Publications (51) View all
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Article: The nature and identification of quantitative trait loci: a community's view.
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ABSTRACT: This white paper by eighty members of the Complex Trait Consortium presents a community's view on the approaches and statistical analyses that are needed for the identification of genetic loci that determine quantitative traits. Quantitative trait loci (QTLs) can be identified in several ways, but is there a definitive test of whether a candidate locus actually corresponds to a specific QTL?Nature Reviews Genetics 12/2003; 4(11):911-6. · 38.08 Impact Factor -
Article: A region on chromosome 15 controls intersession habituation in mice.
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ABSTRACT: Habituation to a novel environment, as measured by a change in exploratory activity over time, can be measured both within (intrasession) and across (intersession) sessions. The role of genetics in intrasession habituation has been investigated previously in quantitative trait loci studies, but little attention has been focused on the role of genetics on intersession habituation. We reported recently that inbred strains respond differently in an intersession habituation test. By testing a total of 25 BXD recombinant inbred lines, we were able to map a chromosomal region that strongly influences the way in which mice habituate. This region located on chromosome 15 appears to the major one affecting habituation and accounts for 80% of the genetic variance. We subsequently confirmed this map position by testing (C57BL/6J x DBA/2J) F2 mice.Journal of Neuroscience 11/2003; 23(28):9435-8. · 7.11 Impact Factor -
Article: Autism-like behavioral phenotypes in BTBR T+tf/J mice.
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ABSTRACT: Autism is a behaviorally defined neurodevelopmental disorder of unknown etiology. Mouse models with face validity to the core symptoms offer an experimental approach to test hypotheses about the causes of autism and translational tools to evaluate potential treatments. We discovered that the inbred mouse strain BTBR T+tf/J (BTBR) incorporates multiple behavioral phenotypes relevant to all three diagnostic symptoms of autism. BTBR displayed selectively reduced social approach, low reciprocal social interactions and impaired juvenile play, as compared with C57BL/6J (B6) controls. Impaired social transmission of food preference in BTBR suggests communication deficits. Repetitive behaviors appeared as high levels of self-grooming by juvenile and adult BTBR mice. Comprehensive analyses of procedural abilities confirmed that social recognition and olfactory abilities were normal in BTBR, with no evidence for high anxiety-like traits or motor impairments, supporting an interpretation of highly specific social deficits. Database comparisons between BTBR and B6 on 124 putative autism candidate genes showed several interesting single nucleotide polymorphisms (SNPs) in the BTBR genetic background, including a nonsynonymous coding region polymorphism in Kmo. The Kmo gene encodes kynurenine 3-hydroxylase, an enzyme-regulating metabolism of kynurenic acid, a glutamate antagonist with neuroprotective actions. Sequencing confirmed this coding SNP in Kmo, supporting further investigation into the contribution of this polymorphism to autism-like behavioral phenotypes. Robust and selective social deficits, repetitive self-grooming, genetic stability and commercial availability of the BTBR inbred strain encourage its use as a research tool to search for background genes relevant to the etiology of autism, and to explore therapeutics to treat the core symptoms.Genes Brain and Behavior 04/2008; 7(2):152-63. · 3.48 Impact Factor -
Article: Localization of two new X-linked quantitative trait loci controlling corpus callosum size in the mouse.
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ABSTRACT: Corpus callosum (CC) size is a complex trait, characterized by a gradation of values within a normal range, as well as abnormalities that include a small or totally absent CC. Among inbred mouse strains with defects of the CC, BTBR T(+)tf/J (BTBR) mice have the most extreme phenotype; all animals show total absence of the CC and severe reduction of the hippocampal commissure (HC). In contrast, the BALB/cByJ (BALB) strain has a low frequency of small CC and consistently normal HC. Reciprocal F(1) crosses between BTBR and BALB suggest the presence of X-linked quantitative trait loci (QTLs) affecting CC size. Through linkage analysis of backcross male progeny, we have localized two regions on the X chromosome, having peaks at 68.5 Mb (approximately 29.5 cM) and at 134.5 Mb (approximately 60.5 cM) that are largely responsible for the reciprocal differences, with the BTBR allele showing X-linked dominant inheritance associated with CC defects.Genes Brain and Behavior 07/2007; 6(4):359-63. · 3.48 Impact Factor -
Article: Genetic and behavioral differences among five inbred mouse strains commonly used in the production of transgenic and knockout mice.
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ABSTRACT: Five strains of mice commonly used in transgenic and knockout production were compared with regard to genetic background and behavior. These strains were: C57BL/6J, C57BL/6NTac, 129P3/J (formerly 129/J), 129S6/SvEvTac (formerly 129/SvEvTac) and FVB/NTac. Genotypes for 342 microsatellite markers and performance in three behavioral tests (rotorod, open field activity and habituation, and contextual and cued fear conditioning) were determined. C57BL/6J and C57BL/6NTac were found to be true substrains; there were only 12 microsatellite differences between them. Given the data on the genetic background, one might predict that the two C57BL/6 substrains should be very similar behaviorally. Indeed, there were no significant behavioral differences between C57BL/6J and C57BL/6NTac. Contrary to literature reports on other 129 strains, 129S6/SvEvTac often performed similarly to C57BL/6 strains, except that it was less active. FVB/NTac showed impaired rotorod learning and cued fear conditioning. Therefore, both 129S6/SvEvTac and C57BL/6 are recommended as background strains for targeted mutations when researchers want to evaluate their mice in any of these three behavior tests. However, any transgene on the FVB/NTac background should be transferred to B6. Habituation to the open field was analyzed using the parameters: total distance, center distance, velocity and vertical activity. Contrary to earlier studies, we found that all strains habituated to the open field in at least two of these parameters (center distance and velocity).Genes Brain and Behavior 07/2004; 3(3):149-57. · 3.48 Impact Factor
