Genetic architecture of natural variation in visual senescence in Drosophila

Abstract

Senescence, i.e., functional decline with age, is a major determinant of health span in a rapidly aging population, but the genetic basis of interindividual variation in senescence remains largely unknown. Visual decline and age-related eye disorders are common manifestations of senescence, but disentangling age-dependent visual decline in human populations is challenging due to inability to control genetic background and variation in histories of environmental exposures. We assessed the genetic basis of natural variation in visual senescence by measuring age-dependent decline in phototaxis using Drosophila melanogaster as a genetic model system. We quantified phototaxis at 1, 2, and 4 wk of age in the sequenced, inbred lines of the Drosophila melanogaster Genetic Reference Panel (DGRP) and found an average decline in phototaxis with age. We observed significant genetic variation for phototaxis at each age and significant genetic variation in senescence of phototaxis that is only partly correlated with phototaxis. Genome-wide association analyses in the DGRP and a DGRP-derived outbred, advanced intercross population identified candidate genes and genetic networks associated with eye and nervous system development and function, including seven genes with human orthologs previously associated with eye diseases. Ninety percent of candidate genes were functionally validated with targeted RNAi-mediated suppression of gene expression. Absence of candidate genes previously implicated with longevity indicates physiological systems may undergo senescence independent of organismal life span. Furthermore, we show that genes that shape early developmental processes also contribute to senescence, demonstrating that senescence is part of a genetic continuum that acts throughout the life span.aging | behavioral genetics | DGRP GWA analysis | phototaxis | xQTL mapping

Genetics of alcohol consumption in Drosophila melanogaster

“…This is expected, since sexual dimorphism is a common feature of the genetic architecture of complex traits and has been documented for every trait analyzed to date in the DGRP, including but not limited to alcohol sensitivity (Morozova et al , 2015), sleep phenotypes (Harbison et al , 2013), olfactory behavior (Swarup et al , 2013), feeding behavior (Garlapow et al , 2015), and visual senescence (Carbone et al , 2016). …”

“…It should be noted, however, that the AIP is derived from only 37 DGRP lines and contains 66% of the allelic variants present in the DGRP. Previous studies showed that despite differences in network compositions derived from GWA analyses in the DGRP and extreme QTL mapping in AIPs the genetic networks relate to the same cellular processes (Carbone et al , 2016, Morozova et al , 2015, Shorter et al , 2015, Swarup et al , 2013). We note that gene interactions and network architecture can vary based on developmental stage, tissue, and environmental conditions.…”

“…We crossed these lines in a round-robin design as described previously (Carbone et al , 2016, Huang et al , 2012). We reared flies in bottles on cornmeal/molasses/agar medium under standard culture conditions (25°C, 12:12 hour light/dark cycle).…”

“…We used an AIP derived from 37 DGRP lines (DGRP_41, DGRP_42, DGRP_45, DGRP_59, DGRP_83, DGRP_91, DGRP_129, DGRP_158, DGRP_177, DGRP_195, DGRP_208, DGRP_217, DGRP_228, DGRP_229, DGRP_235, DGRP_239, DGRP_307, DGRP_315, DGRP_367, DGRP_371, DGRP_375, DGRP_379, DGRP_391, DGRP_399, DGRP_427, DGRP_439, DGRP_491, DGRP_508, DGRP_509, DGRP_517, DGRP_703, DGRP_757, DGRP_765, DGRP_799, DGRP_808, DGRP_843 and DGRP_900), which are free of inversions, free of Wolbachia infection, are maximally homozygous and maximally unrelated. We crossed these lines in a round-robin design as described previously (Carbone et al 2016;Huang et al 2012). We reared flies in bottles on cornmeal/molasses/agar medium under standard culture conditions (25 ∘ C, 12:12 h light/dark cycle).…”

Gene Expression Networks in the Drosophila Genetic Reference Panel

“…To examine the relationship between variation in gene expression and variation in organismal quantitative trait phenotypes, we chose 11 quantitative traits with published phenotypic data (chill coma recovery time and startle response 19 ; starvation resistance 20 ; day and night sleep bout number, day and night total sleep duration, and total waking activity 35 ; food consumption 36 ; male aggression 37 ; phototaxis 38 ); and additionally measured five metabolic traits (levels of free glucose, glycogen, free glycerol, triglyceride and protein) and three metrics of body size (body weight, thorax length, thorax width). All traits were quantified in the same laboratory under the same culture conditions used in this study.…”