Four additional mouse crosses improve the lipid QTL landscape and identify Lipg as a QTL gene

Su, Zhiguang; Ishimori, Naoki; Chen, Yaoyu; Leiter, Edward H.; Churchill, Gary A.; Paigen, Beverly; Stylianou, Ioannis M.

doi:10.1194/jlr.m900076-jlr200

Cited by 31 publications

(27 citation statements)

References 71 publications

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“…We also analyzed the haplotypes of the parental strains for two crosses that failed to detect a QTL at this location, the PERA/EiJ (PERA) × I/LnJ (I/Ln) and the B6 × C3H/ HeJ (C3H) crosses ( 9,15 ). Haplotyping is often helpful with crosses that do not detect a QTL because the parental strains must share the identical haplotype for the QTL gene.…”

Section: Scarb1 Is the Gene Underlying Hdlq1mentioning

confidence: 99%

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Untangling HDL quantitative trait loci on mouse chromosome 5 and identifying Scarb1 and Acads as the underlying genes

Leduc

Korstanje

et al. 2010

Journal of Lipid Research

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This article is available online at http://www.jlr.org human populations; these QTL often map to homologous locations in both species ( 1 ). Detecting QTL has been relatively easy. The next step of identifying causal QTL genes, however, has been more challenging, although the development of bioinformatic methods ( 2, 3 ) and improved genomic resources in the mouse ( 4 ) and genomewide association studies in humans ( 5, 6 ) are improving the success of QTL gene identifi cation.QTL that are in close proximity on the same chromosome remain particularly challenging. In such situations, it is particularly diffi cult to identify the causal QTL genes. Although congenic strains are a powerful tool to separate these QTL, they are time consuming; therefore, we used a more effi cient, genomic approach to decipher the presence of one or multiple QTL and identify the QTL genes. At least seven inbred mouse crosses ( 7-12 ) have identifi ed HDL QTL on mouse distal chromosome (Chr) 5 ( Table 1 ). However, the broad confi dence intervals and shape of the logarithm of the odds ratio (LOD) score plots suggest that at least four of these crosses (B6 × 129, NZB × SM, B6 × NZB, and B6 × CAST) may have two closely linked QTL. We used advanced intercross lines between B6 and NZB at F11, which allows the accumulation of recombination events and thus narrows QTL ( 13 ) and confi rmed that two QTL did exist between these two strains on distal Chr 5. These QTL were named Hdlq1 at 125 Mb and Hdlq8 at 113 Mb ( 11 ).In the present study, we fi rst identifi ed Scarb1 as the causal gene for Hdlq1 . We then confi rmed that Hdlq8 is an independent QTL by crossing two closely related strains that do not differ at the Scarb1 locus and thus were expected not to have a QTL at the Hdlq1 region. As expected, this cross detected Hdlq8 but had no QTL at Hdlq1. Subsequently, we used haplotype analysis, gene sequencing, expression studies, and a spontaneous mutation to demonstrate that Acads was the underlying gene for Hdlq8 .Abstract Two high-density lipoprotein cholesterol quantitative trait loci (QTL), Hdlq1 at 125 Mb and Hdlq8 at 113 Mb, were previously identifi ed on mouse distal chromosome 5. Our objective was to identify the underlying genes. We fi rst used bioinformatics to narrow the Hdlq1 locus to 56 genes. The most likely candidate, Scarb1 (scavenger receptor B1), was supported by gene expression data consistent with knockout and transgenic mouse models. Then we confi rmed Hdlq8 as an independent QTL by detecting it in an intercross between NZB and NZW (LOD = 12.7), two mouse strains that have identical genotypes for Scarb1 . Haplotyping narrowed this QTL to 9 genes; the most likely candidate was Acads (acyl-coenzymeA dehydrogenase, short chain). Sequencing showed that Acads had an amino acid polymorphism, Gly94Asp, in a conserved region; Western blotting showed that protein levels were signifi cantly different between parental strains. A previously known spontaneous deletion causes loss of ACADS activity in BALB/cBy mice. We showed that HDL le...

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Section: Scarb1 Is the Gene Underlying Hdlq1mentioning

confidence: 99%

“…The details of the NZB/BlNJ (NZB) and NZW/LacJ (NZW) intercross were described previously ( 9,13 ). For the BALB/cByJ [(BALB/cBy) × BALB/cJ (BALB/c)] intercross, female BALB/ cBy and male BALB/c mice (The Jackson Laboratory, Bar Harbor, ME) were mated to generate F1 progeny, which were intercrossed to produce 97 F2 progeny.…”

Section: Mice and Dietsmentioning

confidence: 99%

Untangling HDL quantitative trait loci on mouse chromosome 5 and identifying Scarb1 and Acads as the underlying genes

Leduc

Korstanje

et al. 2010

Journal of Lipid Research

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“…3 ). Therefore, we hypothesize that this polymorphism is responsible for the chromosome 18 HDL QTL from the MRL×SM cross in addition to the HDL QTL from the NZB×SM and LG×SM crosses ( 26,29 ). Further in vitro experiments will be necessary to validate the functionality of the polymorphism.…”

Section: Apoa2mentioning

confidence: 99%

“…Because the MRL×SM F2 mice were fed chow ( 28 ), we consider Ppargc1b to be an unlikely QTL gene for this cross. Lipg is located at 75 Mb on chromosome 18, and a change in expression is thought to be responsible for the QTL of three crosses (B6xD2, NZB/BINJxSM/J [NZBxSM], B6xC3H) ( 26 ). Because of the known role of Lipg in HDL regulation and its close location to the MRL×SM chromosome 18 QTL, we investigated whether it could be responsible for our QTL.…”

Section: Apoa2mentioning

confidence: 99%

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Using bioinformatics and systems genetics to dissect HDL-cholesterol genetics in an MRL/MpJ × SM/J intercross

Leduc

Blair

Verdugo

et al. 2012

Journal of Lipid Research

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A higher incidence of coronary artery disease (CAD) is associated with a lower level of HDL-cholesterol ( 1, 2 ), which is determined by multiple environmental and genetic factors. In the past few years, new therapeutic approaches have focused on fi nding ways to increase HDL ( 3, 4 ). To date, however, only a few environmental interventions, such as diet and exercise, have been successful in raising HDL level ( 5 ), whereas drug therapy development is still ongoing and has targeted only a limited number of proteins such as CETP ( 3, 4 ). In the search for a potential drug target to raise HDL and decrease CAD, the identifi cation of new genes involved in HDL determination is essential.The genetic basis of HDL-cholesterol variation has been widely studied in various animal models. In humans, recent genome-wide association studies (GWAS) have identifi ed known HDL genes such as LIPG and CETP in addition to new genes such as GALNT2 ( 6 ). These known genes, however, explain only a small proportion of the total variation, indicating that additional genes are yet to be discovered. Mouse models are a powerful strategy for identifying such genes. A large overlap exists among species for quantitative trait loci (QTL) and genes involved in lipid metabolism ( 7 ). Many study methodologies are similar between human and mouse, but mouse studies offer advantages by capitalizing on genomics tools that are not available and practical for studies of human populations. To date, our laboratory and those of others have identifi ed over 35 mouse HDL QTL (as reviewed in Wang et al., Refs. 7,8 ). In addition, we and others have developed bioinformatics tools to narrow the QTL interval to just a few candidate genes ( 9, 10 ). Application of these tools has led to the discovery of single genes underlying QTL for HDL and

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Mouse BMD quantitative trait loci show improved concordance with human genome-wide association loci when recalculated on a new, common mouse genetic map

Ackert‐Bicknell

Karasik

et al. 2010

Journal of Bone and Mineral Research

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Bone mineral density (BMD) is a heritable trait, and in mice, over 100 quantitative trait loci (QTLs) have been reported, but candidate genes have been identified for only a small percentage. Persistent errors in the mouse genetic map have negatively affected QTL localization, spurring the development of a new, corrected map. In this study, QTLs for BMD were remapped in 11 archival mouse data sets using this new genetic map. Since these QTLs all were mapped in a comparable way, direct comparisons of QTLs for concordance would be valid. We then compared human genome-wide association study (GWAS) BMD loci with the mouse QTLs. We found that 26 of the 28 human GWAS loci examined were located within the confidence interval of a mouse QTL. Furthermore, 14 of the GWAS loci mapped to within 3 cM of a mouse QTL peak. Lastly, we demonstrated that these newly remapped mouse QTLs can substantiate a candidate gene for a human GWAS locus, for which the peak single-nucleotide polymorphism (SNP) fell in an intergenic region. Specifically, we suggest that MEF2C (human chromosome 5, mouse chromosome 13) should be considered a candidate gene for the genetic regulation of BMD. In conclusion, use of the new mouse genetic map has improved the localization of mouse BMD QTLs, and these remapped QTLs show high concordance with human GWAS loci. We believe that this is an opportune time for a renewed effort by the genetics community to identify the causal variants regulating BMD using a synergistic mouse-human approach. © 2010 American Society for Bone and Mineral Research.

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Four additional mouse crosses improve the lipid QTL landscape and identify Lipg as a QTL gene

Cited by 31 publications

References 71 publications

Untangling HDL quantitative trait loci on mouse chromosome 5 and identifying Scarb1 and Acads as the underlying genes

Untangling HDL quantitative trait loci on mouse chromosome 5 and identifying Scarb1 and Acads as the underlying genes

Using bioinformatics and systems genetics to dissect HDL-cholesterol genetics in an MRL/MpJ × SM/J intercross

Mouse BMD quantitative trait loci show improved concordance with human genome-wide association loci when recalculated on a new, common mouse genetic map

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