DNA sequence variability of IGHG3 alleles associated to the main G3m haplotypes in human populations

The present study investigates the molecular basis of the G3m polymorphism expressed by the heavy constant domains of human immunoglobulins gamma 3 ch ains. By using a new protocol allowing the specific cloning of IGHG3 genes, a total of 51 full-length IGHG3 genomic sequences (about 2 kb) isolated fr om African, Siberian, West Asian and European population samples were seque nced. IGHG3 sequences were assigned precise G3m haplotypes on the basis of specific associations between G3m allotypes and IGHG3 RFLPs. Specific DNA s ubstitutions involved in the expression of G3m(5), G3m(6), G3m(15), G3m(16) , G3m(21), G3m(24) and G3m(28) allotypes were then deduced, elucidating alm ost completely the determination of the G3m polymorphism at the DNA level. The molecular evolution of G3m haplotypes was investigated by a maximum lik elihood phylogeny of IGHG3 sequences. Sequence clusters are shown to be G3m haplotype-specific, corroborating the Gm molecular model deduced from sero logy, and showing that populations differentiation is much more recent than G3m haplotypes differentiation. The widely distributed G3m(5,10,11,13,14) haplotype is likely to be ancestral to the other G3m haplotypes presently f ound at high frequencies in different continental areas.