Quantitative Genetics and Genomics of Drosophila Life Span
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2006-11-10
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Abstract
Limited life span and senescence are near-universal characteristics of eukaryotic organisms, controlled by many interacting quantitative trait loci (QTLs) with individually small effects, whose expression is sensitive to the environment. Understanding how genetic and environmental factors interact to limit life span and generate variation between individuals, populations and species, is important from both a human health and an evolutionary theory perspective. To begin to dissect the complex genetic architecture of longevity, it is necessary to identify the genes affecting life span and natural variation in life span. Here we have used quantitative complementation mapping to deficiencies, gene expression analysis, and functional tests to mutations at positional candidate genes to gain a better understanding of genes and categories of genes associated with the aging process. These complementary approaches have allowed us to identify several genomic regions as well as specific candidate genes affecting longevity and variation in longevity.
Quantitative complementation tests to 69 overlapping deficiencies covering approximately 80% of the third chromosome yielded 11 QTLs affecting variation in life span between five old ("O") lines selected for postponed senescence and their five base ("B") control lines. Most QTLs were sex-specific, and all but one affected multiple O lines, suggesting that variation in life span for the B and selected O populations is most often attributable to the effects of common alleles. However, these 11 QTLs spanned over 4874 kb and contained approximately 598 genes.
To identify and prioritize individual genetic loci affecting life span and variation in life span within our chromosomal regions as well as the remaining genome, we used whole genome expression analyses over multiple ages for one B and two O lines. Two separate analyses were used to compare changes in transcript abundance at the same chronological and physiological age between ages and lines. Over 26% of the genome was significantly altered between young and old flies and more than 5% of the genome showed significant changes between control and selected lines (indicating variation in aging effects) at multiple ages. Significant probe sets fell into a diverse group of biological processes and molecular functions, many associated with processes and pathways known to affect aging as well as many correlated traits in O lines. Examination of expression patterns for specific genes showed that O lines commonly exhibited a delayed response to aging, although different patterns of expression were observed as well.
Transcriptional analyses were followed up with functional tests to mutants at positional candidate genes, which were selected, based on significant probe sets for either age or line effects and the availability of mutants. P-element insertion lines and their co-isogenic controls allowed us to test for age effects. Forty-four percent of 27 P-element mutants tested showed significant differences in mean life span from their co-isogenic control lines, with all but one decreasing life span. Quantitative complementation tests to these mutants provided an efficient method to test for variation in aging as 70% of the ten mutants tested yielded significant results. Candidate genes implicated in functional tests for both aging and variation in aging are involved in various categories of biological processes, including oogenesis, chromatin silencing, spermatogenesis, development, defense response, locomotor behavior, and cell death, suggesting that many of the processes that affect aging may affect variation in aging as well.
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quantitative genetics, deficiency complementation mapping, microarray
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PhD
Discipline
Genetics
