Identification of sex–specific quantitative trait loci controlling alcohol preference in C57BL/6 mice

Melo, Justine A.; Shendure, Jay; Pociask, Kara; Silver, Lee M.

doi:10.1038/ng0696-147

Cited by 181 publications

(127 citation statements)

References 36 publications

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“…B6 mice consume large amounts of sweeteners (Lush 1989;Bachmanov et al 1996aBachmanov et al , 1996b, alcohol (Belknap et al 1993;Bachmanov et al 1996aBachmanov et al , 1996b and morphine (Forgie et al 1988) compared with the other mouse strains, and genetic correlations have been found between sweetener and alcohol intake in mice (Belknap et al 1993;Blizard and McClearn 1996;Bachmanov et al 1996a), suggesting that these behaviors may be affected by a common mechanism. However, quantitative trait loci modulating alcohol and morphine preference of B6 mice have been localized to Chrs 1, 2, 6, 10, and 11, but not to Chr 4 (Berettini et al 1994;Melo et al 1996). Although these results do not exclude the existence of loci with pleiotropic effects on these behaviors, they indicate that there are independent mechanisms influencing high consumption of sucrose, alcohol, and morphine by B6 mice.…”

Section: Discussionmentioning

confidence: 48%

Sucrose consumption in mice: Major influence of two genetic Loci affecting peripheral sensory responses

et al. 1997

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Individual variability in sucrose consumption is prominent in humans and other species. To investigate the genetic contribution to this complex behavior, we conducted behavioral, electrophysiological, and genetic studies, using male progeny of two inbred mouse strains (C57BL/6ByJ [B6] and 129/J [129]) and their F 2 hybrids. Two loci on Chromosome (Chr) 4 were responsible for over 50% of the genetic variability in sucrose intake. These loci apparently modulated intake by altering peripheral neural responses to sucrose. One locus affected the response threshold, whereas the other affected the response magnitude. These findings suggest that the majority of difference in sucrose intake between male B6 and 129 mice is due to polymorphisms of two genes that influence receptor or peripheral nervous system activity.

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Section: Discussionmentioning

confidence: 48%

Sucrose consumption in mice: Major influence of two genetic Loci affecting peripheral sensory responses

et al. 1997

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“…The first report of a sex effect on a QTL was that from Lee Silver's laboratory in a study of alcohol preference (Melo et al, 1996), confirmed by a follow-up study (Peirce et al, 1998). There have been four other reports of gender specific QTL that are less well substantiated because they are based on the observation that the LOD score is significant in one sex but not in the other.…”

Section: Mode Of Actionmentioning

confidence: 94%

Analysis of quantitative trait loci that influence animal behavior

2002

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Behavioral differences between inbred strains of mice and rats have a genetic basis that can now be dissected using quantitative trait locus (QTL) analysis. Over the last 10 years, a large number of genetic loci that influence behavior have been mapped. In this article I review what that information has revealed about the genetic architecture of behavior. I show that most behaviors are influenced by QTL of small effect, each contributing to less than 10% of the variance of a behavioral trait. The small effect of each QTL on behavioral variation suggests that the mutational spectrum is different from that which results in Mendelian disorders. Regions of DNA should be appropriately prioritized to find the molecular variants, for instance by looking at sequences that control the level of gene expression rather than variants in coding regions. While the number of allelic loci that can contribute to a trait is large, this is not necessarily the case: the analysis of selected strains shows that a remarkably small number of QTL can explain the bulk of the genetic variation in behavior. I conclude by arguing that genetic mapping has more to offer than a starting point for positional cloning projects. With advances in multivariate analyses, mapping can also test hypotheses about the psychological processes that give rise to behavioral variation.

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“…It is important to note that the allelic effects on behavior in both QTL analyses were in the same direction with respect to B6/I, suggesting that the candidate at the Chr 8 locus should impact both behaviors in the same direction although other segregating loci may dissociate these effects. The negative genetic correlation may be accounted for by the several other overlapping preference and withdrawal loci segregating in inbred mouse populations such as Alcp1 (Melo et al 1996) and Alcw4 (Crabbe et al 1994) and Alcp18 (Gill et al 1998) and Alcw3 (Bergeson et al 2003). Finding other molecular substrates of the relationships among preference and withdrawal will enable better evaluation of competing mechanistic hypotheses.…”

Section: Discussionmentioning

confidence: 99%

Identification of a QTL in Mus musculus for Alcohol Preference, Withdrawal, and Ap3m2 Expression Using Integrative Functional Genomics and Precision Genetics

et al. 2014

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Extensive genetic and genomic studies of the relationship between alcohol drinking preference and withdrawal severity have been performed using animal models. Data from multiple such publications and public data resources have been incorporated in the GeneWeaver database with .60,000 gene sets including 285 alcohol withdrawal and preference-related gene sets. Among these are evidence for positional candidates regulating these behaviors in overlapping quantitative trait loci (QTL) mapped in distinct mouse populations. Combinatorial integration of functional genomics experimental results revealed a single QTL positional candidate gene in one of the loci common to both preference and withdrawal. Functional validation studies in Ap3m2 knockout mice confirmed these relationships. Genetic validation involves confirming the existence of segregating polymorphisms that could account for the phenotypic effect. By exploiting recent advances in mouse genotyping, sequence, epigenetics, and phylogeny resources, we confirmed that Ap3m2 resides in an appropriately segregating genomic region. We have demonstrated genetic and alcohol-induced regulation of Ap3m2 expression. Although sequence analysis revealed no polymorphisms in the Ap3m2-coding region that could account for all phenotypic differences, there are several upstream SNPs that could. We have identified one of these to be an H3K4me3 site that exhibits strain differences in methylation. Thus, by making cross-species functional genomics readily computable we identified a common QTL candidate for two related bio-behavioral processes via functional evidence and demonstrate sufficiency of the genetic locus as a source of variation underlying two traits. FINDING the genetic and genomic basis for complex disorders has been a major challenge, particularly for behavioral traits. This is because the disorders are highly heterogeneous in their manifestation and regulation, requiring a match of numerous genes to many aspects of the disorders. A compelling approach to this problem lies in integration of numerous disparate data sets across species, each aimed at characterizing the mechanistic biological underpinnings for the behaviors underlying these disorders as modeled in various species. Alcoholism and alcohol use-related disorders are complex, heritable traits that have been the subject of extensive genomic and genetic investigations (Morozova et al. 2012). These traits are particularly challenging because of their heterogeneity and the presence of multiple overlapping subsystems that subserve them (Gould and Gottesman 2006;Crabbe 2012). Many rodent quantitative trait loci (QTL) have been mapped for alcohol-related traits (Ehlers et al. 2010), gene expression analyses have been performed in a variety of populations, and a long history of alcoholism genetics in humans has led to numerous genome-wide association studies (GWAS) or linkage studies (Enoch 2013). QTL mapping studies historically had very low resolution, and many have been performed using populations for which...

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Identification of sex–specific quantitative trait loci controlling alcohol preference in C57BL/6 mice

Cited by 181 publications

References 36 publications

Sucrose consumption in mice: Major influence of two genetic Loci affecting peripheral sensory responses

Sucrose consumption in mice: Major influence of two genetic Loci affecting peripheral sensory responses

Analysis of quantitative trait loci that influence animal behavior

Identification of a QTL in Mus musculus for Alcohol Preference, Withdrawal, and Ap3m2 Expression Using Integrative Functional Genomics and Precision Genetics

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