Haplospecific Polymorphism Between HLA B and Tumor Necrosis Factor Xiongwen Wu, Wen Jie Zhang, Campbell S. Witt, Lawrence J. Abraham, Frank T. Christiansen, and Roger L. Dawkins ABSTRACT: Polymorphisms were sought between HLA B and tumor necrosis factor (TNF) using three ge- nomic probes. Extensive polymorphism was detected within a panel of 50 cell lines including 37 homozygotes representing 21 different ancestral haplotypes (AH). Fol- lowing Taq I digestion of genomic DNA, we observed three allelic patterns with probe X (RI7A) and four with probe V (RgA). Seven different allelic patterns were found with probe Y (M20A) after Taq I + Rsa I diges- tion. Family studies showed that the Y, X, and V alleles were inherited and segregated with HLA haplotypes. A striking feature of the allelic patterns detected by these probes was that cells with the same AH had identical Y, X, and V alleles (i.e., the alleles were haplotypic). Of 15 different Y-X-V haplotypes observed, 11 were found to be specific for a particular AH (i.e., were haplospecific). Four were shared by more than one AH, but in these instances there were extensive similarities in other re- gions within the major histocompatibility complex (MHC), for example, the Japanese 46.2 (HLA Bw46- DRw8) and the Chinese 46.1 (Bw46-DR9) share all al- leles between HLA C and C4 and differ only in class II, suggesting their relatively recent divergence by recombi- nation between C4 and DR. Surprisingly, two insulin- dependent diabetes mellitus (IDDM)-resistant but race- specific AHs 52.1 (Bw52-DRB 1" 1502, Japanese) and 7.1 (B7-DRB 1"1501, Caucasoid) carry the same Y-X-V hap- lotype, suggesting the possibility of localizing gene(s) rel- evant to IDDM. The present study confirms that MHC AHs have been conserved en bloc, including the region between HLA B and TNF. Human Immunology 33, 89- 97, (1992) ABBREVIATIONS AH ancestral haplotype MHC major histocompatibility complex RFLP restriction fragment length polymorphism SSO sequence-specific oligonucleotide TNF tumor necrosis factor INTRODUCTION The major histocompatibility complex (MHC) is charac- terized by polymorphism. All polymorphisms, whether within coding or noncoding sequences at MHC classes I, II, and complement loci are haplotypic and often ha- Publication number 9053 of the Department of Clinical Immunology. Royal Perth Hospital, Sir Charles Gairdner Hospital and the University of Western Australia, Perth, Western Australia. From the Departments of Clinical Immunology, Royal Perth Hospital Sir Charles Gairdner Hospital, and the University of Western Australia, Perth, Western Australia. AddreJs reprint requests to R. L. Dawkins, Department of Clinical Immunology, Royal Perth Hospital, GPO Box X2213, Perth, Western Australia 6001. Received August 26, 1991; accepted October 30, 199•. plospecific, as shown by the collaborative studies on a cell panel of well-defined MHC haplotypes within the 10th International Histocompatibility Workshop [1]. The fact that polymorphisms are invariably haplotypic indicates that MHC haplotypes have been conserved en bloc. Thus, apparently unrelated individuals often share the same MHC haplotypes. Accordingly, we use the term ancestral haplotype (AH) to refer to conserved MHC haplotypes that have been maintained through many generations of an ancestral family [2-4]. During recent years a number of novel genes have been identified and mapped to the region between HLA B and C2 [5-7]. We predicted that this region would Human Immunology 33, 89-97 (1992) 89 © American Society for Histocompatibility and Immunogenetics, 1992 0198-8859/92/$5.00