespan; some strains will be long-lived and some will be short-lived due to the particular complement of polymorphisms that each new strain inherits from each parent. We will correlate measures of lifespan with the genomic makeup of each RIL and thus determine which polymorphic loci can modulate aging. The expectation is that novel genetic interactions and loci that modulate lifespan will be identified.

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