Polymorphisms in early neurodevelopmental genes affect natural variation in alcohol sensitivity in adult drosophila.
BACKGROUND
Alcohol abuse and alcoholism are significant public health problems, but the genetic basis for individual variation in alcohol sensitivity remains poorly understood. Drosophila melanogaster presents a powerful model system for dissecting the genetic underpinnings that determine individual variation in alcohol-related phenotypes. We performed genome wide association analyses for alcohol sensitivity using the sequenced, inbred lines of the D. melanogaster Genetic Reference Panel (DGRP) together with extreme QTL mapping in an advanced intercross population derived from sensitive and resistant DGRP lines.


RESULTS
The DGRP harbors substantial genetic variation for alcohol sensitivity and tolerance. We identified 247 candidate genes affecting alcohol sensitivity in the DGRP or the DGRP-derived advanced intercross population, some of which met a Bonferroni-corrected significance threshold, while others occurred among the top candidate genes associated with variation in alcohol sensitivity in multiple analyses. Among these were candidate genes associated with development and function of the nervous system, including several genes in the Dopamine decarboxylase (Ddc) cluster involved in catecholamine synthesis. We found that 58 of these genes formed a genetic interaction network. We verified candidate genes using mutational analysis, targeted gene disruption through RNAi knock-down and transcriptional profiling. Two-thirds of the candidate genes have been implicated in previous Drosophila, mouse and human studies of alcohol-related phenotypes.


CONCLUSIONS
Individual variation in alcohol sensitivity in Drosophila is highly polygenic and in part determined by variation in evolutionarily conserved signaling pathways that are associated with catecholamine neurotransmitter biosynthesis and early development of the nervous system.
Department of Biological Sciences, W. M. Keck Center for Behavioral Biology and Program in Genetics, North Carolina State University, Box 7614, Raleigh, NC, 27695, USA.
Tatiana V
TV
Morozova
Department of Biological Sciences, W. M. Keck Center for Behavioral Biology and Program in Genetics, North Carolina State University, Box 7614, Raleigh, NC, 27695, USA.
Wen
W
Huang
Department of Biological Sciences, W. M. Keck Center for Behavioral Biology and Program in Genetics, North Carolina State University, Box 7614, Raleigh, NC, 27695, USA.
Victoria A
VA
Pray
Department of Biological Sciences, W. M. Keck Center for Behavioral Biology and Program in Genetics, North Carolina State University, Box 7614, Raleigh, NC, 27695, USA.|Department of Biochemistry and Physiology, School of Bioscience and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UK.
Thomas
T
Whitham
Department of Biological Sciences, W. M. Keck Center for Behavioral Biology and Program in Genetics, North Carolina State University, Box 7614, Raleigh, NC, 27695, USA.
Robert R H
RR
Anholt
Department of Biological Sciences, W. M. Keck Center for Behavioral Biology and Program in Genetics, North Carolina State University, Box 7614, Raleigh, NC, 27695, USA. trudy_mackay@ncsu.edu.
Trudy F C
TF
Mackay
D000438:Alcohols / Q000494:pharmacology*; D000818:Animals; D029721:Drosophila Proteins / Q000235:genetics*; D004331:Drosophila melanogaster / Q000187:drug effects* / Q000235:genetics*; D055106:Genome-Wide Association Study; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
D000438:Alcohols; D029721:Drosophila Proteins