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Polymorphisms in the Human Haptoglobin Gene Cluster

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Polymorphisms in the Human Haptoglobin Gene Cluster Proc. Natl. Acad. Sci. USA Vol. 83, pp. 7395-7399, October 1986 Genetics Polymorphisms in the human haptoglobin gene cluster: Chromosomes with multiple haptoglobin-related (Hpr) genes (unequal crossing-over/restriction fragment length polymorphisms/orthogonal pulsed field gradient gel electrophoresis/mouse-human cell hybrids/retrovirus-lke element) NOBUYO MAEDAt, SUSAN M. McEvoyt, HERMAN F. HARRISt, TITUS H. J. HUISMANf, AND OLIVER SMITHIESt tLaboratory of Genetics, University of Wisconsin-Madison, Madison, WI 53706; and tDepartment of Cell and Molecular Biology, Medical College of Georgia, Augusta, GA 30912 Contributed by Oliver Smithies, June 18, 1986 ABSTRACT We have found polymorphisms for the num- 3' end of isoleucine tRNA. This RTVL-I element may be ber of tandemly arranged haptoglobin-related (Hpr) genes in responsible for the apparent inability of the Hpr gene to be the haptoglobin gene cluster of Blacks. Genomic mapping and transcribed. nucleotide sequence analysis indicate that two copies of the Hpr Recombinational events involving the two genes, Hp and gene first resulted from unequal but homologous crossing-over Hpr, appear to have occurred frequently in recent human in a region 3' to the haptoglobin (Hp) and the haptoglobin- evolution. At least two gene conversion events have been related genes. Subsequent increases in the number of Hpr loci detected by DNA sequence analysis. One is at the 3' end of have occurred in some chromosomes. Among 25 American the two genes, where 620 bp oftheir nucleotide sequences are Blacks studied (15 were unrelated), 2 related individuals have identical, although other regions of the genes differ by an one extra copy of the Hpr gene and 5 unrelated individuals have average of 6.4% (6). The other gene conversion event more than two extra Hpr genes. None of 26 Whites and one produced the HplF allele, one ofthe common alleles ofthe Hp Oriental studied have extra copies. In one of the Blacks, six locus, as a consequence of transferring a segment of DNA tandemly arranged Hpr genes were demonstrated in one sequence from the Hpr gene to the Hp gene (N.M., unpub- chromosome by pulsed field gradient electrophoresis. His other lished data). In the present paper, we demonstrate that chromosome had one Hpr gene. The tandem Hpr genes were homologous but unequal crossings-over between the Hp and found in individuals with the haptoglobin genotypes Hp2/Hp2 Hpr genes have also occurred and have resulted in the (3 of3 tested) and Hp9/Hpl (4 of 11 tested), but none were found formation of chromosomes with multiple tandem Hpr genes. in the Hp'/Hp' individuals (11 tested). Fibroblast cell cultures We describe characterization at the DNA level of several from two Hp2/Hp' heterozygotes were fused to mouse cells to different examples of these chromosomes found in Blacks. obtain cell lines retaining a human chromosome 16 on which the haptoglobin gene cluster is located. DNA analysis of the MATERIALS AND METHODS hybrid cells showed that in both individuals the tandemly arranged Hpr genes are linked to the Hp2 allele. These results DNA. DNA was isolated from cultured cells and from suggest that the multiple copies are associated with the Hp2 leukocytes (7, 8). Fifteen unrelated Black individuals were gene. studied. They were not chosen because of their haptoglobin genotypes, but eight had some unusual features in their Haptoglobin, the hemoglobin-binding protein of plasma, P-globin gene cluster that had led to their initial selection. Ten contains two a and two ,B chains that are synthesized relatives of one individual were also studied. Twenty-six colinearly as a single precursor polypeptide and processed Whites and one Oriental were randomly selected. post-translationally (1-3). In humans, there are three com- Genomic Southern Blot Hybridization. Restriction enzyme mon alleles at the locus Hp, which controls synthesis of digests of genomic DNAs (3 ,g) were electrophoresed and haptoglobin. The HplF and HplS alleles code for a-chain transferred to nitrocellulose (9) and hybridized (10) to the polypeptides of equal length that differ in charged amino following probes: the promoter probe, a 620-bp-Sst I/Bgl II acids making them migrate as fast and slow bands during fragment containing the promoter region and first exon of the electrophoresis in acidic starch gels. The Hp2 allele contains Hp gene; the hp2a probe, a 500-bp Pst I/BamHI fragment of an intragenic duplication of 1.7 kilobase pairs (kbp) and codes Hp2 cDNA (4); the hpB probe, a 650-bp BamHI/HindIII for an a chain that is almost twice as long as those coded by fragment of Hp2 cDNA (4). the Hp' alleles (4). Characterization ofthe Crossing-over Point. Genomic DNA DNA studies of the haptoglobin gene have revealed that it from a Black individual (C.G.) was digested with EcoRI, is duplicated in the human genome, with a haptoglobin- ligated to EcoRI-digested DNA from bacteriophage Charon related gene, Hpr, being located 2.2 kbp downstream of the 32, and packaged in vitro (11). The recombinant phages were Hp gene (5, 6). The Hpr gene appears to code for a screened using radiolabeled hp2a probe. The EcoRI fragment structurally functional protein, although no hemoglobin- that contains the Hpr* gene (see Results) was isolated and binding protein with its expected properties has been de- subcloned into p010A ori (12). The nucleotide sequence ofthe scribed in the literature. In addition, no unequivocal tran- region spanning the crossing-over point was determined by scripts corresponding to the Hpr gene have been detected (5). the method of Maxam and Gilbert (13). In the first intron of the Hpr gene there is a retrovirus-like Orthogonal Pulsed Field Gradient Gel Electrophoresis. element (6), named RTVL-I (retrovirus-like isoleucine) be- Fibroblast cells (-2 x 107) were embedded in 0.5% low- cause it has a potential primer binding site homologous to the melting-point agarose (SeaPlaque, FMC, Rockland, ME) beads (2 ml) by the method of Cook (14). The DNA trapped The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" Abbreviations: kbp, kilobase pair(s); RFLP, restriction fragment in accordance with 18 U.S.C. §1734 solely to indicate this fact. length polymorphism. 7395 Downloaded by guest on September 27, 2021 73967MProc.Genetics: Maeda et al. Natl. Acad. Sci. USA 83 (1986) in the beads was digested with Kpn I and subjected to individuals 4, 6, 9, 11, and 12 have more than one copy ofthis orthogonal pulsed field gradient gel electrophoresis in 0.8% gene. A rough estimate by densitometry indicated that agarose using the method of Schwartz and Cantor (15). The individual 6 (C.G.) has four or five and individual 9 (H.F.M.) negative electrodes were 22.5-cm-long linear arrays of 19- has about three copies of Hpr*. diode-isolated platinum wires set up as adjacent sides of a Ten other members of the family of H.N.R. were also right triangle [compare Carle and Olson (16)]. The positive studied. Individuals 1-5 (Fig. lb) are some ofthem. A cousin electrodes were platinum wires placed close to the ends ofthe ofH.N.R. has the same number ofHpr* genes as H.N.R., but hypotenuse. Five-second pulses were applied at 450 V for 5 we could not determine whether the chromosomes involved hr. The buffer was 50 mM Tris HCI/50 mM boric acid/i mM were codescendants. A half-sibling of H.N.R. has three or EDTA, pH 8.3, with HCl. more Hpr* genes (no. 4 in Fig. lb). Eight other individuals in Cell Fusion. Human fibroblast cells (from C.G. or H.F.M.) the family have chromosomes with the usual haptoglobin were fused to mouse LS-24b cells (17), which are defective in gene arrangements, either Hp2-Hpr or Hp'-Hpr. We did not adenine phosphoribosyl transferase, by the method of Da- find any examples of the unusual chromosomes among the 26 vidson and Gerald (18). Twenty-four hours after treatment Whites and one Oriental examined. with polyethylene glycol, cells were trypsinized and redis- Up to Five Hpr* Genes on a Single Chromosome. To tributed in medium containing 0.05 mM azaserine/0.1 mM determine the number of Hpr* genes in each of the chromo- adenine and 0.1 juM ouabain. The medium was changed every somes of C.G. and H.F.M., we used Southern blot analysis 3 days for 3 weeks. Surviving colonies were transferred into of large molecular size DNA separated in agarose gel by new dishes and culture was continued in azaserine/adenine- orthogonal pulsed field gradient gel electrophoresis. Among containing medium. the restriction enzymes that digest outside but not within the haptoglobin cluster, Kpn I was found to be most appropriate RESULTS for our purpose. Fig. 2a shows the ethidium bromide-stained gel and the Southern blot of Kpn I digests of DNA from four Genomic Southern Blot Hybridization. Chromosomes with individuals after hybridization to the hp2a probe. DNA from multiple Hpr genes were first detected by the presence of C.G. shows a hybridizing fragment of =130 kbp as well as a bands with unusual darkness in genomic Southern blots. Fig. 47-kbp fragment. The digest of the control DNA (no. 563 in la shows EcoRI, BamHI, and Bgl II digests ofDNA from two Fig. 2a, a White H2-Hpr homozygote) shows only the 47-kbp individuals, M.K. (White) and C.G. (Black), hybridized to band. Each copy of the Hpr* gene makes the haptoglobin the hp2a probe. Both individuals are Hp2/Hpl heterozy- gene cluster longer by -16 kbp. This result therefore indi- gotes, but a new 10.3-kbp EcoRI band (not separable from the cates that the five copies of the Hpr* genes in C.G.
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