Complete physical map of the human immunoglobulin heavy chain constant region gene complex

We have found by pulsed-field gel electrophoresis that the human immunoglobulin heavy chain constant region gene complex maps entirely to a 350-kilobase (kb) Mlu I fragment. The enzyme Eag I was used with pulsed-field gel electrophoresis alone and in double digests with Spe I to map the region. C gamma 3, of the C gamma 3-C gamma 1-C psi epsilon 1-C alpha 1 cluster, maps 60 kb to the 3' side of C delta; C gamma 2 of the C gamma 2-C gamma 4-C epsilon-C alpha 2 cluster maps 80 kb to the 3' side of C alpha 1, where C gamma 3 encodes the constant region of the immunoglobulin gamma 3 chain, C gamma 1 encodes the constant region of the immunoglobulin gamma 1 chain, etc. C psi gamma maps 35 kb to the 3' side of C alpha 1 and is in the same transcriptional orientation as the other genes. Although in the cloned DNA many CpG-containing restriction sites were identified, most of these were methylated in peripheral blood leukocytes. The sites that were not methylated were predominantly found in three clusters, or Hpa I tiny fragment islands. One was found on the 5' side of C mu; the other two lie 30 kb to the 3' side of each of the C alpha genes and could indicate the presence of regulatory sequences or genes. A region showing strong linkage disequilibrium between all C gamma genes spans at least 160 kb. The 70-kb C mu-C gamma 3 region, however, shows no linkage disequilibrium, possibly indicating a recombination hot spot. The immunoglobulin heavy chain constant region has been almost entirely cloned and mapped, and thus most rearrangements occurring in this region should be detectable.