The phenotypic distribution of quantitative traits in a wild mouse F1 population.

The human complex diseases such as hypertension, precocious puberty, and diabetes have their own diagnostic thresholds, which are usually estimated from the epidemiological data of nature populations. In the mouse models, numerous phenotypic data of complex traits have been accumulated; however, knowledge of the phenotypic distribution of the natural mouse populations remains quite limited. In order to investigate the distribution of quantitative traits of wild mice, 170 F1 progeny aged 8-10 weeks and derived from wild mice collected from eight spots in the suburbs of Shanghai were tested for their values of anatomic, blood chemical, and blood hematological parameters. All the wild mice breeders were of Mus. m. musculus and Mus. m. castaneus maternal origin according to the single nucleotide polymorphism (SNP) markers of the mitochondrial DNA. The results showed that phenotypes in wild mice had a normal distribution with four to six times the standard deviation. For the majority of the traits, the wild outbred mice and laboratory inbred mice have significantly different ranges and mean values, whereas the wild mice did not necessarily show more phenotypic diversity than the inbred ones. Our data also showed that natural populations may have some unique phenotypes related to sugar and protein metabolism, as the mean value of wild mice differ dramatically from the inbred mice in the levels of blood glucose, BUN (blood urea nitrogen), and total blood protein. The epidemiological information of the complex traits in the nature population from our study provided valuable reference for the application of mouse models in those complex disease studies.

A novel strategy for genetic dissection of complex traits: the population of specific chromosome substitution strains from laboratory and wild mice.

The mouse is an irreplaceable model for understanding the precise genetic mechanisms of mammalian physiological pathways. Thousands of quantitative trait loci (QTLs) have been mapped onto the mouse genome during the last two decades. However, only a few genes' underlying complex traits have been successfully identified, and rapid fine mapping of QTL genes still remains a challenge for mouse geneticists. Currently, the Collaborative Cross (CC) has proceeded to the goal of establishing more than 1,000 recombinant inbred strains for the sub-centimorgan mapping resolution of QTL loci. In this article, a novel complementary strategy, designated as population of specific chromosome substitution strains or PSCSS, is proposed for rapid fine mapping of QTLs on the substituted chromosome. One specific chromosome (Chr 1) of recipient mouse strain C57BL/6 J has been substituted by homologous counterparts from five different inbred strains (C3H/He, FVB/N, AKR, NOD/LtJ, NZW/LacJ), an outbred line Kunmin mouse in China, and 23 wild mice captured in different localities. The primary genetic studies on the structure of these wild donor chromosomes (Chr 1) show that these donor chromosomes harbor extensive genetic polymorphisms, with a high density of SNP distribution, abundant variations of STR alleles, and a high level of historical recombination accumulation. These specific chromosome substitution strains eventually form a special population that has the identical genetic background of the recipient strain and differs only in the donor chromosomes. With simple association studies, known QTLs on the donor chromosome can be rapidly mapped in high resolution without requirement of further crosses. This approach, taking advantage of the extensive genetic polymorphisms of wild resources and chromosome substitution strategy, brings a new outlook for genetic dissection of complex traits.

[SNP discovery by F-CSGE in the coding region of mitochondrial DNA in wild house mice from Shanghai suburb].

This study was performed to discover SNPs for genetic polymorphism analysis of mitochondrial DNA from wild house mice. Universal primer florescent PCR, fluorescence-based conformation sensitive gel electrophoresis (F-CSGE) and DNA sequencing were conducted to analyze the coding region of mitochondrial DNA. Different types of unknown mutations were recorded by variable F-CSGE patterns without false positive. Twenty-four SNPs, sixteen of which were first discovered in the coding region of mitochondrial DNA, were found in 64 wild house mice from 4 districts in Shanghai. Therefore, F-CSGE was proved to be powerful technique for SNP discovery in the coding region mitochondrial DNA. The novel SNPs can be used as molecular markers to analyze population structure and genetic polymorphisms of the wild house mice in Shanghai.

A dominant X-linked QTL regulating pubertal timing in mice found by whole genome scanning and modified interval-specific congenic strain analysis.

BACKGROUND: Pubertal timing in mammals is triggered by reactivation of the hypothalamic-pituitary-gonadal (HPG) axis and modulated by both genetic and environmental factors. Strain-dependent differences in vaginal opening among inbred mouse strains suggest that genetic background contribute significantly to the puberty timing, although the exact mechanism remains unknown. METHODOLOGY/PRINCIPAL FINDINGS: We performed a genome-wide scanning for linkage in reciprocal crosses between two strains, C3H/HeJ (C3H) and C57BL6/J (B6), which differed significantly in the pubertal timing. Vaginal opening (VO) was used to characterize pubertal timing in female mice, and the age at VO of all female mice (two parental strains, F1 and F2 progeny) was recorded. A genome-wide search was performed in 260 phenotypically extreme F2 mice out of 464 female progeny of the F1 intercrosses to identify quantitative trait loci (QTLs) controlling this trait. A QTL significantly associated was mapped to the DXMit166 marker (15.5 cM, LOD = 3.86, p<0.01) in the reciprocal cross population (C3HB6F2). This QTL contributed 2.1 days to the timing of VO, which accounted for 32.31% of the difference between the original strains. Further study showed that the QTL was B6-dominant and explained 10.5% of variation to this trait with a power of 99.4% at an alpha level of 0.05.The location of the significant ChrX QTL found by genome scanning was then fine-mapped to a region of approximately 2.5 cM between marker DXMit68 and rs29053133 by generating and phenotyping a panel of 10 modified interval-specific congenic strains (mISCSs). CONCLUSIONS/SIGNIFICANCE: Such findings in our study lay a foundation for positional cloning of genes regulating the timing of puberty, and also reveal the fact that chromosome X (the sex chromosome) does carry gene(s) which take part in the regulative pathway of the pubertal timing in mice.