Reference
The Collaborative Cross (CC) is a large (~1,000 line) panel of recombinant inbred (RI) mouse strains being developed through a community effort (Churchill et al. 2004). The CC combines the genomes of eight genetically diverse founder strains - A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HlLtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ - to capture nearly 90% of the known variation present in laboratory mice. CC strains are derived using a unique funnel breeding scheme. Once inbred, the RI CC lines can be used to generate thousands of potential 'outbred' but completely reproducible genomes through the generation of recombinant inbred crosses (RIX). The designation 'PreCC' is used to describe a mapping population of CC mice that is still at incipient stages of inbreeding.
CTC (2004), Churchill, G. A., et al.. The Collaborative Cross, a community resource for the genetic analysis of complex traits. Nat Genet. 36, 1133-7.
Experiment
A total of 102 reproductive, behavioral, physiological, and morphological
traits were subject to QTL mapping in a set of 414 lines of PreCC#/Unc mice.
Phenotyping and genotyping were performed in at least one breeding pair per line from generations G2:F5G2:F8 for QTL analysis. Most of the genotyped mice came from the G2:F5 generation. From this generation, 235 lines were tested. Approximately 7500 mice of both sexes (except for gonadal fat-pad mass and testes weight) from up to 626 lines were phenotyped for body weight, tail length, fasting plasma glucose level, weights of kidney and heart, and behavioral and physiological traits; of these, about 3000 have been phenotyped for adiposity based on perigonadal fat-pad weight. Of the total number of mice phenotyped, 52% were females and 48% were males.
A custom array using the Illumina iSelect platform for the Infinium system was developed for SNP genotyping. A subset of 11,969 SNPs were chosen from the NIEHS-Perlegen combined SNP panel. A sliding window was used to search for the minimumsized sets of SNPs that could discern all eight progenitor strains. Once a set of SNPs was identified that together could discriminate all eight founder haplotypes within the window or the window length reached 1.86 Mb, the search was terminated and a new window was started. The resulting array enabled genotyping at more than 1200 windows within which the haplotypes from the progenitor strains could be identified.
Several of the traits measured were highly correlated, including 50 sleep-related
parameters and several similar blood measures. Approximately 72
unique though not statistically independent phenotypes were
considered. Among these, eight statistically significant (p < 0.05)
main-effect QTL were detected using a single-locus mapping approach: red cell distribution width, hotplate latency, average percent of sleep time in the dark, distance traveled in open field during the first 3 min, periosteal circumference
of the femur, peak activity onset after sleep deprivation, body
length, and cumulative distance from the center of the open field.
An additional nine suggestive QTL were detected (p < 0.10), six of which received official nomenclature as per MGI's curatorial guidelines. All mapping was performed relative to NCBI mouse genome Build 36.
QTL Bdln10 is significant for body length. It maps to 152.9 - 158.5 Mb on Chromosome 2 with peak LOD score at rs27338024. Alleles originating from WSB/EiJ at the QTL were significantly different from individuals with alleles derived from other strains.
QTL Bodwt3 is suggestive for body weight. It maps to 154.0 - 159.5 Mb on Chromosome 2 with peak LOD score at rs27338024.
QTL Tlcpl1 is suggestive for tail-clip latency. It maps to 11.62 - 12.58 Mb on Chromosome 2 with peak LOD score at rs27085184.
QTL Opl3m1 is significant for open field locomotion in the first 3 min. It maps to 21.1 - 30.4 Mb on Chromosome 4 with peak LOD score at rs27723618.
QTL Hplq1 is significant for hot plate latency. It maps to 45.5 - 61.0 Mb on Chromosome 5 with peak LOD score at rs13478238 and is driven by significant differences among individuals with alleles derived from PWK/PhJ and relative to those with other alleles except for C57BL6/J.
QTL Opfdc1 is significant for open field distance from center. It maps to 89.6 - 93.2 Mb on Chromosome 6 with peak LOD score at rs49495829.
QTL Brwt5 is suggestive for brain weight. It maps to 36.3 - 52.7 Mb on Chromosome 7 with peak LOD score at rs6263981.
QTL Rbcwd1 is significant for red cell width distribution. It maps to 105.5 - 112.5 Mb on Chromosome 7 with peak LOD score at rs31752108.
QTL Slpapn1 is significant for % sleep night on average. It maps to 90.9 - 96.9 Mb on Chromosome 7 with peak LOD score at rs6381934.
QTL Gf7 is suggestive for gonadal fat pad weight. It maps to 64.5 - 80.8 Mb on Chromosome 8 with peak LOD score at rs31954766. Alleles specific to PWK/PhJ were significantly different fromother alleles except for CAST/EiJ and 12S1/SvImJ.
QTL Paasd1 is significant for peak activity after sleep deprivation. It maps to 29.7 30.2 Mb (rs33767143 - rs6264816) on Chromosome 9 with peak LOD score at rs33767143. Wild-derived strains PWK/PhJ and CAST/EiJ differ significantly from WSB/EiJ, CAST/EiJ is significantly different from129S1/SvImJ,PWK/PhJ is significantly different from A/J, and A/J is significantly different from 129SvImJ.
QTL Eosnp1 is suggestive for percent eosonophils. It maps to 12.7 - 22.5 Mb on Chromosome 17 with peak LOD score at rs33325845.
QTL Mnctp1 is suggestive for percent monocytes. It maps to 27.6 - 42.5 Mb on Chromosome 17 with peak LOD score at rs6311776.
QTL Pstc7 is significant for periosteal circumference. It maps to 21.5 - 22.5 Mb on Chromosome 19 with peak LOD score at rs6287522.
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A composite interval mapping approach enabled the detection of additional loci for several phenotypes:
QTL Brwt7 is significant for brain weight. It maps to 173.3033 - 182.7322 Mb on Chromosome 1 with a peak LOD score of 8.94 at rs6263216.
QTL Slpapn2 is significant for % sleep night on average. It maps to 136.7101 - 8088 Mb on Chromosome 1 with a peak LOD score of 7.14 at rs51956473.
QTL Mnctp2 is significant for percent monocytes. It maps to 22.06967 - 25.32117 Mb on Chromosome 2 with a peak LOD score of 9.51 at rs27184231.
QTL Rbcwd2 is significant for red cell width distribution. It maps to 171.3593 - 178.9667 Mb on Chromosome 2 with a peak LOD score of 12.38 at rs6226117.
QTL Opfdc2 is significant for open field distance from center. It maps to 35.95902 - 36.24817 Mb on Chromosome 3 with a peak LOD score of 8.71 at rs30002306.
QTL Eosnp2 is significant for percent eosonophils. It maps to 103.4089 - 155.3209 Mb on Chromosome 4 with a peak LOD score of 7.24 at rs27479104.
QTL Tlcpl2 is significant for tail-clip latency. It maps to 53.91892 - 65.37513 Mb on Chromosome 5 with a peak LOD score of 8.42 at rs32966653.
QTL Bodwt4 is significant for body weight. It maps to 60.82498 - 87.92665 Mb on Chromosome 8 with a peak LOD score of 7.28 at rs31787744.
QTL Slpapn3 is significant for % sleep night on average. It maps to 119.0918 - 124.8805 Mb on Chromosome 8 with a peak LOD score of 6.44 at rs6304230.
QTL Gf8 is significant for gonadal fat pad weight. It maps to 38.47461 - 41.22081 Mb on Chromosome 9 with a peak LOD score of 6.83 at rs6387702.
QTL Opl3m2 is significant for open field locomotion in the first 3 min. It maps to 108.9281 - 113.5698 Mb on Chromosome 9 with a peak LOD score of 7.77 at rs33324954.
QTL Bdln11 is significant for body length. It maps to 75.23059 - 101.45174 Mb on Chromosome 13 with a peak LOD score of 7.15 at rs6216118.
QTL Brwt8 is significant for brain weight. It maps to 30.66086 - 34.12255 Mb on Chromosome 13 with a peak LOD score of 9.23 at rs29513935.
QTL Opfdc3 is significant for open field distance from center. It maps to 14.18877 - 30.94729 Mb on Chromosome 16 with a peak LOD score of 8.11 at rs37822351.
QTL Brwt6 is significant for brain weight. It maps to 55.66926 - 64.91332 Mb on Chromosome 17 with a peak LOD score of 9.3 at rs33558716.
QTL Hplq2 is significant for hot plate latency. It maps to 50.28954 - 55.20643 Mb on Chromosome 18 with a peak LOD score of 8.69 at rs6203819.
QTL Eosnp3 is significant for percent eosonophils. It maps to 57.34491 - 61.13890 Mb on Chromosome 19 with a peak LOD score of 6.68 at rs30748908.
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