Healing quantitative trait loci in a combined cross analysis using related mouse strain crosses

Abstract

Inbred mouse strains MRL and LG share the ability to fully heal ear hole punches with the full range of appropriate tissues without scarring. They also share a common ancestry, MRL being formed from a multi-strain cross with two final backcrosses to LG before being inbred by brother-sister mating. Many gene-mapping studies for healing ability have been performed using these two strains, resulting in the location of about 20 quantitative trait loci (QTLs). Here, we combine two of these crosses (N¼638), MRL/lprÂC57BL/6NTac and LG/JÂSM/J, in a single combined cross analysis to increase the mapping power, decrease QTL support intervals, separate multiple QTLs and establish allelic states at individual QTL. The combined cross analysis located 11 QTLs, 6 affecting only one cross (5 LGÂSM and 1 MRLÂB6) and 5 affecting both crosses, approximately the number of common QTLs expected given strain SNP similarity. Amongst the five QTLs mapped in both crosses, three had significantly different genetic effects, additive in one cross and over or underdominant in the other. It is possible that allelic states at these three loci are different in SM and B6 because they lead to differences in dominance interactions with the LG and MRL alleles. QTL support intervals are 40% smaller in the combined cross analysis than in either of the single crosses. Combined cross analysis was successful in enhancing the interpretation of earlier QTL results for these strains.

Fine-mapping quantitative trait loci affecting murine external ear tissue regeneration in the LG/J by SM/J advanced intercross line

“…In the current study, real progress has been made in narrowing the quantitative trait intervals by use of the (LG,SM) F34 AIL. An important feature of the present work is that QTLs on chromosomes 9, 10, 11, 14 and 18 discovered in earlier studies (Blankenhorn et al, 2009;Cheverud et al, 2012) were confirmed in the AI line, lending further credence to their role in regenerative healing. New QTLs have been identified on chromosomes 1, 7, 12 and 13 in this study.…”

“…New QTLs have been identified on chromosomes 1, 7, 12 and 13 in this study. Healing QTLs reported by Cheverud et al (2012) on chromosomes 2, 4, 6, 8 and 19 did not show up as significant at the 5% Bonferroni-corrected significance threshold in the present study. However, each of these QTL locations did pass a point-wise 5% threshold appropriate for testing an a priori hypothesis in the F34 generation given the earlier F2 results.…”

“…Recently, a linkage study using LG/J Â SM/J (SM) F2 intercrosses identified multiple quantitative trait loci (QTL) that regulate wound healing with regeneration (Blankenhorn et al, 2009). Further analysis of LG,SM QTL show that when compared with the QTL identified in MRL crosses, there are both shared and unique loci (Cheverud et al, 2012).…”

A cellular, molecular, and pharmacological basis for appendage regeneration in mice

“…In our studies, we found that decreased Sdf1 expression and diminished recruitment of Cxcr4 + leukocytes promote tissue regeneration. Our results may also explain the statistically significant linkage of the locus containing Sdf1 to regeneration in QTL studies of MRL mice (Cheverud et al 2012). The balance between inflammatory responses and tissue regeneration is likely to be complex and multiphasic.…”

“…From prior quantitative trait locus (QTL) mapping studies in MRL mice (Cheverud et al 2012), we identified one locus linked to regenerative capacity that contained the gene for stromal cell-derived factor-1 (Sdf1; also known as Cxcl12). Sdf1 binds to the chemokine receptor Cxcr4, and increased Sdf1-Cxcr4 signaling has been linked to increased fibrosis and scar formation in multiple tissues, including the lung, liver, and heart.…”