Although mice and rats are far more commonly used animal models in biomedical research, we still refer to human test populations and volunteers for experiments as “guinea pigs”. Between 1915 and 1925, the Bureau of Animal Industry at the USDA maintained a number of guinea pig strains for genetics research, and this 1933 paper* by Sewall Wright describes the appearance of, and inheritance patterns associated with, “otocephalic monsters” in one inbred strain (“family 13”) of these rodents. First, Sewall described the range of severity of this congenital defect, from the mild form, with slight reduction in the size of the lower jaw (mandible), to the most severe form, with complete absence of the jaws, nose, eyes, and brain (rostral to the medulla). In humans, this anomaly is referred to as agnathia-otocephaly, characterized by absence of the mandible and tongue, a small mouth, and positioning of the ears close to the midline; fortunately, it is quite rare, with an incidence of 1 in 70,000 newborns (Schiffer et al., 2002). The 80 cases published since the first description of agnathia-otocephaly by Kerckring in 1717 have been classified according to the presence of cyclopia and an abnormal brain (holoprosencephaly), or presence of a normal brain in the fetus.
Wright’s grading system for otocephaly; ventral view of the animal’s head
Wright was interested in the relative importance of genetic and environmental factors in the development of “characters”, such as pigmentation patterns and morphological defects, and by examining the records of the stocks of guinea pigs available, determined that otocephaly appeared rarely (34 in 24,000) in animals of mixed ancestry. However, in one of the inbred strains, derived through brother-sister matings, 272 out of 6,275 offspring (4.3%) exhibited otocephaly. In one of the substrains within family 13, the incidence of otocephaly was as high as 65 in 234 offspring, or 27.8%. Because repeated brother-sister mating tends to establish homozygosity in the line, and because a comparison of numbers of corpora lutea, dead fetuses, and live offspring eliminated the hypothesis of balanced lethals, Wright concluded that the otocephalic guinea pigs were not simple Mendelian segregants. In contrast, he suggested that certain combinations of genes became fixed in different substrains of family 13, and that these genetic “complexes” might include an unstable gene or chromosome. Wright also conducted a careful analysis of the frequency of otocephaly in the contexts of litter size, seasonal distribution, and first litter vs. last litter from a particular dam, and found that there was only a slight effect of these environmental conditions.
Wright then considered whether the heredity of otocephaly might reflect a maternal effect, or “that of the egg nucleus before maturation instead of after fertilization”, and thus examined whether the father played a role. He mated females from the line with the highest incidence of otocephaly to males from family 2, which produced no otocephalics, and found no offspring with otocephaly among the 88 cross-bred progeny. Wright concludes thus:
These data, supplemented by that discussed in the next section in connection with sex incidence, demonstrate, it is believed, that the strong hereditary tendency toward otocephaly in the strain of guinea pigs under consideration is neither a matter of toxemia of the mothers of the monsters, nor of cytoplasmic transmission, nor of conditioning of the egg by its nucleus before maturation and fertilization. It is, on the contrary, a function of the heredity of the egg after fertilization.
Although there are typically equal numbers of males and females in a guinea pig litter, females had twice the incidence of otocephaly in this study, and Wright noted that cyclopia is also more common in females than in males. He also recognized that although sporadic otocephaly and cyclopia in mammals were likely to be found with other abnormalities (spina bifida, club foot, situs inversus, polydactyly), the genetic tendency in guinea pig family 13 was related specifically to otocephaly. It is interesting that Wright compares the genetics of otocephaly not only with other defects (white spotting, polydactyly) in guinea pigs, but with incompletely penetrant traits (e.g. reduplicated legs) in Drosophila as well; moreover, he mentions that such mutant lines were often discarded, thus leading to “an exaggerated impression of the frequency with which genes determine clear-cut, absolute effects”. Part of the charm of this paper, as with many other classic papers, is the extensive discussion section, in which the author describes ancient theories of teratogenesis in birds and mammals, as well as the experimental studies of St. Hilaire, Dareste, Born, Stockard, and Spemann, and in which he distinguishes the gene effects for otocephaly from the “monstrosities” produced by experimental manipulation.
Differing severity of otocephaly in Otx2+/- mouse embryos of the B6 strain (Hide et al., 2002)
Of course, I would not have bothered to describe this paper if there were not an identified gene(s) that is an excellent candidate for the mutation(s) identified by Wright in his guinea pig families. Otx1 and Otx2, the mouse cognates for the Drosophila gene orthodenticle, are expressed in patterns indicating that they have roles in patterning the forebrain, sense organs, and rostral neural crest. Though Otx1 null mouse embryos suffer from epileptic seizures and display abnormalities in cortical thickness, layering, and cell number, Otx2+/- heterozygous embryos exhibit head abnormalities similar to those observed by Wright in his otocephalic guinea pigs (Acampora and Simeone, 1999). The severity of this Otx2 agnathia-otocephaly phenotype is dependent on the strain background, and Hide and colleagues (2002) used these differences between B6 and CBA inbred mouse strains to identify and map modifier loci (the existence of which was predicted by Wright). Two genetic loci that modified the severity of the mandible phenotype in Otx2 mutant mice were identified by this group: the Otmf18 locus, linked to phenotypes of no mandible and small mandible, and the Otmf2 locus, linked with the phenotype of no mandible. These modifiers are likely to influence the behavior of neural crest cells that give rise to the mandible, perhaps at early stages of migration and proliferation.
Acampora, D., and Simeone, A. (1999) Understanding the roles of Otx1 and Otx2 in the control of brain morphogenesis. Trends Neurosci. 22, 116-122.
Hide, T., Hatakeyama, J., Kimura-Yoshida, C., et al. (2002) Genetic modifiers of otocephalic phenotypes in Otx2 heterozygous mutant mice. Development 129, 4347-4357.
Schiffer, C., Tariverdian, G., Schiesser, M., Thomas, M.C., and Sergi, C. (2002) Agnathia-otocephaly complex: report of three cases with involvement of two different Carnegie stages. Am. J. Med. Genet. 112, 203-208.
* Wright, S. (1933) On the genetics of subnormal development of the head (otocephaly) in the guinea pig. Genetics 19, 471-505.