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. 2001;2(11):RESEARCH0046.
doi: 10.1186/gb-2001-2-11-research0046. Epub 2001 Oct 22.

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

R W Williams  1 , J Gu, S Qi, L Lu
Affiliations

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

R W Williams et al. Genome Biol. 2001.

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.

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Figures

Figure 1
Figure 1
The BXN map of the mouse genome. The full data table is available in several formats (graphic, text, and Map Manager QTX) as Additional data files and at [30]. Column definitions from left to right: Chr, chromosome assignment based on BXN data set. Our assignments differ in a number of cases from those of the Chromosome Committees' Reports. Locus, an abbreviated version of the locus symbol. To improve legibility we have truncated D1MitNN to D1M NN. CCRcM, the position of the locus given in the most recent chromosome committee reports (2000 or 2001). MIT, the position of the locus given in databases at the Whitehead Institute. BXN, position computed from the current RI data set adjusted for map expansion. GenoM, whole-genome position in morgans with a 5 cM buffer (0.05 M) between chromosomes. This GenoM column can be used to construct whole-genome LOD score plots.
Figure 2
Figure 2
Histogram of interval length in centimorgans between neighboring microsatellite markers in the BXN set.
Figure 3
Figure 3
Genetic similarity of RI strains. The percentage of identical genotypes was computed for all two-way combinations of 108 RI strains. Those pairs of strains for which the percentage of shared genotypes was greater than 75% (see text) were flagged and one member of the pair was eliminated from the BXN set.
Figure 4
Figure 4
Progressive expansion of RI genetic maps during inbreeding. The middle series of points (red) that start at generation 2 shows the addition of map length - and the proportional increase in the numbers of recombination breakpoints - relative to a standard one meiotic generation F2 map. For example, at generation 7, approximately two map lengths have been added to the initial map. By F24 the total RI map is almost precisely four times as long as a standard F2 map. This same addition characterizes other diallele crosses that start near Hardy-Weinberg equilibrium, including advanced intercrosses. A two-strain G8 advanced intercross with a 6,000 cM map length would ultimately produce a G8 RI set with map length of 6,000 + 3 × 1,400 cM = 10,200 cM. The upper series of points (blue) illustrates the accumulation in map length in a four-strain intercross at Hardy-Weinberg equilibrium at generation 0. This cross will gain up to 3.75 map equivalents. The lowest set of points is the inbreeding coefficient at each generation. For a tabulation of these data and methods for calculating two- and four-strain expansion values see [30].
Figure 5
Figure 5
Mean expansion of the genetic map in RI strains. The average is approximately 3.7 for 100 independent RI lines. The x-axis can also be considered as the mean number of recombinations per 100 cM in different RI strains. This can be transformed into the total number of recombinations per strain by multiplying by the genetic length of the mouse genome in morgans (approximately 14 morgans; 2.25x = 31.5 recombinations/strain, 3x = 42 recombinations/strain, 4x = 56 recombinations/strain; and 6x = 84 recombinations/strain).
Figure 6
Figure 6
Density of recombinations for all autosomes compared to a Poisson model. We scored the number of recombinations for each of 2,072 chromosomes (all strains; chromosome X excluded). The mean number is 2.43 recombination breakpoints per chromosome. The particular distribution assumes all 19 autosomes have a length of about 70 cM and this simplification accounts for the high Χ2 (125, p << 0.001, 10 df). Of 250 non-recombinant chromosomes observed only 182 were expected. There are also significantly more chromosomes with an apparent excess of recombinations. These deviations are of course expected because short chromosomes (<70 cM) will contribute more non-recombinants and long chromosomes (> 70 cM) will contribute more highly recombinant chromosomes than predicted by the model.
Figure 7
Figure 7
Correlation of genotypes illustrating non-syntenic associations for 102 strains. This sample from the complete correlation matrix of the BXN set illustrates both the expected syntenic correlations (the large red diagonal region extending down to the right) and several unexpected regions of high non-syntenic correlation between different chromosomes. Red regions are linked with positive correlation between 0.20 and 1.0 (p < 0.05). Darker blue regions are linked with negative correlation of between -0.20 and -0.40 (p < 0.05). Beige and light-blue regions are regions with intermediate correlation that are not statistically different from zero with 100 degrees of freedom. For example, the region of chromosome 1 near D1Mit135 (labeled D1M 135 in this table) is linked positively to the proximal part of chromosome 19 and negatively to the proximal part of chromosome 2. The full data table is available online in several formats as Additional data files and at [30].
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