Ath1 is a quantitative trait locus on mouse chromosome 1 that renders C57BL/6 mice susceptible and C3H/He mice resistant to diet-induced atherosclerosis. The quantitative trait locus region encompasses 11 known genes, including Tnfsf4 (also called Ox40l or Cd134l), which encodes OX40 ligand. Here we report that mice with targeted mutations of Tnfsf4 had significantly (P

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Identifying quantitative trait locus (QTL) genes is a challenging task. Herein, we report using a two-step process to identify Apoa2 as the gene underlying Hdlq5, a QTL for plasma high-density lipoprotein cholesterol (HDL) levels on mouse chromosome 1. First, we performed a sequence analysis of the Apoa2 coding region in 46 genetically diverse mouse strains and found five different APOA2 protein variants, which we named APOA2 a to APOA2 e . Second, we conducted a haplotype analysis of the strains in 21 crosses that have so far detected HDL QTLs; we found that Hdlq5 was detected only in the nine crosses where one parent had the APOA2 b protein variant characterized by an Ala 61 -to-Val 61 substitution. We then found that strains with the APOA2 b variant had significantly higher (P Յ 0.002) plasma HDL levels than those with either the APOA2 a or the APOA2 c variant. These findings support Apoa2 as the underlying Hdlq5 gene and suggest the Apoa2 polymorphisms responsible for the Hdlq5 phenotype. Therefore, haplotype analysis in multiple crosses can be used to support a candidate QTL gene.[Supplemental material is available online at www.genome.org. The following individuals kindly provided reagents, samples, or unpublished information as indicated in the paper: D. Puppione.]Most common human diseases, such as atherosclerosis, diabetes, and obesity, are complex traits determined by many genetic and environmental factors. The genetic factors are usually studied in animal models, most commonly mice, and frequently through a process known as quantitative trait locus (QTL) analysis, which has the advantage of finding novel key genes in a metabolic pathway. To date, more than 1800 mouse QTLs have been found (Mouse Genome Informatics, http://www.informatics.jax.org); however, identifying the genes underlying these QTLs has been an extremely challenging task (Nadeau and Frankel 2000; Korstanje and Paigen 2002).The level of plasma high-density lipoprotein cholesterol (HDL), although not a disease, is also a complex trait. It has been intensely studied because, in humans, it is inversely correlated with the risks of coronary artery disease, and therapies that raise HDL levels may significantly reduce these risks (Boden and Pearson 2000). QTL analysis has identified many genomic regions that regulate HDL levels, both in mice and in humans-to date, 37 mouse and 29 human HDL QTLs have been identified To determine whether Apoa2 was the Hdlq5 gene, we took the approach of haplotype analysis. Recent single nucleotide polymorphism (SNP) maps indicate that the genome of common inbred mouse strains is defined by 1-2 Mb haplotype blocks (Wade et al. 2002;Wiltshire et al. 2003), which can be used to narrow a QTL, because its underlying gene should be in subregions where the parental strains have different haplotypes (Park et al. 2003;Manenti et al. 2004). We extended this haplotype analysis further by using it to identify a QTL gene. In doing so, we performed a sequence analysis of the coding region of Apoa2 in 46 genetically diverse m...

Numerous studies have shown that cerebellar function is related to the plasticity at the synapses between parallel fibers and Purkinje cells. How specific input patterns determine plasticity outcomes, as well as the biophysics underlying plasticity of these synapses, remain unclear. Here, we characterize the patterns of activity that lead to postsynaptically expressed LTP using both in vivo and in vitro experiments. Similar to the requirements of LTD, we find that high-frequency bursts are necessary to trigger LTP and that this burst-dependent plasticity depends on presynaptic NMDA receptors and nitric oxide (NO) signaling. We provide direct evidence for calcium entry through presynaptic NMDA receptors in a subpopulation of parallel fiber varicosities. Finally, we develop and experimentally verify a mechanistic plasticity model based on NO and calcium signaling. The model reproduces plasticity outcomes from data and predicts the effect of arbitrary patterns of synaptic inputs on Purkinje cells, thereby providing a unified description of plasticity.