Major gene determination of liability to spontaneous cleft lip in the mouse.

Two genetic analyses suggested that the spontaneous and low frequency trait of cleft lip (primary palate) in the mouse is determined either by a recessive gene at one autosomal locus or by two loci with duplicate epistasis. The low frequency trait of open eyelids, which is characteristic of the A/J strain and sometimes reported to be associated with cleft lip as part of a "syndrome," has not been analyzed genetically. A backcross and test-mating study between A/J and C57BL/6J, done originally to define the genetic control of embryonic tolerance to cortisone-induced cleft palate (secondary palate), was reanalyzed for the cleft lip and open eyelids traits. Cleft lip frequencies in A/J did not change in dose-response studies of either cortisone- or 6-aminonicotinamide-induced cleft palate; for both teratogens the frequencies of open eyelids differed between doses but did not exhibit any obvious dose response. It appeared that the frequency of 7.6% cleft lip and 17.6% open eyelids in A/J in the genetic study, in which all pregnant A/J test-females were treated with a single dose of cortisone (100 mg/kg, day 12), did reflect the occurrence of the spontaneous traits. Within the A/J strain, the traits were not associated and, as expected on outcrossing to C57BL/6J (A.B6 F1 fetuses), both traits are recessive. Significant bimodality of the cleft lip scores of the BC1 sires (BC2 fetuses), test-mated with A/J, suggested that liability to cleft lip is determined by a single autosomal recessive gene. The distribution of open eyelids scores of the BC1 sires did not differ from one normal distribution, and this trait is, therefore, controlled by more than one genetic locus with additivity between loci. Cleft lip and open eyelids segregated independently and do not form a syndrome, in A/J, with one underlying genetic cause. There was no association between cleft lip and three autosomal marker genes, brown (b, chromosome 4), albinism (c, chromosome 7) and H-2 (chromosome 17), or the genetically independent tolerance traits of cortisone- and 6-aminonicotinamide-induced cleft palate. There was significant association between open eyelids and albinism (c) that is in a direction suggesting linkage or pleiotropy. Whether liability of the embryo to cleft lip is determined by one or two genes may be solved by a concerted effort to map the trait; a marker gene will be the key to further analysis of its cause.