Fine mapping of dental fluorosis quantitative trait loci in mice

Genetic factors underlie the susceptibility and the resistance to dental fluorosis (DF). The A/J (DF susceptible) and 129P3/J (DF resistant) mouse strains have previously been used to detect quantitative trait loci (QTLs) associated with DF on chromosome (Chr) 2 and Chr 11. In the present study, increased marker density genotyping followed by interval mapping was performed to narrow the QTL intervals and improve the logarithm of the odds (to the base 10) (LOD) scores. Narrower intervals were obtained on Chr 2 where LOD ≥ 6.0 (57-84 cM or ≈ 51 Mb), LOD ≥ 7.0 (62-79 cM or ≈ 32 Mb), and LOD ≥ 8.0 (65-74 cM or ≈ 17 Mb); and on Chr 11 where LOD ≥ 6.0 (18-51 cM or ≈ 53 Mb), LOD ≥ 7.0 (28-48 cM or ≈ 34 Mb), and LOD ≥ 8.0 (31-45 cM or ≈ 22 Mb). Haplotype analysis between A/J and 129P3/J mice further reduced the QTL intervals. Accn1 was selected as a candidate gene based upon its location near the peak LOD score on Chr 11 and distant homology with the Caenorhabditis elegans fluoride-resistance gene, flr1. The severity of DF between Accn1(-/-) and wild-type mice was not significantly different. Hence, the loss of ACCN1 function does not modify DF severity in mice. Narrowing the DF QTL intervals will facilitate additional candidate gene selections and interrogation.