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CIS ‐Acting Allele‐Specific Expression Differences Induced by Alcohol and Impacted by Sex as Well as Parental Genotype of Origin
Author(s) -
Lo ChiaoLing,
Lumeng Lawrence,
Bell Richard L.,
Liang Tiebing,
Lossie Amy C.,
Muir Williams M.,
Zhou Feng C.
Publication year - 2018
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.13776
Subject(s) - genotype , allele , genetics , alcohol , biology , expression (computer science) , gene , computer science , biochemistry , programming language
Background Alcohol use disorders ( AUD s) are influenced by complex interactions between the genetics of the individual and their environment. We have previously identified hundreds of polygenic genetic variants between the selectively bred high‐ and low‐alcohol drinking ( HAD and LAD ) rat lines. Here, we report allele‐specific expression ( ASE ) differences, between the HAD 2 and LAD 2 rat lines. Methods The HAD 2 and LAD 2 rats, which have been sequenced, were reciprocally crossed to generate 10 litters of F1 progeny. For 5 of these litters, the sire was HAD 2, and for the other 5 litters, the sire was a LAD 2. From these 10 litters, 2 males and 2 females were picked from each F1 litter ( N = 40 total). The F1 pups were divided, balancing for sex and direction of cross, into an alcohol (15%) versus a water control group. Alcohol drinking started in the middle of adolescence (~postnatal day 35) and lasted 9 weeks. At the end of these treatments, rats were euthanized, the nucleus accumbens was dissected, and RNA was processed for RNA ‐sequencing and ASE analyses. Results Analyses revealed that adolescent ethanol (EtOH) drinking, individual EtOH drinking levels, parentage, and sex‐of‐animal affected ASE s of about 300 genes. The identified genes included those associated with EtOH metabolism (e.g., Aldh2 ); neuromodulatory function (e.g., Cckbr , Slc6a7, and Slc1a1 ); ion channel activity (e.g., Kcnc3 ); and other synaptic and epigenetic functions. Conclusions These data indicate that EtOH drinking differentially amplified paternal versus maternal allelic contribution to the transcriptome. We hypothesize that this was due, at least in part, to EtOH‐induced changes in cis‐regulation of polymorphisms previously identified between the HAD 2 and LAD 2 rat lines. This report highlights the complexity of gene‐by‐environment interactions mediating a genetic predisposition for, and/or the active development of, AUDs.