HOMOLOGY-MEDIATED RECOMBINATION BETWEEN TYPE-I COLLAGEN GENE EXONS RESULTS IN AN INTERNAL TANDEM DUPLICATION AND LETHAL OSTEOGENESIS IMPERFECTA

It has been proposed that the structure of the exons that encode the t riple helical domain of the fibrillar collagen genes arose by repeated tandem duplication of an ancestral unit exon. Because these exons enc ode a repeat motif [(Gly-X-Y)n], sequence homology between exons may h ave driven the recombinational process. We have characterized a tandem duplication mutation within a COL1A1 allele of type I collagen from a n infant with the lethal form of osteogenesis imperfecta. The structur e of the mutation is consistent with the occurrence of an unequal cros sover within a 15 base pair region of sequence identity between exons 14 and 17 of the COL1A1 gene. The recombination produced a new 81 base pair 17/14 hybrid exon and complete duplication of exons 15 and 16. T he sequence implies duplication of 60 amino acid residues within the t riple helical domain with preservation of the Gly-X-Y repeat. These da ta suggest that a recombinational mechanism that explains the hypothet ical evolutionary process is active in cells, but the lethal effect of this mutation raises questions about the role of these events in crea ting new structures for polymeric proteins.