Mcdif2^DBA/1J
QTL Variant Detail

Summary

• QTL variant: Mcdif2^DBA/1J
• Name: melanocyte stem cell differentiation 2; DBA/1J
• MGI ID: MGI:6357950
• QTL: Mcdif2 Location: unknown Genetic Position: Chr7, Syntenic

Variant origin

• Strain of Specimen: DBA/1J

Variant description

• Allele Type: QTL
• Inheritance: Not Specified

Notes

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

J:277534

Age-related hair graying is caused by malfunction in the regenerative potential of the adult pigmentation system. The retention of hair color over the life of an organism is dependent on the ability of the melanocyte stem cells and their progeny to produce pigment each time a new hair grows. Melanocyte stem cell differentiation generally precedes hair graying and is observed in melanocyte stem cells with age.

The authors developed previously a sensitized, mouse modifier screen and discovered that the DBA/1J background is particularly resistant to melanocyte stem cell differentiation in comparison to the C57BL/6J background.

(DBA/1J x C57BL/6J-Tg(DctSox10)/0) F1-Tg(DctSox10)/0 mice were used to map QTL related to DBA/1J-mediated variability in melanocyte stem cell differentiation.

122 N2 mice were phenotyped by examining skin from plucked hair regions of the lower back for the presence of ectopically pigmented melanocyte stem cells (EPMs). Selective genotyping was performed on 79 of the N2 mice exhibiting the highest (>50%, n = 39) and lowest (<20%, n = 40) percentage of hairs exhibiting EPMs. The EPM phenotype was converted to a binary trait with the high EPM phenotype scored as 1 and referred to as 'affected', while the low EPM phenotype was scored as 0 and referred to as 'unaffected'.

Presence of the Tg(Dct-Sox10) transgene was determined by PCR using primers that generate an amplicon spanning the Dct promoter and the Sox10 cDNA. SNP genotyping was performed on a custom panel of 1449 SNPs (equivalent to the Mouse Medium Density Linkage Panel, Illumina) using the GoldenGate Genotyping Universal-32 Assay Kit with UDG (Illumina). In preparation for QTL analysis using R/qtl, 559 non-informative SNPs and SNPs with a high number of no call values were omitted.

A total of 79 mice were initially evaluated, and 3 removed for low-quality genotyping results. QTL linkage analysis of 76 mice (36 with the high and 40 with the low EPM phenotype, 37 males and 39 females) and 890 markers using EPM as a binary trait was performed using the R/qtl software.

The authors identified three QTL associated with variability in melanocyte stem cell differentiation:

Mcdif1 (melanocyte stem cell differentiation 1) maps to Chr 13 with a peak LOD score of 3.56 at 21.79 cM (c13.loc20).

Mcdif2 (melanocyte stem cell differentiation 2) maps to Chr 7 with a peak LOD score of 3.81 at 28.39 cM (rs6160140).

Mcdif3 (melanocyte stem cell differentiation 3) maps to Chr X with a peak LOD score at 46.169 cM.

Mcdif2 and Mcdif3 interact significantly with a LOD score of 5.143, suggesting that these two QTL are epistatic.

Mcdif1 exhibits an effect that suggests that this QTL may be involved in DBA/1J-mediated susceptibility to melanocyte stem cell differentiation. In this case, a high proportion of animals exhibit the affected, high EPM phenotype in association with heterozygosity for the C57BL/6J and DBA/1J alleles.

The effects at Mcdif2 are consistent with the DBA/1J allele conferring resistance to melanocyte stem cell differentiation with a low proportion of animals exhibiting the affected, high EPM phenotype in association with heterozygosity (AB) for the C57BL/6J and DBA/1J alleles. In addition, females exhibit a noticeably larger effect than males, matching additionally described evidence suggesting that Mcdif2 is influenced by sex.

The full model (lod.full) containing Mcdif2 and Mcdif3 provides a better fit to the data than both the best single-QTL model (lod.fv1) and the additive model (lod. add). Interaction between these QTL is also significant (lod.int) suggesting that these QTL are epistasic. When the Mcdif2 and Mcdif3 genotypes are considered together, the effect of Mcdif2 in females is the same; a low proportion of individuals exhibit the affected, high EPM phenotype when heterozygous for Mcdif2, independent of genotype at Mcdif3. In males, however, the effect of Mcdif2 is opposite depending on whether Mcdif3 is C57BL/6J-derived (A allele) or DBA/1J-derived (B allele). Specifically, the effect of Mcdif2 switches from EPM resistance in combination with the Mcdif3 B allele to EPM susceptibility in males with a the Mcdif3 A allele.

References

• Original: J:277534 Fialkowski AC, et al., Identification of Gene Variants Associated with Melanocyte Stem Cell Differentiation in Mice Predisposed for Hair Graying. G3 (Bethesda). 2019 Mar 7;9(3):817-827
• All: 1 reference(s)