Gene clusters and the HLA system

The major human histocompatibility, or HLA system, is now known to include a number of closely linked loci controlling cell surface specificities, components of the complement system and immune response. Three loci, HLA-A, B and C, control serological determinants found on nearly all cells; a fourth locus, HLA-D, codes for determinants controlling the mixed lymphocyte culture reaction that are present only on B lymphocytes and monocytes. The products of the HLA-A, B and C loci are very similar to each other, as expected if they have arisen by duplication from a common ancestor. The HLA-D products however, show no homology with these and each in turn is different from the complement components (C2, C4 and Bf) coded for in the HLA region. If this complex genetic region has arisen by a series of duplications, one must explain how four different structural gene products can arise from a single duplicated nucleic acid sequence. Different proteins could be translated from the same nucleotide sequence through the use either of different reading frames or of different, not necessarily adjacent, parts of a sequence in different combinations. It seems likely that the general organization of the genetic material of higher organisms is into clusters of duplicated genes like the HLA region and that the numbers of such clusters, rather than the number of individual genes, reflects the genetic complexity of higher organisms.