Brml2^C3H/HeJ
QTL Variant Detail

Summary

• QTL variant: Brml2^C3H/HeJ
• Name: bone response to mechanical loading 2; C3H/HeJ
• MGI ID: MGI:3694938
• QTL: Brml2 Location: unknown Genetic Position: Chr8, cM position of peak correlated region/allele: 61.66 cM
• QTL Note: genome coordinates based on the marker associated with the peak LOD score

Variant origin

• Strain of Specimen: C3H/HeJ

Variant description

• Allele Type: QTL
• Mutation: Undefined
• Mutation details: This allele confers increased mechanical loading-induced total volumetric bone mineral density and cortical thickness compared to C57BL/6J. (J:116664)
• Inheritance: Recessive

Expression

In Structures Affected by this Mutation:

1 anatomical structure(s)

Notes

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

J:116664

Linkage analysis was performed on 329 female (C57BL/6J x C3H/HeJ)F2 animals to identify QTLs associated with bone adaptive response to mechanical loading. Parental strain C57BL/6J is a good responder whereas C3H/HeJ is a poor responder. One hundred eleven microsatellite markers at an average spacing of 15 cM were used for the genome scan. Animals were subjected to mechanical loading using a four-point bending model at 10 weeks of age.

Significant linkage to mechanical loading-induced total volumetric bone mineral density (vBMD) mapped to 91.8 cM on mouse Chromosome 1 near D1Mit113 (LOD=3.4). This locus also shows suggestive linkage to cortical vBMD (LOD=2.3) and is named Brml1 (bone response to mechanical loading 1). Homozygosity for C57BL/6J-derived alleles at Brml1 confer a 5.6% increase in BMD compared to homozygosity for C3H/HeJ-derived alleles. Brml1 exhibits dominant inheritance.

Significant linkage to mechanical loading-induced total vBMD (LOD=4.2) and cortical thickness (LOD=3.6) mapped to 60.1 cM cM on mouse Chromosome 8 near D8Mit88. This locus is named Brml2 (bone response to mechanical loading 2). Homozygosity for C3H/HeJ-derived alleles at Brml2 confer a 5.8% increase in BMD compared to homozygosity for C57BL/6J-derived alleles. Brml2 exhibits recessive inheritance. Linkage to mechanical loading-induced periosteal circumference, Brml3, mapped more distally at 68.9 cM near D8Mit49 (LOD=3). Homozygosity for C57BL/6J-derived alleles at Brml3 confers a 10% increase in periosteal circumferencecompared to homozygosity for C3H/HeJ-derived alleles. Brml3 exhibits dominant inheritance.

Significant linkage to mechanical loading-induced cortical vBMD mapped to 50.3 cM on mouse Chromosome 3 near D3Mit320 (LOD=3.6). This locus is named Brml4 (bone response to mechanical loading 4).

Brml5 (bone response to mechanical loading 5) mapped to 13.1 cM on mouse Chromosome 9 near D9Mit2 (LOD=3). Suggestive linkage to mechanical loading-induced total vBMD, cortical vBMD, and periosteal circumference were alsoidentified at 33.9 cM (LOD=2.5 near D9Mit336), 49.2 cM (LOD=2.5 near D9Mit355), and 24 cM (LOD=2.2 near D9Mit97), respectively.

Brml6 (bone response to mechanical loading 6) mapped to 39.3 cM on mouse Chromosome 17 near D17Mit93 (LOD=3) in linkage to cortical thickness, and Brml7 mapped to 0 cM on mouse Chromosome 18 near D18Mit64 (LOD=3) in linkage to periosteal circumference.

Novel QTLs associated with non-loaded bone mineral density mapped to 35 cM on mouse Chromosome 3 (LOD=3.2 at D3Mit137), 62 cMon mouse Chromosome 10 (LOD=3.8 at D10Mit233), and 44 cM on mouse Chromosome 17 (LOD=5.9 at D17Mit93). These loci are named Bmd24 (bone mineral density 24), Bmd25, and Bmd26, respectively

Novel QTLs associated with non-loaded periosteal circumference mapped to 72 cM on mouse Chromosome 3 (LOD=4 at D3Mit320), 52 cM on mouse Chromosome 11 (LOD=4.3 at D11Mit285), 49 cM on mouse Chromosome 15 (LOD=3.1 at D15Mit107), 23 cM on mouse Chromosome 16 (LOD=3.1 at D16Mit60), and 44 cM on mouse Chromosome 17 (LOD=5.1 at D17Mit93). These loci are named Pstc1 (periosteal circumference 1), Pstc2, Pstc3, Pstc4, and Pstc5, respectively. Pstc1, Pstc4, and Pstc5 also exhibit significant linkage to cortical thickness.

Previously identified bone mineral density QTLs that were detected in this study include Bmd5 (83 cM, Chr1), Bmd7 (66.7 cM, Chr4), and Bmd15 (24 cM, Chr16).

J:123127

Linkage analysis was performed on 241 female (C57BL/6J x C3H/HeJ)F2 animals to identify QTLs associated with bone marker gene expression in response to mechanical loading. Animals were subjected to mechanical loading using a four-point bending model at 10 weeks of age. RNA was extracted from loaded and non-loaded tibiae and assayed for bone sialoprotein (BSP) and alkaline phosphatase (ALP) expression. Parental strain C57BL/6J exhibits increased BSP and ALP expression in response to mechanical loading compared to parental strain C3H/HeJ. One hundred eleven microsatellite markers at an average spacing of 15 cM were used for the genome scan.

A locus at 91.8 cM on mouse Chromosome 1 (LOD=10.4 at D1Mit113) shows significant linkage to BSP expression in response to mechanical bone loading. This locus may be identical to Brml1 (bone response to mechanical loading 1) from a previous study by the same authors. This locus also overlaps with previously identified bone trait QTLs Fbtq1 (71 cM), Bntq1 (74 cM), and Fembrs5 (101 cM). Significant linkage to ALP expression in response to mechanical bone loading mapped to 47 cM near D1Mit215 (LOD=7.5) and 75.4 cM near D1Mit102 (LOD=7.6). These new loci are named Brml8 and Brml9, respectively.

Linkage to general (housekeeping) gene expression in response to mechanical bone loading mapped to 48.1 cM on mouse Chromosome 2 near D2Mit66 (LOD=2.8). This new locus is named Brml14 (bone response to mechanical loading 14).

ALP expression in response to mechanical bone loading mapped to 59 cM on mouse Chromosome 3 near D3Mit147 (LOD=8.3). This locus is identical to previously identified QTL Brml4 (bone response to mechanical loading 4). Bntq4 is a previously identified bone trait QTL located near Brml4.

Linkage to ALP expression in response to mechanical bone loading mapped to 54.6 cM near D4Mit308 (LOD=5.6). This locus is named Brml10 (bone response to mechanical loading 10). Bntq6 is a previously identified bone trait QTL near Brml10. Linkage to BSP and ALP expression in non-loaded bone mapped to 76.5 cM near D4Mit42 (LOD=2.7 and 2.8, respectively). This locus is named Brml13. Suggestive linkage to ALP expression mapped to 82 cM near D4Mit256 (LOD=5).

Suggestive linkage to BSP expression in response to mechanicalbone loading mapped to 73.2 cM on mouse Chromosome 5 near D5Mit143 (LOD=5.2).

Significant linkage to BSP and ALP expression in response to mechanical loading mapped to 60.1 cM on mouse Chromosome 8 near D8Mit88 (max LOD=12.3). This locus spans 38 cM - 69 cM and isidentical to previously identified QTL Brml2 (bone response to mechanical loading 2). Potential candidate genes in this region include Ptger1 (38 cM), Junb (38.6 cM), Mt1 (45 cM), Mt2 (45 cM), Cdh11 (46.5 cM), Hsd11b2 (50.8 cM), Cdh1 (53.3 cM), Cbfb (51 cM), Hsd17b2, and Il17c. Previously identified bone trait QTL Fbtq3 (60 cM) and Bntq9 (57 cM) are located near Brml2.

Significant linkage BSP and ALP expression in response to mechanical loading mapped to 69.9 cM on mouse Chromosome 9 near D9Mit151 (maxLOD=7.4). This locus is named Brml11 (bone response to mechanical loading 11). Brml11 also showed linkage to beta-actin expression in response to mechanical loading, therefore it is unclear if this QTL affects general housekeeping genes or bone-specific genes. Previously identified bone trait QTLs Bntq11 (65 cM) and Fembrs6 (43 cM) map near Brml11. Linkage to BSP-only expression mapped to 13.1 cM near D9Mit2 with LOD=7. This locus may be identical to Brml5. Bntq10 (7 cM) is a previously identified bone trait QTL near Brml5.

Significant linkage to BSP and ALP expression in response to mechanical loading mapped to 14.2 cM on mouse Chromosome 17 near D17Mit51 (max LOD=12.3). This locus spans 0 cM - 25 cM and is identical to Brml6 (bone response to mechanical loading). Potential candidate genes for Brml6 include Map3k4 (6.5 cM), Clcn7 (10 cM), Thbs2 (8.1 cM), Traf7, Tnf (19 cM), Notch3 (20 cM), Vegfa (24.2 cM), and Runx2 (28 cM). Fembrs4 (18 cM) and Bntq16 (16 cM) are previously identified QTLs located nearBrml6.

Significant linkage to BSP and ALP expression in response to mechanical loading mapped to 38 cM on mouse Chromosome 18 near D18Mit144 (max LOD=12.6). This locus is identical to Brml7 (bone response to mechanical loading 7) identified in a previous study by the same authors. Potential candidate genes mapping near the Brml7 interval (15 cM - 40 cM) include Lox (29 cM), Pdgfrb (30 cM), Adrb2 (34 cM), Mc4r, Mapk4, Nfatc1 (54 cM), and Galr1 (55 cM).

Significant linkage to BSP and ALP expression inresponse to mechanical loading mapped to 3.3 cM on mouse Chromosome 19 near D19Mit68 (max LOD=10.7). This new locus is named Brml12 (bone response to mechanical loading 12). Potential candidate genes mapping near the Brml12 interval (0 cM - 24 cM) include Gal (2 cM), Lrp5, Esrra (3 cM), Lpxn, Ostf1 (14 cM), and Jak2 (24 cM).

References

• Original: J:116664 Kesavan C, et al., Identification of genetic loci that regulate bone adaptive response to mechanical loading in C57BL/6J and C3H/HeJ mice intercross. Bone. 2006 Sep;39(3):634-43
• All: 2 reference(s)