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The genetic structure of recombinant inbred mice: high-resolution consensus maps for complex trait analysis.

ABSTRACT: BACKGROUND:Recombinant inbred (RI) strains of mice are an important resource used to map and analyze complex traits. They have proved particularly effective in multidisciplinary genetic studies. Widespread use of RI strains has been hampered by their modest numbers and by the difficulty of combining results derived from different RI sets. RESULTS:We have increased the density of typed microsatellite markers two- to five-fold in each of several major RI sets that share C57BL/6 as a parental strain (AXB, BXA, BXD, BXH and CXB). A common set of 490 markers was genotyped in just over 100 RI strains. Genotypes of around 1,100 additional microsatellites in one or more RI sets were generated, collected and checked for errors. Consensus RI maps that integrate genotypes of approximately 1,600 microsatellite loci were assembled. The genomes of individual strains typically incorporate 45-55 recombination breakpoints. The collected RI set - termed the BXN set - contains approximately 5,000 breakpoints. The distribution of recombinations approximates a Poisson distribution and distances between breakpoints average about 0.5 centimorgans (cM). Locations of most breakpoints have been defined with a precision of < 2 cM. Genotypes deviate from Hardy-Weinberg equilibrium in only a small number of intervals. CONCLUSIONS:Consensus maps derived from RI strains conform almost exactly to theoretical expectation and are close to the length predicted by the Haldane-Waddington equation (x3.6 for a 2-3 cM interval between markers). Non-syntenic associations between different chromosomes introduce predictable distortions in quantitative trait locus (QTL) datasets that can be partly corrected using two-locus correlation matrices.

SUBMITTER: Williams RW

PROVIDER: S-EPMC59991 | biostudies-literature | 2001

REPOSITORIES: biostudies-literature

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The genetic structure of recombinant inbred mice: high-resolution consensus maps for complex trait analysis.

Williams R W RW Gu J J Qi S S Lu L L

Genome biology 20011022 11

<h4>Background</h4>Recombinant inbred (RI) strains of mice are an important resource used to map and analyze complex traits. They have proved particularly effective in multidisciplinary genetic studies. Widespread use of RI strains has been hampered by their modest numbers and by the difficulty of combining results derived from different RI sets.<h4>Results</h4>We have increased the density of typed microsatellite markers two- to five-fold in each of several major RI sets that share C57BL/6 as a ...[more]

PMID: 11737945

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Project description:A/J mice develop progressive hearing loss that begins before 1 month of age and is attributed to cochlear hair cell degeneration. Screening tests indicated that this strain also develops early onset vestibular dysfunction and has otoconial deficits. The purpose of this study was to characterize the vestibular dysfunction and macular structural pathology over the lifespan of A/J mice. Vestibular function was measured using linear vestibular evoked potentials (VsEPs). Macular structural pathology was evaluated using light microscopy, scanning electron microscopy, transmission electron microscopy, confocal microscopy and Western blotting. Individually, vestibular functional deficits in mice ranged from mild to profound. On average, A/J mice had significantly reduced vestibular sensitivity (elevated VsEP response thresholds and smaller amplitudes), whereas VsEP onset latency was prolonged compared to age-matched controls (C57BL/6). A limited age-related vestibular functional loss was also present. Structural analysis identified marked age-independent otoconial abnormalities in concert with some stereociliary bundle defects. Macular epithelia were incompletely covered by otoconial membranes with significantly reduced opacity and often contained abnormally large or giant otoconia as well as normal-appearing otoconia. Elevated expression of key otoconins (i.e., otoconin 90, otolin and keratin sulfate proteoglycan) ruled out the possibility of reduced levels contributing to otoconial dysgenesis. The phenotype of A/J was partially replicated in a consomic mouse strain (C57BL/6J-Chr 17(A/J)/NaJ), thus indicating that Chr 17(A/J) contained a trait locus for a new gene variant responsible to some extent for the A/J vestibular phenotype. Quantitative trait locus analysis identified additional epistatic influences associated with chromosomes 1, 4, 9 and X. Results indicate that the A/J phenotype represents a complex trait, and the A/J mouse strain presents a new model for the study of mechanisms underlying otoconial formation and maintenance.

Dataset Information

The genetic structure of recombinant inbred mice: high-resolution consensus maps for complex trait analysis.

Publications

The genetic structure of recombinant inbred mice: high-resolution consensus maps for complex trait analysis.

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