The Human Kell Blood Group Gene Maps to Chromosome 7q33 and its Expression Is Restricted to Erythroid Cells

By Soohee Lee, Eleni D. Zambas, W. Laurence Marsh, and Colvin M. Redman

The Kell blood group is one of the major antigenic systems in human red blood cells. To determine the location of the Kell gene on human chromosomes, panels containing ge- nomic DNA of human-hamster somatic cell hybrids were hybridized with radiolabeled cDNA probe specific for the Kell locus. Only the samples containing DNA from chro- mosome 7 gave positive hybridization signals. In situ hy- bridization analysis, using genomic clones isolated with the

ELL IS ONE of the major human red blood cell (RBC) K groups. It is an important system in clinical medicine, for Kell antibodies can cause severe hemolytic reactions if incompatible blood is transfused. Furthermore. active ma- ternal-fetal Kell group incompatibility may cause severe he- molytic disease in a newborn infant. The Kell blood group system is characterized by its complexity; it is composed of at least 23 different antigens. No example of recombination within the Kell locus has been recorded and it has been as- sumed that the observed complexity reflects a single gene with many sites at which mutations can occur.’.*

The Kell antigens reside on a 93-Kd RBC trans-membrane glycoprotein that is surface-exposed and probably attached to the underlying cytoskeleton.’“ Molecular cloning of the Kell gene has shown that it is a 73 1 amino acid protein that spans the membrane once and has a 46 amino acid N-ter- minal domain within the RBC and a large C-terminal extra- cellular segment.’

Until recently, Kell was the only major blood group system whose locus had not been mapped. Zelinski et alx have shown that the Kell blood group locus is linked to the prolactin- inducible protein (PIP) locus, which has been localized to 7q32-36. This assignment was confirmed by linkage analysis between KEL and 3 DNA markers that are linked to the cystic fibrosis marker.’ We have now used genomic clones as probes to localize the KEL gene in a more defined area and we also show that expression of the KEL gene is restricted to erythroid tissues.

MATERIALS AND METHODS

Approval was obtained from the Institutional Review Board of the New York Blood Center for these studies. Persons were informed that samples were obtained for research purposes and that their privacy would be protected.

Human bone marrow was stored at -70°C in 5 vol (wt/vol) of 6 mol/L guanidine thiocyanate, 12.5

Northern hlot analwis.

From the Lindslq F. Kimhall Research Institiite ofrhe New York

Siihmitted Septemher 17. 1992: accepted Janiiary 5. 1993. Supported hy National 1nstitiite.y of Health Grant No. HL33841. Addre.n reprint reqiie.yts to Colvin M . Redman. PhD. Neu York

Blood Center. 310 E 67th SI. New York. NY 10021. The piiblication costs of this article were defrayed in part by page

charge payment. This article milst therefore he herehy marked “advertisement” in accordance with 18 U.S.C. section I734 sole1.v to indicate this fact.

Blood Center, New York, NY.

0 I993 bv The American Society of Hematology. 0006-4971/93/81 IO-0040$3.00/0

cDNA, localized the KEL gene to 7q33. Northem blot anal- ysis of poly(A)+ RNA from human brain, kidney, lung, fetal and adult liver, and bone marrow showed that Kell tran- scripts were only present in fetal liver and bone marrow. This indicates that the Kell protein, which carries the Kell antigens, may only be expressed in erythroid tissues. 0 1993 by The American Society of Hematology.

Kb Kb

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4.4-

2.4 -

-9.2 - 7.

- 4.4

- 2.4

- 1.4

I .4- -0.24

0.24 -

2.4 -

I .4- 1 2 3 4 5 6 7

Fig 1. Northem blot analyses of RNA from several tissues. Lanes 1 to 5 contain 10 pg each of poly(A)+ RNA from human bone mar- row, brain, kidney fetal liver, and adult liver. Lane 6 contains 24 pg of human bone marrow poly(A) + RNA. Lane 7 has 10 pg of human lung poly (A)’ RNA that was analyzed in a separate experiment. Northem blot hybridizations were performed with 32P-labeled Kell cDNA (upper panel) or with cDNA to human @-actin (lower panel). Molecular weight markers are indicated on the sides of the auto- radiograms.

2804 Blood. Vol8 1, No 10 (May 15). 1993: pp 2804-2809

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KELL BLOOD GROUP GENE

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mmol/L sodium citrate, pH 7.0, and 5% 2-mercaptoethanol. RNA was isolated by the combined methods of CsCI-gradient centrifugation followed by acid guanidinium thiocyanate-phenol-chloroform ex- traction.I0 Poly(A)+ RNA was isolated using an mRNA isolation kit (Fast-Track) from Invitrogen (San Diego, CA). Other poly(A)+ RNAs were purchased from Clonetech Laboratories (Palo Alto, CA).

Poly(A)+ RNAs were separated on 1.2% agarose gels containing formaldehyde. '*P random-labeled 0.5- and 1.9-kb cDNA fragments from Kell clone no. 191,' which contain the entire open reading frame for Kell protein, were used as probes. The analysis was per- formed as described by Sambrook et al."

Two chro- mosome panels containing human, human-hamster cell hybrid, and

Chromosome panel blots of somatic cell hybrid DNA.

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hamster DNAs were digested with EcoRI, electrophoresed on 0.8% agarose gels, and transferred to a neutral nylon membrane. The lanes with human or hamster DNA contained 5 pg of DNA and those with somatic cell hybrid line DNAs contained 8 hg. The blots were purchased from Bios Corp (New Haven, CT).

Southern blot hybridizations were performed with random-labeled (Random Primed DNA labeling kit; US Biochemical, Cleveland, OH) 0.5- and I .9-kb cDNA fkgments from Kell clone no. I9 1' as described by Sambrook et al."

Genomic clones. A human placental DNA genomic library con- structed in EMBL-3 (Clonetech) was screened'' using labeled 0.5- and 1.9-kb cDNA fragments from Kell clone no. 191.7 Fourteen genomic clones were obtained and three genomic clones (2, 8, and

CHROMOSOME PANEL I CHROMOSOME PANEL I I

CELL LINES CELL LINES

C H R 0 M 0 S 0 M E

Fig 2. Composition of human-hamster somatic cell hybrid panels. The DNA composition of two panels is shown. On the left side is panel I and on the right panel II. Each panel contains 22 lanes. As controls, lanes 1 and 12 of each panel contain human DNA and lanes 11 and 22 contain hamster DNA. Lanes 2 through 10 and 13 through 21 contain chromosomal DNA from the human-hamster somatic cell lines listed. X means that more than 75% of the cells contain the noted human chromosome. The numbers are the percentages of the cell population containing the noted chromosome. D is a deletion at p15.1-15.2 and Dq indicates multiple deletions in 5q. These panels are from Bios Corp, as revised on September 19, 1990.

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2806 LEE ET AL

B) were chosen as probes for in situ hybridization. These three clones, which range in size from approximately I I to 18 kb, are overlapping and span the entire KEL gene (Lee et al. unpublished).

Chromosome mapping was performed by the FISH method of Lichter et a1.I2 Equal amounts of DNA from genomic clones 2, 8, and B were combined and nick- translated with digoxigenin-l IdUTP. The labeled probes were com- bined with sheared human DNA and hybridized in 50% formamide. 2X SSC. and IO% dextran to normal metaphase chromosomes. Hy- bridization was detected with antidigoxigenin-fluorescein isothiocy- anate (FITC). The chromosomes were counterstained with propidium iodide. To confirm the identity of the labeled chromosome a similarly labeled probe, specific for the centromere of chromosome 7. D7ZI I3-IS was mixed with the three KEL genomic probes and used to cohybridize the chromosomes. The location of the KEL gene on the chromosome was determined by measuring the distance from the centromere to the telomere of the long arm of chromosome 7 and calculating the percent distance of the Kell-specific signal. These procedures were performed by Bios Corp.

DNA was isolated from leukocytes present in the buffy coat of blood from a person with common Kell phenotype. as previously described,'6 and digested with EcoRI or Ilindlll. Digested DNA ( I O pg) was separated on 0.8% agarose gels and transferred to Hybond-N+ membranes. The filters were hybridized with '*P random-labeled 0.5- and I .9-kb cDNA h g - mentsof Kell clone no. 191'asdescribed by Sambrook et al."

Flirorcwcnt in situ h.vbriclizurion ( F N I ) .

DNA i.wlutic~n und resiricti(in cwzvmc~ analvsis.

RESULTS

KEL expression is restricred t o erytliroid rissiies. Northern blot analyses of Poly(A)+ RNA from human bone marrow, brain, kidney, fetal liver, adult liver, and lung were performed with radiolabeled cDNA fragments covering the entire Kell open reading frame. Hybridization signals were only obtained with RNA from bone marrow and fetal liver. The major transcript in both fetal liver and bone marrow was 2.5 kb. Larger transcripts of 6.6, I I .5, and 13.2 kb were also noted in both fetal liver and bone marrow, but the I I .5- and 13.2-kb transcripts were difficult to detect in bone marrow (Fig I) .

The hybridization signal was severalfold greater in fetal liver than in bone marrow. Two different concentrations of poly(A)+ RNA ( I O pg and 24 pg) were used for bone marrow. and in each instance the signal was much less than that noted for fetal liver. Hybridization with "P-labeled &actin cDNA was used as a control to evaluate the quantity of RNA from the various tissues (Fig I).

These data show that Kell transcripts are not detected in brain, kidney, adult liver, and lung, but are expressed in bone marrow and fetal liver, indicating that expression is likely to be restricted to erythroid tissues.

Chromosome locarion qf KEL bv Southern blots qf somatic cell hybrids. Kell cDNA fragments were used to screen two panels containing chromosomal DNA of human-hamster somatic cell hybrids. Each panel also contained human and hamster DNA as controls. The composition of the panels is shown in Fig 2. Positive hybridization signals were obtained in the lanes containing human DNA (lane I , panels I and II , Fig 3) and in 3 of 36 hybrid cell lines that contained DNA from human chromosome 7 (lane 8, panel I, and lanes 7 and 8, panel 11, Fig 3). In these samples, 3 radioactive bands of

Chromosome Panel I Human Somatic cell hybrid lines Hamster

I ' 2 3 4 5 6 7 8 9 10'11

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Chromosome Panel II Human Somatic cell hybrid lines t ,rMlSter

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Fig 3. Southem blot analysis of DNA from human-hamster so- matic cell hybrids. Southem blot analysis was performed on two panels containing genomic DNA digested with EcoRI. Radiolabeled cDNA specific for Kell was used as a probe. The panels had t h e following DNA composition. Lanes 1 and 12 contained human DNA; lanes 1 1 and 22 had hamster DNA; and lanes 2 through 10 and 3 through 21 contained human-hamster hybrid DNA from various cell lines with different chromosome compositions. Autoradiograms of two different panels are shown.

approximately I I .5, 10.5, and 6.5 kb were noted. The I I .5- and 10.5-kb bands were not well separated and appear as a single signal. Two of the three lanes that gave positive signals (lane 8, panel I, and lane 7, panel I I ) are derived from cell line no. 1006 and had DNA from human chromosomes 4, 5, 7, 8, 13. 15, 19, and 21. The other cell line (no. 756) that gave a positive signal (lane 8. panel I I ) had DNA from human chromosomes 5, 6, 7, 12, 13. 14, 19, 20, 21, and Y (Fig 2). All of the other cell lines were negative. They only had weak signals similar to those obtained with hamster DNA (lanes I I and 22, panels 1 and I I ) and different than that seen with human DNA. Absence of a positive signal from these other lanes eliminated human chromosomes 5, 13, 19, and 21,

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KELL BLOOD GROUP GENE 2807

which, together with chromosome 7, are shared by cell lines 1006 and 756. This combination of positive signals in the presence of DNA from chromosome 7 and absence of signals in cell lines with other chromosomes localizes the KEL gene on chromosome 7.

To determine the approx- imate size of the gene, genomic DNA was digested with EcuRI and HindIII and hybridized with probes that encompass the entire open reading frame of Kell protein. The sum of the respective EcoRI or HindIII fragments indicated that Kell gene is approximately 30 kb (data not shown).

To define further the segment of chromosome 7 in which the Kell gene is located, three Kell genomic clones

Restriction enzyme analysis.

FISH.

(Kell clones 2, 8, and B) were labeled with the fluorescent tag digoxigenin and in situ hybridization to human chro- mosome metaphase spreads was performed. Specific hybrid- izations were seen on the long arm of a C-group chromosome whose morphology indicated that it was chromosome 7. To confirm the identity of the labeled chromosome, a probe (D7ZI) specific for the centromeric region of chromosome 713.15 was cohybridized with genomic clones no. 2, 8, and B to metaphase chromosomes. The results are shown in Fig 4. All chromosomes that contained a centromeric signal, iden- tifying them as chromosome 7, also contained hybridization signals on the distal long arm. Measurements of hybridized chromosomes indicate that the Kell hybridization signal is

Fig 4. In situ hybridization showing labeling of chromo- some 7. Normal human meta- phase (A) and prometaphase chromosomes (B) were cohy- bridized with fluorescent-la- beled Kell-specific genomic DNA and with a chromosome 7- specific centromeric probe.

I"

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2808

1 CFTR

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located 82% of the distance from the centromere to the telo- mere of the long arm of chromosome 7. This distance cor- responds to band 7q33. A diagram showing the location where the KEL gene maps is given in Fig 5.

DISCUSSION

Many RBC membrane proteins occur, or have similar counterparts, in other t i~sues . l~* '~ However, the 93-Kd protein that carries the Kell antigens appears to be only expressed in

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Fig 5. Diagram of chromosome 7 showing the location of the Kell gene. The banding pattern of chromosome 7 is shown and the location of the Kell gene (KEL) and of some neighboring genes on the long arm are noted. Also shown is that the Colton blood group (CO) maps to the short arm. AChE, acetylcholine esterase; YT, Cartwright blood group; EPO, erythropoietin; MDR, multidrug resistance; CFTR, cystic fibrosis transmembrane conductance regulator; CLM, cutisaxa with Marfanoid phenotype; DLD, dihy- drolipoamide dehydrogenase; BCP, blue cone pigment; CPAl , carboxypeptidase A1 (pancreatic); EPHT, eph tyrosine kinase/ erythropoietic-producing hepatoma-amplified sequence; PIP, pro- lactin-induced protein; TRY1 , trypsin 1; ABPl , amyloroide-binding protein; CHRMZ. cholinergic receptor muscarinic 2; EPB3Ll , erythrocyte surface protein band 3-like 1. The location of AChE has been described by Getman et aPO and the other loci are reported by the committee on the genetic constitution of chromosome 7.32

LEE ET AL

erythroid tissues. Northern blot analyses did not detect tran- scripts in human brain, kidney. lung, or adult liver, but expression was noted in bone marrow and in fetal liver. Kell protein is not homologous to any known protein, but has most similarity with the common acute lymphoblastic antigen (CALLA) and the enkephalinase~,~ a group of zinc metallo- endoproteinases that are widely distributed in many cell types and have broad substrate specificities. The role of these en- dopeptidases is to process peptide hormones such as the en- kephalins, neurotensin, angiotensin, oxytocin, and bradyki- r ~ i n . ' ~ - ~ * In addition, Kell also shares a pentameric consensus sequence with a large family of zinc metalloproteases present in nearly all organisms and having a variety of proteolytic roles.23 The physiologic role of Kell on RBC membranes has not been elucidated, but because zinc metalloproteases are widely distributed, it may not be necessary for Kell, if it has peptidase activity, to be expressed in nonerythroid tissues. It should be noted that Ko(nul1) persons, who lack Kell protein on RBC membranes, are healthy and, presumably, there are compensatory mechanisms that take over the role of Kell.

Some of the zinc endopeptidases are membrane-spanning proteins that act as cell-surface antigens. For example,

and BP-1/6C3*4 antigens are both, like Kell, proteins that span the membrane once, have small cyto- plasmic domains, and contain the common zinc-binding en- dopeptidase active site consensus sequence on the extracel- lular segment. It has been suggested that the role of these enzymes on the surfaces of several different cell types may be to control growth and differentiation in both hematopoietic and epithelial systems.25 However, other roles, such as pro- cessing of extracellular hormones or matrices, must also be considered.

In bone marrow and fetal liver, the major transcript noted by Northern blot analysis was 2.5 kb. This size is in the range expected to code for an 80-Kd protein, such as deglycosylated Ke11.26 The reasons for the presence of larger transcripts, of approximately 6.6, 11.5, and 13.2 kb, are not clear. Both bone marrow and fetal liver have a 6.6-kb transcript and fetal liver also has larger 11.5- and 13.2-kb sizes. Only a single 93- Kd glycoprotein has been identified as carrying Kell anti- g e n ~ , ~ - ~ and thus only a single-size mRNA may be expected. However, mRNAs with large 3' untranslated regions are not uncommon and these larger transcripts may have such un- translated structures.

The in situ hybridization studies localized the KEL gene to a single chromosome region 7q33. This confirms the ge- netic linkage studies of Zelinski et a1,' who have mapped the KEL gene to 7q32-36 based on its linkage with the prolactin- induced protein. Two other blood group loci, Colton (CD) and Cartwright (YT), have also been assigned to chromosome 7. Colton is on the short arm of chromosome 727 and YT, which has a loose linkage with KEL,28 is an antigen located on erythrocyte acetylcholinestera~e,~~ which maps to 7q22.30 Spence et a13' reported the linkage of the classical genetic marker for phenylthiocarbamide-tasting (PTC) to KEL and, thus, PTC has also been assigned to chromosome 7. As noted by Zelinski et al,' now only 2 of the 19 recognized blood group systems (Diego and Dombrock) have not yet been as- signed a chromosomal location.

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KELL BLOOD GROUP GENE 2809

ACKNOWLEDGMENT

We thank James L. German 111 and Nathan Ellis for many helpful discussions throughout the course of the study, Cathy Falk for reading the article, Tellervo Huima for aid in the illustrations, and Helen Cume for preparing the manuscript.

REFERENCES I. Marsh WL, Redman CM: Recent developments in the Kell

blood group system. Transfus Med Rev 1:4, 1987 2. Marsh WL, Redman CM: The Kell blood group system: A

review. Transfusion 30: 158, 1990 3. Redman CM, Marsh WL, Mueller KA, Avellino GP, Johnson

CL: Isolation of Kell-active protein from the red cell membrane. Transfusion 24: 176, 1984

4. Redman CM, Avellino G, Pfeffer SR, Mukherjee TK, Nichols M, Rubinstein P, Marsh W L Kell blood group antigens are part of a 93,000 Dalton red cell membrane protein. J Biol Chem 26 1:952 1, 1986

5. Wallas C, Simon R, Sharpe MA, Byler C: Isolation of a Kell- reactive protein from red cell membranes. Transfusion 26: 173, 1986

6. Jaber A, Blanchard D, Goossens D, Bloy C, Lambin P, Rouger P, Solmon C, Cartron JP: Characterization of the blood group Kell (Kl) antigen with a human monoclonal antibody. Blood 73:1597, 1989

7. Lee S, Zambas ED, Marsh WL, Redman CM: Molecular cloning and primary structure of Kell blood group protein. Proc Natl Acad Sci USA 88:6353, 1991

8. Zelinski T, Coghlan G, Myal Y, Shiu RPC, Phillips S, White L, Lewis M: Genetic linkage between the Kell blood group system and prolactin-inducible protein loci: Provisional assignment of KEL to chromosome 7. Ann Hum Genet 55:137, 1991

9. Purohit KR, Weber JL, Ward U, Keats BJB: The Kell blood group locus is closed to the cystic fibrosis locus on chromosome 7. Hum Genet 89:457, 1992

10. Chomczynski P, Sacchi N: Single-step method of RNA iso- lation by acid quanidinium thiocyanate-phenol-chloroform extrac- tion. Anal Biochem 162:156, 1987

1 I . Sambrook J, Fritsch EF, Maniatis T: Molecular Cloning: A Laboratory Manual (ed 2). Cold Spring Harbor, NY, Cold Spring Harbor Laboratory, 1989

12. Lichter P, Tang CC, Call K, Hermanson G, Evans GA, Hous- man D, Ward DC High resolution mapping of human chromosome 1 1 by in situ hybridization with cosmid clones. Science 247:64, 1990

13. Jorgensen AL, Bostock CJ, Bak AL: Chromosome-specific subfamilies within human alphoid repetitive DNA. J Mol Biol 187: 185, 1986

14. Waye JS, England SB, Willard H F Genomic organization of alpha satellite DNA on human chromosome 7: Evidence for 2 distinct alphoid domains on a single chromosome. Mol Cell Biol7:349, 1987

15. Weverick R, Willard H F Long-range organization of tandem array of alpha satellite DNA at the centromeres of human chromo- somes: High frequency array polymorphism and meiotic stability. Proc Natl Acad Sci USA 86:9394, I989

16. Bertelson CJ, Pogo AO, Chaudhuri A, Marsh WL, Redman

CM, Banerjee D, Symmans WA, Simon T, Frey D, Kunkel LM: Localization of the McLeod locus (XK) within Xp21 by deletion analysis. Am J Hum Genet 42:703, 1988

17. Bennett V: The membrane skeleton of human erythrocytes and its implications for more complex cells. Ann Rev Biochem 5 4 273, 1985

18. Anstee DJ, Spring FA: Red cell membrane glycoproteins with a broad tissue distribution. Transfus Med Rev 3:13, 1989

19. Devault A, Lazure C, Nault C, LeMoual H, Seidah NG, Chre- tien M, Kahn P, Powell J, Mallet J, Beaumont A, Roques B, Crine P, Boileau G: Amino acid sequence of rabbit kidney neutral endo- peptidase 24.1 1 (enkephalinase) deduced from a complementary DNA. EMBO J 6:1317, 1987

20. Malfroy G, Kuang W-J, Seeburg PH, Mason AJ, Schofield PR: Molecular cloning and amino acid sequence of human enkepha- linase (neutral endopeptidase). FEBS Lett 229:206, I988

2 1. Letarte M, Vera S, Tran R, Addis JBL, Onizuka RJ, Quack- enbush EJ, Jongeneel CV, McInnes, RR: Common acute lymphocytic leukemia antigen is identical to neutral endopeptidase. J Exp Med 168:1247, 1988

22. Shipp MA, Vijayaraghaven J, Schmidt EV, Masteller EL, DAdamio LD, Hersh LB, Reinherz E L Common acute lympho- blastic antigen (CALLA) is active neutral endopeptidase 24.1 1 (“en- kephalinase”): Direct evidence by cDNA transfected analysis. Proc Natl Acad Sci USA 86:297, 1989

23. Jongeneel CV, Bonvier J, Bairoch A: A unique signature iden- tifies a family of zinc-dependent metallopeptidases. FEBS Lett 242: 211, 1989

24. Wu Q, Lahti JM, Air GM, Burrows PD, Cooper MD: Molec- ular cloning of the murine BP-l/6C3 antigen: A member of the zinc- dependent metallopeptidase family. Proc Natl Acad Sci USA 87:993, 1990

25. Kenny AJ, O’Hara MJ, Gusterson BA: Cell-surface peptidase as modulators of growth and differentiation. Lancet 2:785, 1989

26. Redman CM, Lee S, Ten Bokkel Huinink D, Rabin BI, John- son CL, Oyen R, Marsh WL: Comparison of human and chimpanzee Kell blood group systems. Transfusion 29:486, 1989

27. Zelinski T, Kaita H, Gibson T, Coghlan G, Phillips S, Lewis M: Linkage between the Colton blood group locus and ASSPII on chromosome 7. Genomics 6:623, 1990

28. Coghlan G, Kaita H, Belcher E, Phillips S, Lewis M: Evidence for genetic linkage between the KEL and YT blood group loci. Vox Sang 57238, 1989

29. Spring FA, Anstee DJ: Evidence that the Yt blood group an- tigens are located on human erythrocyte acetylcholinesterase (AchE). Transfus Med 1:42, 1991 (abstr, suppl2)

30. Getman DK, Eubanks JH, Camp S, Evans GA, Taylor P: The human gene encoding acetylcholinesterase is located on the long arm of chromosome 7. Am J Hum Genet 5 1: 170, 1992

3 1. Spence MA, Falk CT, Neiswanger K, Field LL, Marazita ML, Allen FH, Siergovel RM, Roche AF, Crandall BF, Sparkes RS: Es- timating the recombination frequency for the PTC-Kell linkage. Hum Genet 678:183, 1984

32. Tsui LC, Farrall M: Report of the committee on the genetic constitution of chromosome 7. Cytogenet Cell Genet 58:337, 1991

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S Lee, ED Zambas, WL Marsh and CM Redman expression is restricted to erythroid cellsThe human Kell blood group gene maps to chromosome 7q33 and its 

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