• PARC home
• About PARC
• Alcoholism & Treatment Resources
• PARC Scientists
• Research
  Component & Core
  Structure
• Publications
• Research
  Resources:
  Library
  Data Sharing
  Animal Models
• Education & Outreach
• Contribute to PARC

-
-

PI: John Belknap
Co-Is: John Crabbe, Robert Hitzemann, Pamela Metten

Most recent successes in identifying genes underlying QTLs in rodents have shown significant expression differences between the key genotypes of the identified gene, thus establishing gene expression as a very promising means for discovering genes responsible for QTLs.

Prior work in the PARC has established that two alcohol traits, acute withdrawal severity and preference drinking, are genetically correlated in several C57BL/6J (B6) x DBA/2J (D2) populations, which strongly suggests the presence of common QTLs influencing these two traits, and thus also common genetically-mediated mechanisms.

Aim 1
A B6xD2 F2 population will be tested for both alcohol traits and subjected to microarray analysis using the new Affymetrix 430 2.0 mouse microarray containing 39,000 probe sets (transcripts). This will allow us to perform QTL analyses on variation in transcript abundance for all transcripts as well as variation in the acute withdrawal and the preference drinking traits.

A major goal of this dual QTL mapping is to determine where in the genome expression QTLs (eQTLs) and QTLs affecting the two alcohol traits (aQTLs) coincide for each alcohol trait taken separately and both traits taken jointly.

Aim 2
We will carry out bidirectional selective breeding for each of the two alcohol traits for four generations starting from a B6xD2 F2 (single trait selection). Because of the greatly increased frequency of extreme phenotypes and associated genotypes compared to an F2, detection of eQTLs and their coincidence with aQTLs will be greatly leveraged, facilitating the detection of aQTLs and eQTLs influencing either trait separately as well as both traits jointly.

We will also investigate the effects of either alcohol testing regimen on gene expression independent of genotype.

Aim 3
In addition, we will develop dual trait selected lines bred for a composite of both traits to help identify those QTLs that account for the genetic correlation. Because the correlation is negative, these will be the oppositely-selected LOW/HIDR (Low Withdrawal–High Preference Drinking) and HIW/LODR (High Withdrawal–Low Preference Drinking) dual trait selection lines. Compared to single trait selection, much greater selection pressure will be applied to those QTLs responsible for the negative genetic correlation.

Aim 4
Using congenic strains we have developed to isolate a QTL influencing one of the two alcohol traits, we will look for differences for the other trait in congenic vs background strain comparisons when the appropriate strain is available. We will also use congenics to increase QTL map resolution when feasible.

Back to PARC Components

by Mark Rutledge-Gorman
You are visitor #