Juriloff D M, Harris M J, Brown C J
Department of Medical Genetics, University of British Columbia, 6174 University Boulevard, Vancouver, B.C., V6T 1Z3, Canada.
Mamm Genome. 2001 Jun;12(6):426-35. doi: 10.1007/s003350010284.
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 testcrosses of 10 recombinant inbred (RI) strains (AXB/Pgn or BXA/Pgn), were used for gene mapping and for inference of genetic architecture. The A/WySnJ maternal genotype increased cleft lip risk in reciprocal crosses; the relevant genetic difference between AXB-6/Pgn (8%) and A/WySnJ (24%) is entirely maternal. 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, clf1, and candidate genes Itgb3 and Crhr, to between D11Mit146/360 and D11Mit166/147. A screen of 54 YACs for 46 genes and 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 of cleft lip liability and markers in testcrossed RI strains. Specific combinations of marker genotypes associated with cleft lip risk indicated that high risk in A/WySnJ mice is caused by epistatic interaction between clf1 and clf2 in the context of a genetic maternal effect. Human homologs of clf1 and clf2 are expected to be on 17q and 5q/9q.
“A”系小鼠和人类的非综合征性唇裂在遗传上较为复杂，且与孤立性腭裂不同。在1485只来自A/WySnJ（唇裂发生率24%）与C57BL/6J（无唇裂）杂交的A/WySnJ母本的第一代回交（BC1）分离后代中，有2.4%出现唇裂胚胎；在10个重组近交（RI）品系（AXB/Pgn或BXA/Pgn）的测交中出现的唇裂胚胎，被用于基因定位和遗传结构推断。在正反交中，A/WySnJ母本基因型增加了唇裂风险；AXB - 6/Pgn（8%）和A/WySnJ（24%）之间的相关遗传差异完全来自母本。新的定位面板（325个减数分裂）、新标记以及一个重组唇裂胚胎相结合，重新确定了对唇裂风险至关重要的隐性因子clf1以及候选基因Itgb3和Crhr的位置，位于D11Mit146/360和D11Mit166/147之间。对54个酵母人工染色体（YAC）进行46个基因和简单序列长度多态性（SSLP）位点的筛查，将Wnt15、Wnt3、Crhr、Mtapt、Itgb3、Dlx3和Dlx7定位在clf1候选区域内。通过对BC1分离后代的基因组筛查，clf2位点被新定位到13号染色体上，并通过测交RI品系中唇裂易感性和标记的菌株分布模式进一步确定到D13Mit13/54和D13Mit231之间的4厘摩区域。与唇裂风险相关的标记基因型的特定组合表明，A/WySnJ小鼠的高风险是由遗传母性效应背景下clf1和clf2之间的上位性相互作用引起的。预计clf1和clf2的人类同源基因位于17q和5q/9q上。
