Dopa decarboxylase (Ddc) affects variation in Drosophila longevity

Abstract

Mutational analyses in model organisms have shown that genes affecting metabolism and stress resistance regulate life span, but the genes responsible for variation in longevity in natural populations are largely unidentified. Previously, we mapped quantitative trait loci (QTLs) affecting variation in longevity between two Drosophila melanogaster strains. Here, we show that the longevity QTL in the 36E;38B cytogenetic interval on chromosome 2 contains multiple closely linked QTLs, including the Dopa decarboxylase (Ddc) locus. Complementation tests to mutations show that Ddc is a positional candidate gene for life span in these strains. Linkage disequilibrium (LD) mapping in a sample of 173 alleles from a single population shows that three common molecular polymorphisms in Ddc account for 15.5% of the genetic contribution to variance in life span from chromosome 2. The polymorphisms are in strong LD, and the effects of the haplotypes on longevity suggest that the polymorphisms are maintained by balancing selection. DDC catalyzes the final step in the synthesis of the neurotransmitters, dopamine and serotonin. Thus, these data implicate variation in the synthesis of bioamines as a factor contributing to natural variation in individual life span.

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“…A further advantage to doing QTL analyses in Drosophila is that, after a QTG is identified, it is theoretically possible to identify quantitative-trait nucleotides (QTNs) that contribute to the quantitative phenotype (De Luca et al, 2003). The rationale of QTN analyses is that one could identify the exact nucleotide polymorphism that causes the quantitative trait.…”

“…QTN analyses are conducted by measuring the quantitative traits in outbred populations, or more specifically in "chromosomesubstitution lines" (De Luca et al, 2003). Chromosomesubstitution lines, which have been constructed in both flies and mice, consist of one chromosome from strains obtained in the wild, and the remaining chromosomes from an isogenic laboratory strain.…”

“…Currently, the most thorough example of a QTN analysis was on the effects of SNPs in the dopa decarboxylase (DDC) gene on longevity in Drosophila (De Luca et al, 2003). However, further validation of the QTNs by showing that they affect DDC gene expression levels or enzyme activities has not yet been completed.…”

“…The QTN technique has high power in Drosophila because outbred populations in a small area, such as near a farmers market in Raleigh, North Carolina, contain potentially millions of individual flies and multiple generations (De Luca et al, 2003). In fact, adjacent SNPs, or SNPs just a few nucleotides from each other, can often be in "genetic equilibrium," which means that multiple recombination events has occurred between the adjacent SNPs (De Luca et al, 2003).…”

“…In fact, adjacent SNPs, or SNPs just a few nucleotides from each other, can often be in "genetic equilibrium," which means that multiple recombination events has occurred between the adjacent SNPs (De Luca et al, 2003). QTN mapping in Drosophila outbred populations is arguably almost equivalent to the classic recombination experiments in the 1960's at the RIIB locus in T4 bacteriophage, wherein, it is now known, recombination events were recovered at almost adjacent nucleotide positions (Parma et al, 1979).…”