Systems genetics of lifespan and senescence in Drosophila melanogaster

As populations age, the number of people with age-related chronic diseases increases, causing significant social, economic and health problems. Natural variation in lifespan depends on multiple interacting genes and environmental exposures. Its short generation time and many resources make Drosophila melanogaster an advantageous model to uncover the genetic architecture that underlies variation in lifespan.

We performed whole genome sequencing on young and old flies, sexes separately, in an outbred advanced intercross population (AIP) derived from inbred, sequenced lines from the Drosophila Genetic Reference Panel (DGRP). We identified mostly sex-specific variants (extreme Quantitative Trait Loci; xQTLs) at 1,107 genes associated with increased lifespan. We used the same AIP for RNA sequencing of heads, bodies and reproductive tissues for males and females weekly to 10 weeks of age. We identified 2,613 genes with age-related changes, of which 186 had xQTLs. Over half of the significant effects of gene expression with age included sex- and/or tissue-specific context-dependent effects, many of which were antagonistic, indicating complex trade-offs in gene regulation in the context of lifespan. We mapped genes whose expression changes with age onto known gene-gene and protein-protein interactions to construct interaction networks anchored by xQTLs. These networks were enriched for evolutionarily conserved mitochondrial, metabolic, neuronal, immune and developmental genes. Human orthologs of Drosophila genes associated with senescence and lifespan were prevalent indicating the translational potential of results from Drosophila to human populations.

Natural genetic variation in Drosophila identifies sex- and/or tissue-specific genetic variation and networks enriched for evolutionarily conserved genes.