Bbaa3^C3H/HeNCr
QTL Variant Detail

Summary

• QTL variant: Bbaa3^C3H/HeNCr
• Name: B.burgdorferi-associated arthritis 3; C3H/HeNCr
• MGI ID: MGI:2156195
• QTL: Bbaa3 Location: Chr5:99455285-112465722 bp Genetic Position: Chr5, cM position of peak correlated region/allele: 47.29 cM
• QTL Note: genome coordinates based on the marker associated with the peak LOD score

Variant origin

• Strain of Specimen: C3H/HeNCr

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers increased arthritis severity compared to C57BL/6NCr. (J:52017)
• Inheritance: Dominant

Notes

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

J:52017

A genome scan was performed on 150 animals from an (C3H/HeNCr x C57BL/6NCr)F2 intercross (195 loci, average spacing = 20 cM) to identify QTLs associated with Lyme disease related arthritis phenotypes such as ankle swelling, thickening of tendon sheath, and tissue histopathology. C3H/HeNCr develop severe arthritis after infection with B.burgdorferi where as C57BL/6NCr develops mild arthritis.

Linkage was detected for ankle swelling on mouse chromosome 4 between flanking markers D4Mit87 and D4Mit145 witha peak LOD score of 4.70 at D4Mit145. The QTL was labeled Bbaa1, B. burgdorferi-asociated arthritis phenotype 1. The C3H/HeNCr allele conferred dominant influence to susceptibility to severe arthritis at this locus. Mapping between 33-45cM it is syntenic with regions 9q32-q33, and 9p21-p23 of the human genome. The Lps gene, Tlr4, is a possible candidate gene for Bbaa1.

Another QTL linked to ankle swelling mapped to mouse chromosome 5 between flanking markers D5Mit24 and D5Mit98 with a peak LOD score of 4.07 at D5Mit431. This QTL was labeled Bbaa2. Recessively inherited C3H/HeNCr alleles influenced susceptibility to severe arthritis at this locus. Mapping between 60-80cM Bbaa2 is syntentic with regions 22q11, 12q22-24.3, 7q11.23, and 7q21.3-q22.1 of the human genome. Interaction appears to occur between Bbaa1 and Bbaa2.

Linkage to histopathology and tendon sheath thickness was detected on mouse chromosome 5 between flanking markers D5Mit308 and D5Mit91 with a peak LOD score of 3.68 at D5Mit91. The thickness of tendon sheath was associated with a LOD score of 4.07 at D5Mit312 in this same interval. This QTL was labeld Bbaa3. Dominantly inherited alleles from C3H/HeNCr conferred arthritic severity. Mapping between 44-53cM Bbaa3 is syntenic with region 4q11-q21.1 of the human genome. Possible candidate genes for Bbaa3 are Bmp3, Ibsp, Spp1, Pdgfra, and Gro1.

Linkage to histopathology scoring was also detected on mouse chromosome 11 between flanking markers D11Mit350 and D11Mit120 with a peak LOD score of 3.91 at D11Mit120. This QTL was labeled Bbaa4. Recessively inherited alleles from C3H/HeNCr mice contribute to severe arthritis at this locus. Mapping between 34-47cM Bbaa4 is syntenic with regions 17p11-p13 and 17q11-q12 of the human genome. Possible candidate genes for Bbaa4 are Tnfaip1, Pafah1b1, and Nos2.

Linkage to a QTL regulating the elevation to total IgM production and B.burgdorferi-specific IgM production was detected on mouse chromosome 6 mapping between flanking markers D6Mit105 abd D6Mit15. The QTL was labeled Bbaa5 with linkage to total IgM mapping between 45-74cM, with a peak LOD score of 6.52 at D6Mit338, and specific IgM mapping to 67-74cM, with a peak LOD score of 4.96 at D6Mit15 within the same interval. Recessively inherited allelesfrom C57BL/6NCr mice contribute to lower levels of IgM production at this locus. Mapping between 45-74cM Bbaa5 is syntenic with regions 3p24-p26, 3q21-q25, 10q11.2 and 12p11-13 of the human genome.

Linkage to total IgG and total IgM production was detected on mouse chromosome 12 between flanking markers D12Mit121 and D12Mit133. This QTL was labeled Bbaa6 with linkage to total IgM mapping between 46-56cM, with a peak LOD score of 4.71 at D12Mit133, and total IgG with a peak LOD of 3.61 also at D12Mit133. Recessively inherited alleles from C3H/HeNCr mice contributed to elevated levels of both IgG and IgM production. Mapping between 46-56cM this QTL is syntenic with regions 14q24.3-q32.3 and 14q32.1-q32.3 of the human genome. Interaction appears to occur between Bbaa6 and Bbaa9 with respect to total IgG production.

Linkage to B.burgdorferi-specific IgM production was detected on mouse chromosome 11 between flanking markers D11Mit82 and D11Mit235 with a peak LOD score of 3.79 at D11Mit51. This QTL was labeled Bbaa7. Dominantly inherited alleles from C57BL/6NCr mice influence lower Ig levels at this locus. Mapping between 14-20cM Bbaa7 is syntenic with regions 16p13.3 and 5q31.1-q35 of the human genome.

Linkage to B.burgdorferi-specific IgM production wasalso detected on mouse chromosome 17 between flanking markers D17Mit175 and D17Mit215 with a peak LOD score of 3.78 at D17Mit232. This QTL is Bbaa8. Mice with heterozygous alleles at Bbaa8 had the lowest levels if specific IgM. Mapping between 17-23cM Bbaa8 is syntenic with regions 19q13.3-13.4, 16p12-13.4 and 6p13.2-p21.2 of the human genome.

Linkage to total IgG production was detected on mouse chromosome 9 between flanking markers D9Mit48 and D9Mit73 with a peak LOD score of 3.62 at D9Mit73. This QTLislabeled Bbaa9. Dominantly inherited alleles from C57BL/6NCr mice reduced the levels of total IgG at this locus. Mapping between 34-41cM Bbaa9 is syntenic with region 15q21-q25 of the human genome.

J:73060

Composite interval mapping (CIM) was used for localization of QTL involved in modulating response to infection with Borrelia burgdorferi. Parental strains C3H/HeN and C3H/HeJ are susceptible to B.burgdorferi-induced arthritis whereas parental strains C57BL/6N and BALB/cAnN are resistant. Four different backcrosses and the reanalysis of a previous intercross were performed.

In the (C57BL/6N x C3H/HeN) x C57BL/6N backcross authors state that previoulsy identified QTL Bbaa2 and Bbaa6, on Chrs 5 and 12 respectively, were reproduced.

[10.28.2015 Curator Note: Because Bbaa2 and Bbaa6 were originally mapped in J:52017 in 1999 using an (C3H/HeNCr x C57BL/6NCr)F2 intercross which differs from the backcross used here, we consider the current study a separate mapping experiment and have named the Chr 5 QTL Bbaa24 and the Chr 12 QTL Bbaa27.]

On Chr 5 Bbaa24 is linked to ankle swelling, mapping from 66-81 cM between markers D5Mit431 and D5Mit101 with an LRT of 31.7 accounting for 12.0% of trait variance. The QTLis also linked to histopathology, mapping from 66-78 cM between markers D5Mit431 and D5Mit98 with an LRT of 20.8 accounting for 8.8% of the trait variance. [Table 2.]

In the (C57BL/6N x C3H/HeN) x C57BL/6N backcross another Chr 5 QTL linked to tendon sheath mapped to 70 cM with marker D5Mit214, LRT=16.1 accounting for 12.9% of the variance. Authors also equate this QTL with the previoulsy identified Bbaa2. [Curator Note: Since the cross used here also differs from the orginal mapping population for Bbaa2 we have named this QTL, Bbaa25.] [Table 2.]

In the (C3H/HeJ x BALB/cAnN) x C3H/HeJ backcross another QTL that was also equated with Bbaa2 was mapped. [Curator Note: Since the cross used here also differs from the orginal mapping population for Bbaa2 we have named this QTL, Bbaa26.] [Table 2.]

Bbaa26 maps to Chr 5 linked to ankle swelling at 72 cM with marker D5Mit30, LRT=47.1 accounting for 29% variance. It also linked to histopathology from 56-78 cM between markers D5Mit115 and D5Mit31, LRT=33.4 accounting for 20.6% of variance and to tendon histology from 58-72 cM between markers D5Mit239 and D5Mit30, LRT=24.7 accounting for 16.0% variance. [Table 2.]

The reanalysis of the (C57BL/6N X C3H/HeN)F2 intercross also confirmed the previoulsy identified QTL Bbaa2 and Bbaa3 on Chr 5. Using CIM Bbaa2, linked to ankle swelling, mapped to 73.0 cM with marker D5Mit63, LRT=18.7. Bbaa3, linked to histopathology, mapped from 53.0 - 60.0 cM between markers D5Mit91 and D5Mit24, LRT=25.1 [Table 3.]

C3H/HeN-derived alleles are associated with increased arthritis susceptibility and severity at all QTL mapped in this experiment.

References

• Original: J:52017 Weis JJ, et al., Identification of quantitative trait loci governing arthritis severity and humoral responses in the murine model of Lyme disease. J Immunol. 1999 Jan 15;162(2):948-56
• All: 4 reference(s)