Heal1^C57BL/6NTac
QTL Variant Detail

Summary

• QTL variant: Heal1^C57BL/6NTac
• Name: wound healing/regeneration 1; C57BL/6NTac
• MGI ID: MGI:2157054
• QTL: Heal1 Location: Chr8:103443553-103443701 bp Genetic Position: Chr8, cM position of peak correlated region/allele: 52.0 cM
• QTL Note: genome coordinates based on the marker associated with the peak LOD score

Variant origin

• Strain of Specimen: C57BL/6NTac

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers increased wound healing compared to MRL/MpJ. (J:50111)
• Inheritance: Other (see notes)

Notes

Heal1 exhibits additive inheritance.

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

J:50111

MRL/MpJ-Fas^lpr is the only inbred mouse strain capable of complete wound healing after introduction of surgical holes to the ear. Healing includes angiogenesis, regeneration of hair follicles, sebaceous glands, cartilage, and a complete lack of scarring. MRL/MpJ animals exhibit the same super healing trait as MRL/MpJ-Fas^lpr. C57BL/6NTac exhibits poor healing and when crossed to MRL/MpJ-Fas^lpr F1 animals display intermediate healing phenotype with wide variability.

(MRL/MpJ-Fas^lpr x C57BL/6NTac)F2 animals and (MRL/MpJ-Fas^lpr x C57BL/6NTac)F1) x MRL/MpJ-Fas^lpr backcross animals were used to map QTLs involved in wound healing. A genome scan was performed on the 19 autosomes with an average marker density of 20 cM. Polymorphisms could not be detected on the X chromosome and therefore was excluded from the scan. Ninty-two markers detected alleleic variants in the parental strains and were used for genotyping the segregating populations. Markers were chosen with 20cM between to generate a complete genome-wide scan.

The 92 polymorphic microsatellite markers were used to map the wound healing/regeneration trait in 101 mice from the (MRL/MpJ-Fas^lpr x C57BL/6NTac)F2 intercross. Threshold values for significance were determined by permutaion testing, based on a regression model (p ^0.05).

Values for an additive model of inheritance in the F2 were calculated in terms of a likelihood ratio statistic (LRS). The threshold for suggestive significance was LRS 3.3; for significant linkage LRS > 10.7. Threshold values in the backcross were LRS>3.7 and 11.8 respectively.

TABLE 2:

Heal2 and Heal3 mapped to Chromosome 13 at 11cM ( p=0.0019, LRS = 9.7 at D13Mit115) and 60cM ( p=0.0010, LRS = 10.8 at D13Mit129), respectively, in the (MRL/MpJ-Fas x C57BL/6NTac)F2 intercross and were confirmed in the (MRL/MpJ-Fas x C57BL/6NTac)F1) MRL/MpJ-Fas backcross.

Significant QTL Heal1 mapped to chromosome 8 at 49cM (p=0.0011, LRS = 10.7 at D8Mit211), and Heal4 mapped to chromosome 15 at 56.8cM (p=0.0011, LRS = 10.7 at D15Mit244) in the (MRL/MpJ-FasxC57BL/6NTac)F2 intercross.

Highly suggestive QTLs Heal7 and Heal8 also mapped to Chromosome 13 at 32cM (p=0.0014, LRS = 10.2 at D13Nds1) and 44 cM (p=0.0014, LRS = 10.2 at D13Mit191), respectively, in only the F2 intercross. Msx2 is found in the region near D13Nds1 and is expressed in regenerating amphibian tissue as well as regrowing fingertips in neonatal mice.

Heal6, also highly suggestive, mapped to Chromosome 7 at 52.4cM (p=0.0014, LRS = 10.2 at D7Mit220) in the (MRL/MpJ-Fas x C57BL/6NTac)F1) x MRL/MpJ-Fas backcross. Candidate genes for Heal1 include Gnao1 [Table 4].

Heal5 mapped to Chromosome 12 at 52cM ( p=0.0009, LRS = 10.9 at D12Mit132) also in only the backcross. The gene encoding retonic acid gamma (Rarg), is found near the Heal5 QTL. The retinoic acid pathway is known for its role in regeneration in amphibians.

All healing QTLs are additive and associated with MRL/MpJ-Fas alleles except Heal1 where the healing phenotype is associated with C57BL/6NTac alleles. Heal3 may be recessive; animals homozygous for MRL/MpJ-Fas alleles show increased healing.

In the present study none of the healing QTLs nor the highly suggestive regions identified displayed linkage to the Fas gene.

J:216720

Inbred mouse strains MRL and LG share the ability to fully heal ear hole punches with the full range of appropriate tissues without scarring. In the current study, two crosses (n=638) (MRL/lpr x C57BL/6NTac)F2 and (LG/J x SM/J)F2, were combined in a single cross analysis to increase the mapping power, decrease QTL support intervals, separate multiple QTL and establish allelic states at individual QTL.

Three separate analyses were performed: 356 F2 mice from the (MRL/MpJ-Fas^lpr x C57BL/6NTac); 282 F2 mice from (LG/J x SM/J); and 638 F2 mice from the combined crosses. DNA was extracted from livers and microsatellite and SNP typing was performed. Ear pinnae were punched (2 mm deficit) bilaterally in 6-week old mice and read on day 15 and day 30 post injury. Mapping was performed using R/QTL.

Fourteen QTL were mapped in the (LG/J x SM/J)F2 cross to Chromosomes 2, 4, 6, 8, 9(3), 10(3), 11, 14, 18 and 19, Table 1:

QTL Heal30 (wound healing/regeneration 30) mapped to Chromosome 2 in male mice with a logarithm of probability score (LPR) of 2.12 in the full model at 11.0 cM, spanning a confidence interval from 0.0 to 40.0 cM. The QTL was equated with the previously identified QTL Heal15 in Table 1. Curator Note: Since Heal15 was originally identified in an (MRL/MpJ x CAST/EiJ)F2 intercross [J:91865], which differs from the mapping population used here, we have named the QTL identified here Heal30. The LG/J allele was associated with improved healing at this locus.

QTL Heal31 (wound healing/regeneration 31) mapped to Chromosome 4 in both sexes with an LPR score of 2.46 at 88 cM in the dominance model, spanning a confidence interval from 72.0 to 95.0 cM. The QTL was equated with the previously identified QTL Heal8 in Table 1. Curator Note: Since Heal8 was originally identified in an (MRL/MpJ-Fas^lpr x C57BL/6NTac)F2 intercross [J:50111], which differs from the mapping population used, here we have named the QTL identified here Heal31. The locus is under dominant with heterozygotes healing relatively poorly.

A novel QTL, Heal32 (wound healing/regeneration 32), mapped to Chromosome 6 in both sexes with an LPR score of 2.81 for the additive model at 71.0 cM, within a confidence interval from 28.0 to 87.0 cM. The LG/J allele was associated with improved healing at this novel locus.

QTL Heal33 (wound healing/regeneration 33) mapped to Chromosome 8 in both sexes with an LPR score of 2.05 at 51.0 cM in the dominance model, within a confidence interval from 34.0 to 72.0 cM. The QTL was equated with the previously identified QTL Heal1 in Table 1. Curator Note: Since Heal1 was originally identified in an (MRL/MpJ-Fas^lpr x C57BL/6NTac)F2 intercross [J:50111], which differs from the mapping population used, here we have named the QTL identified here Heal33. The locus was over dominant with heterozygotes healing more fully than the homozygotes.

QTL Heal34 (wound healing/regeneration 34) mapped to Chromosome 9 in both sexes with an LPR score of 14.75 at 58.0 cM, in the additive model, within a confidence interval spanning between 39.0 and 64.0 cM. The LG/J allele at this locus significantly improved healing. The QTL was equated with QTL Stheal8 and Stheal9 in Table 1. Curator Note: Since Stheal8 and 9 were originally mapped in an (MRL/MpJ x SJL/J)F2 cross [J:73197], which differs from the mapping population used here, we have not equated the QTL identified here with either QTL. Heal28 and Heal29 were mapped in J:156191 to Chromosome 9 using an (LG/J x SM/J) F2 mapping population. QTL Heal34 may be equivalent with either Heal28 or Heal29.

QTL Heal35 (wound healing/regeneration 35) mapped to Chromosome 9 in male mice with an LPR score of 5.60 in the additive model at 30.0 cM, within a confidence interval from 24.0 to 66.0 cM. The LG/J allele at this locus significantly improved healing. The QTL was equated with Sth8a in Table 1. Curator Note: Sth8a was mapped using MRL.SJL congenics [J:127710], a mapping population that differs from the population used here, so we have assigned unique nomenclature to this QTL, Heal35. The LG/J allele was associated with improved healing at this locus.

QTL Heal36 (wound healing/regeneration 36) mapped to Chromosome 9 in female mice with an LPR score of 9.96 in the additive model, within a confidence interval from 54.0 to 63.0 cM. The LG/J allele at this locus significantly improved healing. The QTL was equated with Sth9b in Table 1. Curator Note: Sth9b was mapped using MRL.SJL congenics [J:127710], a mapping population that differs from the population used here, so we have assigned unique nomenclature to this QTL, Heal36. The LG/J allele was associated with improved healing at this locus.

QTL Heal16 (wound healing/regeneration 16) was confirmed in the (LG/J x SM/J)F2 cross, mapping to Chromosome 10 in both sexes with an LPR score of 5.89 at 29.0 cM in the additive model. The confidence interval spanned from 24.0 to 37.0 cM. The SM/J allele was associated with improved healing at this locus.

QTL Heal37 (wound healing/regeneration 37) mapped to Chromosome 10 in both sexes with an LPR score of 5.28 at 47.0 cM in the additive model, within a confidence interval spanning from 41.0 to 53.0 cM. The SM/J allele was associated with improved healing. The QTL was equated with Chr10b in Table 1. Curator Note: Chr10b was suggestively mapped in an (LG/J x SM/J)F2 intercross [J:156191]. We have assigned unique nomenclature to the QTL identified here, Heal37.

A novel QTL, Heal38 (wound healing/regeneration 38), mapped to Chromosome 10 in both sexes with an LPR score of 5.36 at 63.0 cM in the additive model. The confidence interval spanned from 62.0 to 67.0 cM. The SM/J allele was associated with improved healing at this locus also.

QTL Heal26 (wound healing/regeneration 26) mapped to Chromosome 11 in both sexes with an LPR score of 4.63 at 51.0 cM in the full model, within a confidence interval from 45.0 to 56.0 cM. The QTL was equated with Heal10 in Table 1. Curator Note: However, Heal10 was originally mapped using (MRL/MpJ-Fas^lpr x C57BL/6J)F2 mice [J:82708]. Heal26 was mapped to the same location using the same mapping population used here [J:156191], the LG/J allele also conferred increased healing at this locus in both studies, consequently we have equated the QTL identified here with Heal26.

QTL Heal39 (wound healing/regeneration 39) mapped to Chromosome 14 in both sexes with an LPR score of 3.33 at 17.0 cM in the dominance model, with a confidence interval from 10.0 to 24.0 cM. The locus is underdominant with heterozygotes healing relatively poorly. The QTL was equated with Heal12 in Table 1. Curator Note: Since Heal12 was originally mapped using an (MRL/MpJ x CAST/EiJ)F2 intercross [J:91685] which differs from the mapping population used here, we have assigned a unique identifier to the locus identified here, Heal39.

QTL Heal40 (wound healing/regeneration 40) mapped to Chromosome 18 in both sexes with an LPR score of 2.84 at 24.0 cM in the additive model, with a confidence interval from 7.0 to 38.0 cM. The LG/J allele was associated with improved healing at this locus. The QTL was equated with Heal9 in Table 1. Curator Note: Heal9 was originally mapped in an (MRL/MpJ-Fas^lpr x C57BL/6J)F2 mapping population [J:82708] which differs from the mapping population used here, so we have assigned unique nomenclature to the QTL identified here, Heal40.

A novel QTL, Heal41 (wound healing/regeneration 41), mapped to Chromosome 19 in both sexes with an LPR score of 3.00 at 0.0 cM in the full model. The confidence interval spanned from 0.0 to 4.0 cM. The locus was underdominant with heterozygotes healing relatively poorly.

Ten healing QTL were mapped in the (MRL/MpJ-Fas^lpr x C57BL/6NTac)F2 cross to Chromosomes 1,4,8, 9,11,12,13,16 and 18(2); Table 2:

QTL Heal42 (wound healing/regeneration 42) mapped to Chromosome 1 in female mice with an LPR score of 2.91 at 101.0 cM in the dominant model, with a confidence interval that spanned from 93.0 to 106.0 cM.

QTL Heal43 (wound healing/regeneration 43) mapped to Chromosome 4 in both sexes with an LPR score of 3.09 at 66.0 cM in the additive model, with a confidence interval that spanned from 62.0 to 79.0 cM.

QTL Heal1 (wound healing/regeneration 1) was mapped to Chromosome 8 in both sexes with an LPR score of 4.44 at 51.0 cM in the additive model, with a confidence interval that spanned from 42.0 to 73.0 cM.

QTL Heal44 (wound healing/regeneration 44) mapped to Chromosome 9 in male mice with an LPR score of 2.95 at 60 cM in the dominant model, with a confidence interval that spanned from 48.0 to 74.0 cM. Table 2 equates this QTL with Sth9b. Curator note: Sth9b was originally mapped using MRL.SJL congenics [J:127710], a mapping population that differs from the population used here, so we have assigned unique nomenclature to this QTL, Heal44.

QTL Heal45 (wound healing/regeneration 45) mapped to Chromosome 11 in male mice with an LPR score of 4.28 at 55.0 cM in the additive model, with a confidence interval that spanned from 46.0 to 72.0 cM. Tabl 2 equated this QTL with Heal10. Curator Note: Heal10 was originally mapped using (MRL/MpJ-Fas^lpr x C57BL/6J)F2 mice [J:82708] which differ from the mapping population used here, so we have assigned unique nomenclature to this QTL, Heal45.

QTL Heal46 (wound healing/regeneration 46) mapped to Chromosome 12 in both sexes with an LPR score of 2.26 at 13.0 cM in the additive model, with a confidence interval that spanned from 0.0 to 19.0 cM.

QTL Heal7 (wound healing/regeneration 7) mapped to Chromosome 13 in both sexes with an LPR score of 4.22 at 30.0 cM in the full model, with a confidence interval that spanned from 21.0 to 37.0 cM.

QTL Heal47 (wound healing/regeneration 47) mapped to Chromosome 16 in male mice with an LPR score of 2.48 at 12.0 cM in the full model, with a confidence interval that spanned from 3.0 to 22.0 cM. Table 2 equated this QTL with Heal11. Curator Note: Heal11 was originally mapped using (MRL/MpJ-Fas^lpr x C57BL/6J)F2 mice [J:82708] which differ from the mapping population used here, so we have assigned unique nomenclature to this QTL, Heal47.

QTL Heal48 (wound healing/regeneration 48) mapped to Chromosome 18 in both sexes with an LPR score of 1.84 at 24.0 cM in the additive model, with a confidence interval that spanned from 0.0 to 36.0 cM. Table 2 equates this QTL with Heal9. Cuator Note: Heal9 was originally mapped using (MRL/MpJ-Fas^lpr x C57BL/6J)F2 mice [J:82708] which differ from the mapping population used here, so we have assigned unique nomenclature to this QTL, Heal48.

QTL Heal49 (wound healing/regeneration 49) mapped to Chromosome 18 in female mice with an LPR score of 2.74 at 43.0 cM in the dominant model, with a confidence interval that spanned from 0.0 to 47.0 cM. Table 2 equates this QTL with Heal9. Cuator Note: Heal9 was originally mapped using (MRL/MpJ-Fas^lpr x C57BL/6J)F2 mice [J:82708] which differ from the mapping population used here, so we have assigned unique nomenclature to this QTL, Heal49.

Alleles from the healing strain MRL improved healing at 4 loci, those on chrs 4, 11, 13 and proximal 18. The B6 allele promoted healing at the loci mapping to Chrs 8, 12, and 16.

The proximal Chr 18 QTL affected both sexes and had a strong additive effect,

The distal Chr 18 locus affected on female mice and had an over dominant effect with heterozygotes healing well. Chrs 4, 8, 11 and 12 were co-dominant with heterozygotes experiencing intermediate healing, whereas 1 and 9 were under dominant with heterzygotes healing poorly healing poorly relative to homozygotes.

Table 3: Healing QTL discovered in the Combined F2 intercross:

The combined cross-genome scan identified 11 QTL on chromosomes 4, 8, 9, 10, 11, 13, 14, 18 and 19 including three distinct peaks on chr 10. Five of the 11 loci were significant at the genome-wide level whereas 6 were significant at the chromosome-specific level.

In the Combined data analysis:

A QTL was mapped to Chromosome 4, peaking at 88.0 cM with an LRP of 3.16, that was mapped in each of the independent crosses. The QTL was labeled Heal31 in the (LG/J xSM/J)F2 intercross and Heal43 in the (MRL/MpJ-Fas^lpr x C57BL/6NTac)F2 intercross.

A QTL was mapped to Chromosome 8, peaking at 55.0 cM with an LRP of 3.27, that was mapped in each of the independent crosses. The QTL was labeled Heal33 in the (LG/J xSM/J)F2 intercross and Heal14 in the (MRL/MpJ-Fas^lpr x C57BL/6NTac)F2 intercross.

A QTL was mapped to Chromosome 9, peaking at 58.0 cM with an LRP of 14.35, that was mapped in each of the independent crosses. The QTL was labeled Heal36 in the (LG/J xSM/J)F2 intercross and Heal44 in the (MRL/MpJ-Fas^lpr x C57BL/6NTac)F2 intercross.

QTL Heal16 was mapped to Chromosome 10, peaking at 29.0 cM with n LRP of 4.39. The QTL was previously mapped in the (LG/J xSM/J)F2 intercross.

QTL Heal37 was mapped to Chromosome 10, peaking at 47.0 cM with n LRP of 4.33. The QTL was previously mapped in the (LG/J xSM/J)F2 intercross.

QTL Heal38 was mapped to Chromosome 10, peaking at 63.0 cM with n LRP of 4.03. The QTL was previously mapped in the (LG/J xSM/J)F2 intercross.

A QTL was mapped to Chromosome 11, peaking at 51.0 cM with an LRP of 5.51, that was mapped in each of the independent crosses. The QTL was labeled Heal26 in the (LG/J xSM/J)F2 intercross and Heal45 in the (MRL/MpJ-Fas^lpr x C57BL/6NTac)F2 intercross.

QTL Heal7 was mapped to Chromosome 13, peaking at 30.0 cM with an LRP of 2.37. The QTL was previously mapped in an (MRL/MpJ-Fas^lpr x C57BL/6NTac)F2 intercross [J:50111].

QTL Heal39 was mapped to Chromosome 14, peaking at 17.0 cM with an LRP of 2.03. The QTL was previously mapped in the (LG/J xSM/J)F2 intercross.

A QTL was mapped to Chromosome 18, peaking at 24.0 cM with an LRP of 2.43, that was mapped in each of the independent crosses. The QTL was labeled Heal40 in the (LG/J xSM/J)F2 intercross and Heal48 in the (MRL/MpJ-Fas^lpr x C57BL/6NTac)F2 intercross.

QTL Heal41 was mapped to Chromosome 19, peaking at 0.0 cM with an LRP of 2.23. The QTL was previously mapped in the (LG/J xSM/J)F2 intercross.

References

• Original: J:50111 McBrearty BA, et al., Genetic analysis of a mammalian wound-healing trait. Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):11792-7
• All: 2 reference(s)