Mapping Data

Experiment

• Experiment
  TEXT-QTL-Candidate Genes
• Chromosome
  12
• Reference
  J:290561 Villani RM, et al., Murine dorsal hair type is genetically determined by polymorphisms in candidate genes that influence BMP and WNT signalling. Exp Dermatol. 2020 May;29(5):450-461
• ID
  MGI:6448171

Genes

Gene
Sostdc1
Twist1

Notes

• 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
  In both humans and mice there are multiple distinct hair types, each of which differs in size and shape. Hair curl is generated largely by kinks in the hair follicle (HF) through which the hair grows. Mouse dorsal coat hair types, guard, awl, auchene and zigzag, develop in three consecutive waves. To date, it is unclear if these hair types are determined genetically through expression of specific factors or can change based on their mesenchymal environment. The authors undertook a novel approach to this question by studying individual hair type in 67 Collaborative Cross (CC) mouse lines and found significant variation in the proportion of each type between strains. Variation in the proportion of zigzag, awl and auchene, but not guard hair, was largely due to germline genetic variation.
  
  Hair samples of 384 mice across 67 CC strains were collected. The strains included the following: 129S, A/J, BALIN, BEM, BOM, BOON, DAVIS, DET3, DOD, DONNELL, FEW, FIM, FIV, GALASUPREME, GAV, GEK2, GET, GIG, GIT, HAX2, HAZ, HIP, JUD, JUNIOR, KAV, LAK, LAM, LAT, LAX, LEL, LEM, LEM2, LIL, LIP, LIV, LOD, LOM, LOT, LUF, LUG, LUV, LUZ, MERCURI, MOP, NOD, NUK, PAT, PEF, PEF2, PIPING, POH, PUB, SAT, SEH, STUCKY, TAS, TOFU, TOP, VIT, WAB2, WOB2, WOT2, XAD, XAI, XAV, XAW2, YID, YOX and ZIF2.
  
  Genome-wide scan was performed using linear regression model by GeneMiner software. Hair proportion was used as the quantitative trait. Analyses were performed based upon 77,818 informative SNP markers from the MegaMUGA set. Founder haplotype blocks were reconstructed using a Hidden Markov model, and the founder alleles contributing to each trait were determined by deriving coefficients (logarithm of odds, LOD), and a one-way ANOVA chi-square test was performed to derive the P-value of association.
  
  To define how germline genetic variation could influence murine pelage hair type, the authors looked for QTL across the CC that modify the proportion of zigzag hairs. The phenotype was encoded as mean proportion of each hair type per strain using counts from at least 3 mice per strain. All genome coordinates relative to GRCm39/mm10.
  
  Two significant QTL for zigzag hair proportion were identified:
  
  Zgzag1 (zigzag hair proportion 1) maps to Chr 12: 30.89 - 46.02 Mb with a peak LOD score of 8.2. The PWK/PhJ allele contributes to low zigzag proportion at Zgzag1. NOD/ShiLtJ, C57BL/6J, and NZO/HlLtJ alleles contribute to high zigzag proportion at Zgzag1.
  
  Zgzag2 (zigzag hair proportion 2) maps to Chr 12: 8.38 - 20.28 Mb with a peak LOD score of 7.5. The PWK/PhJ allele contributes to low zigzag proportion at Zgzag2. NOD/ShiLtJ, C57BL/6J, and NZO/HlLtJ alleles contribute to high zigzag proportion at Zgzag2.
  
  As an additional test to validate the linkage analysis, the authors performed a genome-wide association (GWAS) analysis using the Mouse Universal Genotyping Array (MUGA) SNP set. This method is based on the segregation of SNPs rather than segregation of inferred CC founder haplotypes. SNPs between 32.24 and 41.00 Mb on Chr 12 are suggestively associated (p < 1 x 10⁵). SNPs of highest significance (2.73 x 10⁶) are located between 31.98 and 32.93 Mb. NOD/ShiLtJ strain has the highest zigzag proportion, and HAX2 has the lowset.
  
  Two significant QTL for Awl hair proportion were also identified:
  
  Awl1 (awl hair proportion 1) maps to Chr 12: 30.89 - 46.02 Mb with a peak LOD score of 8.2. The PWK/PhJ allele contributes to high awl proportion at Awl1. NOD/ShiLtJ, C57BL/6J, and NZO/HlLtJ alleles contribute to low awl proportion at Awl1.
  
  Awl2 (awl hair proportion 2) maps to Chr 12: 8.38 - 20.28 Mb with a peak LOD score of 7.5. The PWK/PhJ allele contributes to high awl proportion at Awl2. NOD/ShiLtJ, C57BL/6J, and NZO/HlLtJ alleles contribute to low awl proportion at Awl2.
  
  In the SNP-based analysis, the authors again obtained a significant peak only on Chr 12, with a peak LOD between 31.9 and 33.8 Mb (p = 5.93 x 10⁸). The peak on Chr 16 at 35.38 Mb did not reach genome-wide significance (p = 5.16 x 10⁵).
  
  Using the two genetic analysis methods, the authors obtained several non-significant but suggestive linkage peaks for auchene hairs. The only major peak coming up using both types of analysis was on Chr 3 [58.60 - 61.09 Mb using the haplotype method, and 58.63 - 60.84 Mb using the SNP method (p = 6.02 x 10⁶).
  
  The authors mapped QTL on chromosome 12 that appear to influence a decision point switch controlling the propensity for either second (awl and auchene) or third wave (zigzag) hairs to develop. These loci contain two strong candidates, Sostdc1 (Zgzag1 and Awl1) and Twist1 (Zgzag1 and Awl1), each of which carry several ENCODE regulatory variants, specific to the causal allele, that can influence gene expression, are expressed in the developing hair follicle, and have been previously reported to be involved in regulating human and murine hair behaviour, but not hair subtype determination. Both of these genes are likely to play a part in hair type determination via regulation of BMP and/or WNT signalling.