Heal16^LG/J
QTL Variant Detail

Summary

• QTL variant: Heal16^LG/J
• Name: wound healing/regeneration 16; LG/J
• MGI ID: MGI:5636702
• QTL: Heal16 Location: Chr10:47974499-47974630 bp Genetic Position: Chr10, Syntenic

Variant origin

• Strain of Specimen: LG/J

Variant description

• Allele Type: QTL

Notes

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

J:156191

LG/J mice, which display the same wound/regenerative healing phenotype as MRL/MpJ mice were crossed with the smaller SM/J mice. LG/J mice completely close wounds in their ear pinnae and SM/J do not. An F2 population of 357 progeny was scored for healing and genotypes were determined at 203 polymorphic markers. Composite interval mapping was then performed on the dataset to determine more precise QTL intervals.

Tests of significant linkage for a QTL were reported as a likelihood ratio test (LRT).

1000 permutations of the datasetgave the following estimates of QTL linkage:

LRT= 19.6 = highly significant;

LRT= 16.1 = significant; and

LRT= 14.5 = strongly suggestive.

Two highly significant peaks were identified on Chromosome 9, Heal28 and Heal29 respectively. Heal28 (chr9a) peaked at 60.0Mb with marker D9Mit207. Heal29 (chr9b) peaked between 85.0-98.0Mb with markers D9Mit12/rs13480313. The healing allele was derived from the LG/J parent for both QTL; neither QTL displayed sexual dimorphism.

03.04.2015 Curators Note: The authors suggest that these two QTL may be equivalent to Stheal8 and Stheal9, first mapped in 2001 (J:73197_Masinde). An (MRL/MpJ x SJL/J)F2 cross was used in that study, which differs from the cross used here, we consider this a separate map experiment and have named the QTL identified here, Heal28 and Heal29 respectively.

Two suggestively significant peaks, in female mice only, were observed on Chromosome 10. The stronger QTL of the two (chr10a) was labeled Heal16. It maps to 48.0Mb peaking with marker D10Mit170. The other, chr10b, mapped to approximately 85.0Mb peaking at marker rs8258353. Healing alleles were derived from the SM/J parent for both of these QTL.

Another highly significant marker, Heal26, mapped to Chromosome 11. This dimorphic marker mapped with significant linkage in males only between 83.0-92.0Mb peaking between markers D11Mit101-D11Mit122. The healing allele was derived from the LG/J parental strain.

03.04.2015 Curators Note: Heal26 is referred to in the map study asHeal10. Since Heal10 was orginally mapped in J:82708 in 2003 using (MRL/MpJ-Fas^lpr x C57BL/6J)F2 mice, which differs from the cross used here, we consider this a separate map study and have named the QTL Heal26.

A QTL, Heal27, mapped to chromosome 15. Significant linkage was seen at day 15 of healing. It mapped between 68.0-69.0Mb with peak markers rs13482628/D15Mit66. The allele was contributed from the SM/J.

03.03.2015 Curators Note: Author's note that this QTL co-localizes with Heal4. SinceHeal4was originally mapped using an (MRL/MpJ-Fas^lpr x C57BL/6NTac)F2 intercross (J:50111) we consider the QTL mapped here, using a different cross, a novel QTL and have named it Heal27.

A suggestive QTL which the authors refer to as Heal15, mapped to Chromosome 2 with a peak between 0.0-3.8Mb.

1.20.2015 Curators Note: Heal15 was originally mapped in J:91685 in 2004 using an (MRL/MpJ x CAST/EiJ)F2 intercross. It appeared as only a suggestive marker in that cross also.

Haplotype asociation mapping analysis combined with global expression studies provides a list of candidate genes associated with healing and regeneration, see TABLE 4.

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:156191 Blankenhorn EP, et al., Genetic loci that regulate healing and regeneration in LG/J and SM/J mice. Mamm Genome. 2009 Nov-Dec;20(11-12):720-33
• All: 2 reference(s)