Estimation of Genetic Correlation: Interpretation of Experiments Using Selectively Bred and Inbred Animals

Abstract

There is increasing interest in determining the extent to which multiple characters related to drug sensitivity are influenced by common genes. The principal method for testing for the existence of such genetic correlations has been examination of pairs of mouse or rat lines selectively bred for sensitivity or resistance to a single behavioral effect of a drug. When a pair of selected lines is found to differ significantly on some trait other than the one on which they were selected, it is commonly concluded that significant genetic correlation between the traits exists, implying the action of a common set of genes on the two responses. In addition, results from comparisons of lines of animals selected for trait X and tested for trait Y may be compared with results from lines selected for trait Y and tested for trait X. As the number of correlated responses in selected lines increases, it becomes more important to adhere to sensible, consensual guidelines for interpreting such line differences. The principles underlying phenotypic and genotypic correlational analyses with selected lines are discussed. A scheme is presented to allow standardization across laboratories of inferences about the relative strength of genetic association from experiments with selected lines. Statistical and practical experimental issues are addressed. Estimates of genetic correlations may also be derived from the correlation of mean trait values across a panel of inbred strains. Existing data have sometimes found estimates of genetic correlations made with one approach to be inconsistent with those estimated in other ways. Possible reasons for this are discussed. Finally, the relationship between phenotypic correlations and genetic correlations is discussed. Phenotypic and genetic correlations for a pair of traits may differ widely, and may even be opposite in sign. Both are characteristic of the population from which they are sampled. Phenotypic correlations estimated within selected lines may change over time, as the additive genetic variance in the selected trait is exhausted. A specific example of this phenomenon is given.

Ethanol Withdrawal-Associated Drinking and Drinking in the Dark: Common and Discrete Genetic Contributions

“…There is a second replicate line of the HDID selection (HDID-2) that could be tested for withdrawal-associated drinking, but this line is in an earlier selected generation and has not yet diverged from the progenitor HS genotype to the extent that HDID-1 has [3]. Were the HDID-2 mice to show much greater (or much lesser) withdrawal-associated drinking increases than HS it is conceivable that we would conclude that there was moderate evidence for a genetic correlation, but the magnitude of the difference between HDID-2 and HS would have to be extreme given the lack of a difference between HDID-1 and HS (for discussion, see [15]). Any vapor inhalation study such as this that attempts to maintain multiple genotypes at nearly identical BECs yields fluctuations in daily BECs.…”

“…Thus, the evidence for common genetic contributions to preference drinking and DID is generally consistent, but is stronger in inbred strain comparisons than in studies where lines selected on one trait have been tested for the other. Some technical reasons why these two approaches to assessing genetic correlation among traits may yield different answers are discussed elsewhere [15]. …”

“…To test whether the genetic influences in common for the DID phenotype vs consumption in two-bottle preference tests might also influence post-CIE drinking, we used two methods to assess the genetic correlations among traits – testing lines selectively bred for extremes on one trait for correlated responses to selection on the other trait, and comparisons (correlations) among inbred strain mean values on the two traits [15]. First, we compared naive animals from the HDID-1 line with its non-selected control population, HS/Npt mice using the methods of Becker & Lopez [9,10].…”

Ethanol drinking in rodents: is free-choice drinking related to the reinforcing effects of ethanol?

“…For example, when a pair of selected lines is found to differ significantly on some trait other than the one for which they were selected, one may say that a genetic correlation between the traits exists. Taking this one step further, there may be a common set of genes or gene for the two responses (Crabbe et al, 1990). Such assessment can be useful for eventually understanding underlying mechanisms of action in complex behaviors such as ethanol abuse.…”

Decreased anticonvulsant efficacy of allopregnanolone during ethanol withdrawal in female Withdrawal Seizure-Prone vs. Withdrawal Seizure-Resistant mice

“…Selective breeding offers the opportunity to study genetically correlated traits by comparing the selected lines on responses in addition to the selected phenotype (see Crabbe et al, 1990). The WSP and Withdrawal Seizure-Resistant (WSR) mouse lines have been selectively bred for severe (WSP) or mild (WSR) chronic ethanol withdrawal, measured by handling-induced convulsions (HICs), following 72 hr ethanol vapor exposure.…”