A strategy for the integration of QTL, gene expression, and sequence analyses

Hitzemann, Robert; Malmanger, Barry; Reed, Cheryl; Lawler, Maureen; Hitzemann, Barbara; Coulombe, Shannon; Buck, Kari J.; Rademacher, Brooks L.; Walter, Nicole A.R.; Polyakov, Yekatrina; Sikela, James M.; Gensler, Brenda; Burgers, Sonya; Williams, Robert W.; Manly, Ken; Flint, Jonathan; Talbot, Chris J.

doi:10.1007/s00335-003-2277-9

Cited by 64 publications

(56 citation statements)

References 42 publications

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“…Kcnj9 has been identified as the likely quantitative trait gene controlling basal locomotor behavior (39). Kcnj9 is highly expressed in strains with low basal locomotor activity.…”

Section: Discussionmentioning

confidence: 99%

Natural variation and genetic covariance in adult hippocampal neurogenesis

Kempermann

Chesler

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Adult hippocampal neurogenesis is highly variable and heritable among laboratory strains of mice. Adult neurogenesis is also remarkably plastic and can be modulated by environment and activity. Here, we provide a systematic quantitative analysis of adult hippocampal neurogenesis in two large genetic reference panels of recombinant inbred strains (BXD and AXB͞BXA, n ‫؍‬ 52 strains). We combined data on variation in neurogenesis with a new transcriptome database to extract a set of 190 genes with expression patterns that are also highly variable and that covary with rates of (i) cell proliferation, (ii) cell survival, or the numbers of surviving (iii) new neurons, and (iv) astrocytes. Expression of a subset of these neurogenesis-associated transcripts was controlled in cis across the BXD set. These self-modulating genes are particularly interesting candidates to control neurogenesis. Among these were musashi (Msi1h) and prominin1͞CD133 (Prom1), both of which are linked to stem-cell maintenance and division. Twelve neurogenesis-associated transcripts had significant cis-acting quantitative trait loci, and, of these, six had plausible biological association with adult neurogenesis (Prom1, Ssbp2, Kcnq2, Ndufs2, Camk4, and Kcnj9). Only one cis-acting candidate was linked to both neurogenesis and gliogenesis, Rapgef6, a downstream target of ras signaling. The use of genetic reference panels coupled with phenotyping and global transcriptome profiling thus allowed insight into the complexity of the genetic control of adult neurogenesis.gene array ͉ hippocampus ͉ precursor ͉ quantitative trait loci ͉ stem cell N eurogenesis in adult mammals is modulated by complex interactions among genetic and environmental factors. Our goal is to use a systems genetics approach to determine how the development of new neurons and glia is modulated by gene polymorphisms, activity, and environmental stimuli. A first step toward this goal is to analyze natural variation and genetic covariance among key neurogenesis parameters such as proliferation, survival, and differentiation of new cells. We have shown that natural variation is substantial among different strains of mice (1-3). The normal range of variation often exceeds the effects of single gene mutations in engineered lines of mice.In this study, we extended this analysis of normal variation and applied a systems genetics approach to study the covariance structure of four key parameters of adult hippocampal neurogenesis across two large genetic reference populations consisting of a total of 52 recombinant inbred strains. This approach allowed us to exploit covariance of diverse traits to demonstrate biological linkage and pleiotropy (4, 5). The analysis, however, extends beyond a correlative approach. Both of the genetic reference populations used, the BXD and AXB͞BXA sets, are standard mapping panels, making it possible to search for gene loci, so-called quantitative trait loci (QTL), that produce common variation and pleiotropy among traits linked to adult hippocampal neurogenesis.A...

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“…Kcnj9 has been identified as the likely quantitative trait gene controlling basal locomotor behavior (39). Kcnj9 is highly expressed in strains with low basal locomotor activity.…”

Section: Discussionmentioning

confidence: 99%

Natural variation and genetic covariance in adult hippocampal neurogenesis

Kempermann

Chesler

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

179

162

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“…They found that 31% of these genes are heritable and median heritability is 0.34. Additional studies have been carried out in yeast (Brem et al 2002), mouse (Hitzemann et al 2003;Bystrykh et al 2005;Chesler et al 2005), rat (Hubner et al 2005), and human (Morley et al 2004) mapping populations.…”

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confidence: 99%

Inheritance Patterns of Transcript Levels in F1 Hybrid Mice

et al. 2006

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Genetic analysis of transcriptional regulation is a rapidly emerging field of investigation that promises to shed light on the regulatory networks that control gene expression. Although a number of such studies have been carried out, the nature and extent of the heritability of gene expression traits have not been well established. We describe the inheritance of transcript levels in liver tissue in the first filial (F 1 ) generation of mice obtained from reciprocal crosses between the common inbred strains A/J and C57BL/6J. We obtain estimates of genetic and technical variance components from these data and demonstrate that shrinkage estimators can increase detectable heritability. Estimates of heritability vary widely from transcript to transcript, with one-third of transcripts showing essentially no heritability (,0.01) and onequarter showing very high heritability (.0.50). Roughly half of all transcripts are differentially expressed between the two parental strains. Most transcripts show an additive pattern of inheritance. Dominance effects were observed for 20% of transcripts and a small number of transcripts were identified as showing an overdominance mode of inheritance. In addition, we identified 314 transcripts with expression levels that differ between the reciprocal F 1 animals. These genes may be related to maternal effect.

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“…6,7 Another approach to reduce the number of candidate genes is to investigate the expression of the genes in the QTL. 8,9 In this way, polymorphisms in regulatory or promoter regions resulting in differences in mRNA expression will be detected. This kind of experiment is well suited in a distinct system like a congenic strain, where the noise of genetic differences between strains is reduced.…”

Section: Introductionmentioning

confidence: 99%

Gene expression profiling of arthritis using a QTL chip reveals a complex gene regulation of the Cia5 region in mice

et al. 2005

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One of the major quantitative trait loci (QTLs) associated with arthritis in crosses between B10.RIII and RIIIS/J mice is the Cia5 on chromosome 3. Early in the congenic mapping process it was clear that the locus was complex, consisting of several subloci with small effects. Therefore, we developed two novel strategies to dissect a QTL: the partial advanced intercross (PAI) strategy, with which we recently found the Cia5 region to consist of three loci, Cia5, Cia21 and Cia22, and now we introduce the QTL-chip strategy, where we have combined congenic mapping with a QTL-restricted expression profiling using a novel microarray design. The expression of QTL genes was compared between parental and congenic mice in lymph node, spleen and paw samples in five biological replicates and in dye-swapped experiments at three time points during the induction phase of arthritis. The QTL chip approach revealed 4 genes located in Cia21, differently expressed in lymph nodes, and 14 genes in Cia22, located within two clusters. One cluster contains six genes, differently expressed in spleen, and the second cluster contains eight genes, differently expressed in paws. We conclude the QTL-chip strategy to be valuable in the selection of candidate genes to be prioritized for further investigation.

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A strategy for the integration of QTL, gene expression, and sequence analyses

Cited by 64 publications

References 42 publications

Natural variation and genetic covariance in adult hippocampal neurogenesis

Natural variation and genetic covariance in adult hippocampal neurogenesis

Inheritance Patterns of Transcript Levels in F1 Hybrid Mice

Gene expression profiling of arthritis using a QTL chip reveals a complex gene regulation of the Cia5 region in mice

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