Ncdq1^NOD/ShiLtJ
QTL Variant Detail

Summary

• QTL variant: Ncdq1^NOD/ShiLtJ
• Name: nevus cell density QTL 1; NOD/ShiLtJ
• MGI ID: MGI:6342087
• QTL: Ncdq1 Location: Chr9:28111296-36111296 bp Genetic Position: Chr9, Syntenic

Variant origin

• Strain of Specimen: NOD/ShiLtJ

Variant description

• Allele Type: QTL
• Inheritance: Not Specified

Notes

Mapping and Phenotype information for this QTL, its variants and associated markers

J:277000

QTL Reference Notes

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.

Congenital nevi develop before birth and sometimes cover large areas of the body. They are presumed to arise from the acquisition of a gene mutation in an embryonic melanocyte that becomes trapped in the dermis during development. Mice bearing the Cdk4^R24C/R24C::Tyr-NRAS^Q61K transgenes develop congenital nevus-like lesions by post-natal day 10, from melanocytes escaping the confines of hair follicles. The authors interbred these mice with the Collaborative Cross (CC) and examined variation in nevus cell density in the resulting 66 CC-cross strains.

By breeding Cdk4^R24C/R24C::Tyr-NRAS^Q61K males with females from many CC strains, the authors generated progeny heterozygous for both the Cdk4 and NRAS mutations.

The authors collected skin from >3 mice of each cross, and the density of nevus cells in dermis was scored between 1 (least dense) and 10 (most dense).

For mapping, the authors used a logistic regression matrix model over the reconstructed haplotypes matrix to produce genomewide distribution of P-values (ANOVA chi-squared). They used a false discovery rate of P = 0.0001 to define significant genomewide linkage.

One significant QTL was mapped:

Ncdq1 (nevus cell density QTL 1) mapped to Chr 9: 28.2 - 36.2 Mb with a peak LOD score of 12.0 at 35 Mb (derived from Fig. 2). The causal variant at Ncdq1 is derived from the NOD/ShiLtJ founder strain.

Two suggestive QTL were also detected:

One at Chr 11: 12.3 - 17.4 Mb, and

one at Chr 19: 38.5 - 42.8 Mb.

The nevus "susceptibility" allele is inherited from NOD/ShiLtJ at both suggestive QTL.

The authors report that the best candidate for a gene that exacerbates congenital nevus development in the context of an NRAS mutation is Cdon (cell adhesion molecule-related/down-regulated by oncogenes), a positive regulator of sonic hedgehog (Shh) that is expressed mainly in keratinocytes.

References

• Original: J:277000 Chitsazan A, et al., A mutation in the Cdon gene potentiates congenital nevus development mediated by NRAS(Q61K). Pigment Cell Melanoma Res. 2016 Jul;29(4):459-64
• All: 1 reference(s)