Intragenic recombination at the human phosphoglucomutase 1 locus: predictions fulfilled.

In 1982, we advanced a phylogeny that attributed eight alleles of the phosphoglucomutase 1 locus (PGM1) to three independent mutations in a primal allele, followed by four intragenic recombination events involving these mutants [Takahashi, N., Neel, J. V., Satoh, C., Nishizaki, J. & Masunari, N. (1982) Proc. Natl. Acad. Sci. USA 79, 6636-6640]. The recent description of a cDNA probe for this locus [Whitehouse, D. B., Putt, W., Lovegrove, J. U., Morrison, K., Hollyoake, M., Fox, M. F., Hopkinson, D. A. & Edwards, Y. H. (1992) Proc. Natl. Acad. Sci. USA 89, 411-415] now renders it possible to test the validity of this phylogeny. cDNAs of PGM1 reverse-transcribed from mRNAs obtained from Japanese individuals possessing eight different electrophoretically defined alleles (PGM1*1+, PGM1*1-, PGM1*2+, PGM1*2-, PGM1*3+, PGM1*3-, PGM1*7+, PGM1*7-) were amplified by PCR and the sequences were determined. Only three different base substitutions were identified when PGM1*1+ was taken as the reference allele, as follows: an A to T transversion at residue 265, a C to T transition at residue 723, and a T to C transition at residue 1320. The second of these substitutions creates a Bgl II restriction enzyme site and the third creates a Nla III site. At the amino acid level, these substitutions alter amino acid 67 from Lys to Met, amino acid 220 from Arg to Cys, and amino acid 419 from Tyr to His, respectively. These mutations resulted in the electrophoretic properties defining PGM1*7+, the PGM1*2+, and the PGM1*1- alleles, respectively. Subsequent intragenic recombinational events resulted in the remaining four alleles. For two of these latter alleles (PGM1*7- and PGM1*3-), more than one type of intragenic crossover can produce the allele. These findings verify the predicted phylogeny and provide a case study in the evolution of complexity at a genetic locus.