Unravelling the complex genetics of cleft lip in the mouse model

Nonsyndromic cleft lip in "A" strain mice and humans is genetically complex and is distinct from isolated cleft palate. Cleft lip embryos recovered in 2.4% of 1485 first backcross (BC1) segregants from a cross of A/WySnJ (24% cleft lip) and C57BL/6J (no cleft lip) in A/WySnJ mothers, and in testcros ses of 10 recombinant inbred (RI) strains (AXB/Pgn or BXA/Pgn), were used f or gene mapping and for inference of genetic architecture. The A/WySnJ mate rnal genotype increased cleft lip risk in reciprocal crosses, the relevant genetic difference between AXB-6/Pgn (8%) and A/WySnJ (24%) is entirely mat ernal. A combination of new mapping panels (325 meioses), new markers, and a recombinant cleft lip embryo redefined the location of a recessive factor essential to cleft lip risk, clfI, and candidate genes Itgb3 and Crhr, to between D11MitI46/360 and D11Mit166/147. A screen of 54 YACs for 46 genes a nd SSLP loci located Wnt15, Wnt3, Crhr, Mtapt, Itgb3, Dlx3, and Dlx7 within the clf1 candidate region. The clf2 locus was newly mapped to Chromosome ( Chr) 13 by a genome screen of BC1 segregants, and further defined to a 4-cM region between D13Mit13/54 and D13Mit231 by strain distribution patterns o f cleft lip liability and markers in testcrossed RI strains. Specific combi nations of marker genotypes associated with cleft lip risk indicated that h igh risk in A/WySnJ mice is caused by epistatic interaction between clfI an d clf2 in the context of a genetic maternal effect. Human homologs of clf1 and clf2 are expected to be on 17q and 5q/9q.