The high alcohol preference trait displayed by Indiana's selectively bred P and HAD1-2 rat lines models an important endophenotype of human alcoholism. Our long-term goal is to use these rat models to identify genomic signatures and illuminate CNS pathways that underile alcohol preference. By Integrating unbiased genomic analyses described here with traditional hypothesis-driven research done by others, we fully expect to open up exciting new windows on the pathogenesis of alcoholism. The central hypothesis is that both genomic and epigenomic mechanisms account for the variation in alcohol preference. Over the last 15 years, we have some success in locating a number of major QTLs and identifying several likely genes that contribute to alcohol preference using our rat models;however, there are uncertainties and many questions remain unanswered. We now want to exploit next generation sequencing (NGS) technologies to better understand the genomic signatures of selection and the interactions between genetic changes and environmental assaults that contribute to excessive alcohol consumption. By taking advantage of NGS studies, we can significantly increase the level of resolution and power of analysis to explain a greater portion of the genetic variation in alcohol preference in these rat models, to localize the genetic variations to genes and even down to SNPs, and to examine the potential importance of the epigenome on alcohol preference.
The Specific Aims (SAs) are: SAI-To identify the genomic signatures of bi-directional selection (i.e. marks of selection) that explain the contrasting alcohol preference in the P/NP and HAD1-2/LAD1-2 rat lines. SA2-To delineate potentially causative variations in the selected regions identified in SA1 by searching for coding and regulatory differences associated with allele-specific expression (ASE). SA3-To examine the effects of parental alcohol use on Cytosine to Thymine transitions and their association with ASE. Through these studies, we expect to discover several hundred regions of selection that lead to functional consequences (altered gene expression and ASE) in the reward circuit, and ultimately uncover the coordinated genetic mechanisms that underlie the multifactorial nature of alcohol preference.
By analyzing genomic signatures of selection and ASE, we will illuminate the majority of genetic variants and CNS pathways of alcohol preference. By examining the effects of parental alcohol consumption during successive generations of selective breeding on Cytosine to Thymine SNPs and their association with ASE, we will address how alcohol consumption can turn epigenetic alterations to genetic changes. The results will further our understanding of genes and their mode of actions on aberrant alcohol drinking behaviors.
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