Multiple Cross Mapping (MCM) markedly improves the localization of a QTL for ethanol‐induced activation

Hitzemann, Robert; Malmanger, Barry; Cooper, Shelley; Coulombe, Shannon; Reed, Cheryl; Demarest, Kristin; Koyner, Jay L.; Cipp, Laura; Flint, Jonathan; Talbot, Chris J.; Rademacher, Brooks L.; Buck, Kari J.; McCaughran, James A.

doi:10.1034/j.1601-183x.2002.10403.x

Cited by 47 publications

(49 citation statements)

References 42 publications

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“…Wade and colleagues (1) estimate in a comparison between C57BL͞6 and 129 that Ͼ90% of the genome can be classified as either high (45 per 10 kb) or low (1.0 per 10 kb) SNP content occurring in segments with an average size of 1.2 Mb. Consequently, a QTL could be mapped into a region of about 2 Mb by using sequence variant information, and combining mapping information from additional strains could further reduce the interval (3,5).…”

Section: Discussionmentioning

confidence: 99%

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Unexpected complexity in the haplotypes of commonly used inbred strains of laboratory mice

Yalcin

Fullerton

Miller

et al. 2004

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

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101

106

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Investigation of sequence variation in common inbred mouse strains has revealed a segmented pattern in which regions of high and low variant density are intermixed. Furthermore, it has been suggested that allelic strain distribution patterns also occur in well defined blocks and consequently could be used to map quantitative trait loci (QTL) in comparisons between inbred strains. We report a detailed analysis of polymorphism distribution in multiple inbred mouse strains over a 4.8-megabase region containing a QTL influencing anxiety. Our analysis indicates that it is only partly true that the genomes of inbred strains exist as a patchwork of segments of sequence identity and difference. We show that the definition of haplotype blocks is not robust and that methods for QTL mapping may fail if they assume a simple block-like structure.

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Section: Discussionmentioning

confidence: 99%

“…Understanding the structure of sequence variation is important because correlations between genetic and phenotypic variation could help identify the molecular variants underlying quantitative trait loci (QTL) (1,5), which have proved so refractory to positional cloning (6).…”

mentioning

confidence: 99%

Unexpected complexity in the haplotypes of commonly used inbred strains of laboratory mice

Yalcin

Fullerton

Miller

et al. 2004

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

Self Cite

101

106

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“…However, several of the inbred strains had mosiac haplotypes that were much smaller than 1 Mb, sometimes spanning only a few hundred base pairs. Therefore, methods of gene and allele identification that assume long stretches of identity by descent among inbred strains (Hitzemann et al, 2002) should be applied with caution.…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms in the Taste Receptor Gene (Tas1r3) Region Are Associated with Saccharin Preference in 30 Mouse Strains

Reed

Li²,

Li³

et al. 2004

J. Neurosci.

167

146

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The results of recent studies suggest that the mouse Sac (saccharin preference) locus is identical to the Tas1r3 (taste receptor) gene. The goal of this study was to identify Tas1r3 sequence variants associated with saccharin preference in a large number of inbred mouse strains. Initially, we sequenced ϳ6.7 kb of the Tas1r3 gene and its flanking regions from six inbred mouse strains with high and low saccharin preference, including the strains in which the Sac alleles were described originally (C57BL/6J, Sac b ; DBA/2J, Sac d ). Of the 89 sequence variants detected among these six strains, eight polymorphic sites were significantly associated with preferences for 1.6 mM saccharin. Next, each of these eight variant sites were genotyped in 24 additional mouse strains. Analysis of the genotype-phenotype associations in all 30 strains showed the strongest association with saccharin preference at three sites: nucleotide (nt) Ϫ791 (3 bp insertion/deletion), nt ϩ135 (Ser45Ser), and nt ϩ179 (Ile60Thr). We measured Tas1r3 gene expression, transcript size, and T1R3 immunoreactivity in the taste tissue of two inbred mouse strains with different Tas1r3 haplotypes and saccharin preferences. The results of these experiments suggest that the polymorphisms associated with saccharin preference do not act by blocking gene expression, changing alternative splicing, or interfering with protein translation in taste tissue. The amino acid substitution (Ile60Thr) may influence the ability of the protein to form dimers or bind sweeteners. Here, we present data for future studies directed to experimentally confirm the function of these polymorphisms and highlight some of the difficulties of identifying specific DNA sequence variants that underlie quantitative trait loci.

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“…Coincident mapping to the same chromosome region of these two susceptibility loci derived from two different susceptible strains might indicate inheritance of a common allele (implying that the cancer causative polymorphism occurred in an ancestral strain). 27,28 In the present case, Mcstm1 might also include several subloci and the SPRD-Cu3 Mcstm1 alleles (or at least some of them) might thus be identical to the WF Mcs5 alleles, but distinct from the WKY alleles. Examination of the haplotype structure across the candidate region might reveal regions that segregate appropriately with the phenotypic modification and therefore may harbor the causative polymorphism.…”

Section: Chromosome 5 Congenic Rat Strain (Sprd-cu3wky-mcstm1)mentioning

confidence: 99%

“…This strategy is on the basis of the fact that distinct inbred strains can exhibit the same phenotype as a result of a shared haplotype, which must include the allele(s) controlling the phenoptype in question. 27,28 Therefore, we chose to analyze the genetic basis of mammary cancer susceptibility in the rat strain SPRD-Cu3, highly susceptible to spontaneous and chemically-induced tumors, which we crossed with WKY, highly resistant. Using linkage based mapping analysis, we previously defined several QTLs that control the susceptibility to 7,12-dimethylbenz[a]anthracene (DMBA) induced mammary carcinoma susceptibility.…”

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confidence: 99%

Isolation of two regions on rat chromosomes 5 and 18 affecting mammary cancer susceptibility

Stieber¹,

Piessevaux²,

Riviere³

et al. 2007

Intl Journal of Cancer

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We previously mapped several quantitative trait loci (QTLs) controlling DMBA-induced mammary tumor development in female rats derived from a SPRD-Cu3 (susceptible strain) 3 WKY (resistant strain) cross. Two of these QTLs were assigned to chromosomes 5 and 18. In the present study, we generated and characterized congenic strains in which a segment of WKY chromosomes 5 or 18 was introduced in the SPRD-Cu3 genetic background, thereby physically demonstrating that each of these two chromosomes controls mammary tumor multiplicity. The chromosome 5 QTL (Mcstm1) accounts for 7 tumors per animal (versus a total of 11 tumors per SPRD-Cu3 rat). The chromosome 18 QTL (Mcstm2) accounts for 3 tumors per animal and is the first chemically-induced mammary cancer susceptibility locus assigned to this chromosome. In addition, the Mcstm1 region was shown to also controls tumor latency. These loci thus play a major role in chemically-induced mammary tumor development. QTLs controlling chemically-induced or estrogen-induced mammary tumor development have independently been identified on chromosomes 5 and 18, using susceptible strains others than SPRD-Cu3. Therefore the haplotype structure of the relevant chromosome regions was analyzed in the different strains. Some chromosome regions were found to be highly mosaic (haplotype blocks < 1 Mb), while one region showed an apparently conserved haplotype block of 7.5 Mb. This analysis points to limited regions that could harbor the causative genes and also indicates that at least Mcstm2 is a novel QTL. ' 2007 Wiley-Liss, Inc.Key words: rat; mammary cancer; cancer susceptibility; congenics; haplotype Breast cancer is a complex, multi-factorial disease affecting about 10% of women in industrials countries. One major risk factor for breast cancer is genetic predisposition (for reviews, see Refs. 1 and 2). Two major breast cancer susceptibility genes (BRCA1, BRCA2) have been identified, [3][4][5][6] and 5-10% of all breast cancers can be explained by the inheritance of mutations in one of these two genes.7 However, a great deal remains to be understood as regards the possible role of other genes involved in susceptibility to breast cancer.2,7-10 Some other susceptibility/ modifier genes have been identified and/or evaluated, mainly by means of association tests, 1,2,11 but it is reasonable to assume that several additional genes remain to be discovered. It is assumed that if 50% of this breast cancer modifier genes could be identified it would be possible to assign 80% of the total breast cancer risk to 50% of the population.10 Such a risk-prone population could then be chosen for increased surveillance. It thus seems justified to search for high-frequency, low-penetrance modifier alleles that either increase or decrease breast cancer risk and thereby help to delimitate the aforementioned at risk population. However, identifying genes that are not highly penetrant in human populations is a difficult task, 12 owing to the genetic and environmental heterogeneity of most of these populations.On...

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Multiple Cross Mapping (MCM) markedly improves the localization of a QTL for ethanol‐induced activation

Cited by 47 publications

References 42 publications

Unexpected complexity in the haplotypes of commonly used inbred strains of laboratory mice

Unexpected complexity in the haplotypes of commonly used inbred strains of laboratory mice

Polymorphisms in the Taste Receptor Gene (Tas1r3) Region Are Associated with Saccharin Preference in 30 Mouse Strains

Isolation of two regions on rat chromosomes 5 and 18 affecting mammary cancer susceptibility

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