GENETIC-MAPPING OF THE HUMAN HOMOLOG (T) OF MOUSE T(BRACHYURY) AND A SEARCH FOR ALLELE ASSOCIATION BETWEEN HUMAN T AND SPINA-BIFIDA

We describe a genetic analysis of the human homologue (T) of the mouse T (Brachyury) gene; human T was recently cloned in our laboratory. Th e protein product of the T gene is a transcription factor crucial in v ertebrates for the formation of normal mesoderm. T mutant Brachyury mi ce die in midgestation with severe defects in posterior mesodermal tis sues; heterozygous mice are viable but have posterior axial malformati ons. In addition to its importance in development, T has intrigued gen eticists because of its association with the mouse t-haplotype; this h aplotype is a variant form of the t-complex and is characterized by tr ansmission ratio distortion, male sterility and recombination suppress ion. We have identified a common polymorphism of human T by single str and conformation polymorphism (SSCP) and used this in mapping studies and to re-investigate the idea that human Tis involved in susceptibili ty to the multifactorial, neural tube defect, spina bifida. Our mappin g data show that human T maps to 6q27 and lies between two other genes of the t-complex, TCP1 and TCP10. These data add to the evidence that in man the genes of the t-complex are split into two main locations o n the short and long arms of chromosome 6. We have used an allele asso ciation test which is independent of mode of inheritance and penetranc e to analyse data from the spina bifida families. Using this test we f ind evidence for a significant (p = 0.02) association between transmis sion of the TIVS7-2 allele of the human T gene and spina bifida.