ORIGINAL PAPER Hodjattallah Rabbani Qiang Pan Naomi Kondo C. I. Edvard Smith Lennart Hammarstro ¨m Received: 14 June 1996/Revised: 2 August 1996 AbstractmA limited number of deletions and duplications within the human immunoglobulin heavy chain constant locus (IGHC) has previously been reported. We studied the IGHC locus in about 500 individuals representing three major races of human, Negroid (Gambian), Mongoloid (Japanese and Chinese), and Caucasoid (Iranian and Swed- ish). The haplotype frequency of duplications is highest in the Mongoloid population (22%), followed by the Cauca- sian (10%) and Negroid (5%) populations. The correspond- ing frequency of deletions are 2, 1.5, and 3.5%, respec- tively. New types of multiple duplications were found in this study on different genetic (H haplotype and racial) backgrounds. The most common duplication, found in all populations studied, encompasses the IGHA1-IGHE genes. The only deletion common to all racial groups is an isolated deletion of the IGHG4 gene. Our data are consistent with the hypothesis that the Caucasoid-Mongoloid group di- verged from the hominoid ancestor after development of the Negroid populations, with subsequent evolution within the respective groups thereafter. The human immunoglobulin heavy chain constant gene locus (IGHC) is composed of nine functional and two pseudogenes, located on the long arm of chromosome 14 (14q32.2; Hofker et al. 1989). The human G, E, and A heavy chain constant region genes are organized into two blocks: IGHG3-IGHG1-IGHEP1-IGHA1 and IGHG2- IGHG4-IGHE-IGHA2 (Flanagan and Rabbitts 1982; Le- franc et al. 1982, 1983). Considerable genetic variation in this locus has been observed, consisting of single or multi- ple gene deletions and duplications. The mechanism under- lying the formation of duplications or deletions has been postulated to be either non-equal homologous recombina- tion (NEHR) or looping out excision (Bottaro et al. 1989 a). This region is polymorphic both at the protein (Gm and A2m allotypes) and the DNA levels (restriction fragment length polymorphisms for the G, E, and A genes, the switch mu-, gamma- and alpha-chain-encoding regions and the I gamma and I alpha chain-encoding regions). Most of the polymorphisms are due to short insertions/deletions or due to the presence or absence of a given restriction site as a consequence of a point mutation (Ghanem et al. 1988). These polymorphisms have constituted valuable tools for determining the organization of the IGHC locus, as well as for a variety of population genetics and immunological investigations. In addition to a pseudoepsilon gene on chromosome 9, the human IGHC complex maps to a 350 kilobase (kb; or 370 kb) Mlu I fragment (Fig. 1). The Mlu I restriction enzyme cuts 5 of IGHM and 3 of IGHA2, generating a polymorphic band identifiable with all IGHC probes (CM, CD, CG, CE, CA; Bottaro et al. 1989, 1991; Hofker et al. 1989). Any insertion/deletion greater than 10 kb in this region is detectable using the restriction enzyme Mlu I and pulsed field gel electrophoresis (PFGE). The RFLPs pro- duced by Bam HI can be used as markers for the constant region heavy chain genes, IGHGP , IGHG2, and IGHG4. These RFLPs have been found nonrandomly associated in the population (Bech-Hansen et al. 1983; Hofker et al. 1989) and there are eight possible RFLP combinations (haplotypes H1–H8; Table 1). We have previously reported a higher frequency of gene duplications than deletions in this locus in the general Caucasoid population, and a statistically significant differ- ence in serum levels of the affected subclasses between individuals carrying duplicated versus nonduplicated genes H. Rabbani 1 ( ) Q. Pan C. I. E. Smith L. Hammarstro ¨m Department of Bioscience at Novum, Karolinska Institute, S-141 57 Huddinge, Sweden N. Kondo Department of Pediatrics, Gifu University School of Medicine, Tsukasa-Machi 40, Gifu 500, Japan Present address: 1 Department of Bioscience at Novum, Karolinska Institute, S-14157 Huddinge, Sweden Immunogenetics (1996) 45: 136 – 141  Springer-Verlag 1996