title: 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.
authors: Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695; W. M. Keck Center for Behavioral Biology, North Carolina State University, Raleigh, NC 27695; Program in Genetics, North Carolina State University, Raleigh, NC 27695.
authors: Mary Anna
authors: MA
authors: Carbone
authors: Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695; W. M. Keck Center for Behavioral Biology, North Carolina State University, Raleigh, NC 27695; Program in Genetics, North Carolina State University, Raleigh, NC 27695.
authors: Akihiko
authors: A
authors: Yamamoto
authors: Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695; W. M. Keck Center for Behavioral Biology, North Carolina State University, Raleigh, NC 27695; Program in Genetics, North Carolina State University, Raleigh, NC 27695; Initiative in Biological Complexity, North Carolina State University, Raleigh, NC 27695.
authors: Wen
authors: W
authors: Huang
authors: Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695.
authors: Rachel A
authors: RA
authors: Lyman
authors: Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695.
authors: Tess Brune
authors: TB
authors: Meadors
authors: Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695.
authors: Ryoan
authors: R
authors: Yamamoto
authors: Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695; W. M. Keck Center for Behavioral Biology, North Carolina State University, Raleigh, NC 27695; Program in Genetics, North Carolina State University, Raleigh, NC 27695; Initiative in Biological Complexity, North Carolina State University, Raleigh, NC 27695.
authors: Robert R H
authors: RR
authors: Anholt
authors: Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695; W. M. Keck Center for Behavioral Biology, North Carolina State University, Raleigh, NC 27695; Program in Genetics, North Carolina State University, Raleigh, NC 27695; Initiative in Biological Complexity, North Carolina State University, Raleigh, NC 27695 trudy_mackay@ncsu.edu.
authors: Trudy F C
authors: TF
authors: Mackay
mesh_terms: D000375:Aging / Q000235:genetics*; D000818:Animals; D000076103:Biological Variation, Individual; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D014644:Genetic Variation; D016678:Genome; D055106:Genome-Wide Association Study; D006801:Humans; D000071444:Phototaxis; D040641:Quantitative Trait Loci; D014785:Vision, Ocular / Q000235:genetics
chemical_list: D029721:Drosophila Proteins; D005136:Eye Proteins
keywords: DGRP GWA analysis; aging; behavioral genetics; phototaxis; xQTL mapping