Rafar^C57BL/6NClr
QTL Variant Detail

Summary

• QTL variant: Rafar^C57BL/6NClr
• Name: retinoic acid induced forelimb autopod reduction; C57BL/6NCrl
• MGI ID: MGI:3580539
• QTL: Rafar Location: Chr11:87691198-87691366 bp Genetic Position: Chr11, cM position of peak correlated region/allele: 52.22 cM
• QTL Note: genome coordinates based on the marker associated with the peak LOD score

Variant origin

• Strain of Specimen: C57BL/6NCrl

Variant description

• Allele Type: QTL
• Mutation: Undefined
• Mutation details: This allele confers increased incidence of retinoic acid induced forelimb deformities compared to SWV/Fnn. (J:98848)

Expression

In Structures Affected by this Mutation:

1 anatomical structure(s)

Notes

Rafar appears to interact epistatically with a locus at D18Mit64 namaed Rafaril. Retinoic acid exposed fetuses homozygous for C57BL/6NCrlBR-derived alleles at Rafar and Rafaril exhibited the highest incidence of forelimb defects (43%).

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

J:98848

Linkage analysis to identify QTLs associated with sensitivity to retinoic acid induced limb malformations was assessed in 406 male fetuses from a C57BL/6NCrlBR x (C57BL/6NCrlBR x SWR/Fnn)F1 backcross. C57BL/6NCrlBR females backcrossed to F1 fathers were injected with retinoic acid on day 9.25 of gestation and sacrificed on day 18 for analysis of fetuses. Parental strain C57BL/6NCrlBR is highly susceptible to retinoic acid induced limb deformities whereas parental strain SWR/Finn is resistant. Forelimb deformity and the severity and type of deformity were phenotyped for semiquantitative trait analysis. 88 microsatellite markers at an average spacing of 15.4 cM were used for the genome scan.

Highly significant linkage to limb deformities mapped to 46 cM on mouse Chromosome 11 near D11Mit39 with a maximum LOD score of 9.0. This locus shows linkage to both pre- and post-axial forelimb deformities and is named Rafar (retinoic acid induced forelimb autopod reduction). Rafar explains 7.5% of the variance. This QTL was confirmed in a duplicate backcross involving 545 (C57BL/6NCrlBR x SWR/Fnn)F1 x C57BL/6NCrlBR backcross fetuses. Linkage was confirmed at D11Mit39 with LOD scores between 2.7 and 3.0. A locus associated with pre-axial forelimb deformities mapped to 77 cM near D11Mit48 with a LOD score of 2.8 in the duplicate backcross population.

Previously identified bone QTLs mapping near Rafar are Pbd1 (51.8 cM), Bmd11 (31 cM), Sbmd4 (49 cM), and Pcir2 (43.7 cM). Potential candidate genes near the Rafar locusare Alox12 (40 cM), Alox15 (40 cM), Tbx2 (49 cM), Nog (50.5 cM), Col1a1 (56 cM), Hoxb (56 cM), Rara (57.8 cM), Wnt3 (63 cM), and Wnt9b (63 cM). The human syntenic region to Rafar is involved with Meckel syndrome, a disease with many features including pre-axial polydactyly. The Meckel syndrome locus maps to a 1 cM interval on 17q23.

Rafar appears to interact epistatically with a locus at D18Mit64 named Rafaril (Rafar interacting locus). Retinoic acid exposed fetuses homozygous for C57BL/6NCrlBR-derived alleles at Rafar and Rafaril exhibited the highest incidence of forelimb defects (43%). The effect of the Rafaril locus appears dependent upon the genotype at Rafar.

Significant linkage to limb deformities also mapped to 66.6 cM on mouse Chromosome4 near D4Mit170 with a LOD score of 2.7. This locus is named Rafar2 and explains 2.7% of the variance.

References

• Original: J:98848 Lee GS, et al., A Gene(s) for All-trans-Retinoic Acid-Induced Forelimb Defects Mapped and Confirmed to Murine Chromosome 11. Genetics. 2005 May;170(1):345-53
• All: 1 reference(s)