GENOMICS

13, 803408

(19%)

A Radiation Hybrid Map of 18 Growth Factor, Growth Factor Receptor, Hormone Receptor, or Neurotransmitter Receptor Genes on the Distal Region of the Long Arm of Chromosome 5 J. A. WARRINGTON,* 5. K. BAILEY,* E. ARMsmoNG,t 0. APRELIKovA,t K. ALiTALo,t G. M. DOLGANOV,$ A. S. WILCOX,~ J. M. SIKELA,~ S. F. WOLFE, 11M. LOVETT,$ AND J. J. WASMUTH*,’ *Department of Biological Chemistry, University of California, Irvine, California 9277 7; t Cancer Biology Laboratory, Departments Virology and Pathology, University of Helsinki, Helsinki, Finland; SCenelabs, Inc., 505 Penobscot Drive, Redwood City, California 94063; §Department of Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado 80262; I/Genetics Institute, 87 Cambridge Park Drive, Cambridge, Massachusetts 02 740 Received

February

13, 1992;

The distal portion of the long arm of human chromosome 5 contains an impressive number of genes encoding growth factors, growth factor receptors, and hormone/neurotransmitter receptors. The order of and relative distance between 18 of these genes was determined by radiation hybrid mapping. There is only a single gap in a contiguous radiation map from 5q225q35. For this set of radiation hybrids, one map unit (centiray) corresponds to 20-50 kb of DNA. Close physical proximity for several pairs of loci was predicted by the map. Two sets of these were found to be contained in single YAC clones. The physical map produced by radiation hybrid mapping should prove useful in efforts to identify four disease genes that have been assigned to distal 5q by linkage studies. c ISSZ Academic Press,

Inc.

INTRODUCTION

The distal region of the long arm of human chromosome 5 (5q) has been shown to contain a number of growth factor, growth factor receptor, hormone receptor, and neurotransmitter receptor genes including IL3, IL4, IL5, CSF2 (GMCSF), CSFlR, ADRBB, FGFA, GRL, PDGFRB, GABRAl, DRDl, and ADRAl (Wasmuth et al., 1989; Sunahara et al., 1990; Yang-Feng et aZ., 1990). Previous work using radiation hybrid mapping in conjunction with a natural deletion mapping panel determined the order of and relative distance between 10 of these loci: IL3, IL4, IL5, CSFlR, ADRBB, FGFA, CD14, GRL, GABRAl, and DRDl (Warrington et al., 1991). CD14, which is a monocyte cell differentiation antigen, is a leucine-rich protein and its expression profile supports its inclusion as a receptor (Ferrer0 and Goyert, 1988). Eight additional genes, IL9, NKSFl (originally referred to as NKSFp40), IRFl, GLRl (originally re’ To whom

correspondence

should

be addressed.

revised

of

April 8, 1992

ferred to as GLUHl), GABRGB, FGFR4, FLT4, and EGRl, which encode growth factors or receptors and map to distal 5q, have been added to the radiation hybrid map of this region (Mock et al., 1990; Wolfe et al., 1991; Itoh et al., 1991; Puckett et al., 1991; Armstrong et al., 1992; Aprelikova et al., 1992; Sukhatme et al., 1988). Here we report the order of and relative distances between all 18 of these loci. Seven of these genes, IL9, NKSFl, IRFl, IL3, IL4, IL5, and FGFA, encode cytokines or cytokine regulatory factors. Nine of the genes, GLRl, GABRGB, FGFR4, FLT4, GABRAl, ADRB2, DRDl, GRL, and CSFlR, encode neurotransmitter, hormone, or growth factor receptors, and one of the genes, EGRl, encodes an early growth response gene. IL9, a member of the interleukin family, encodes a T-cell and mast cell growth factor (Hultner et al., 1990). NKSF, a heterodimeric cytokine, is composed of the subunits ~35 and p40 (Wolf et al., 1991). Segments of the NKSFl amino acid sequence show similarity to the cytokine binding domain of several human cytokine receptors including IL6, IL4, IL7, IL2, CGSFR, GMCSFR, and EPOR (Merberg et al., 1992). Interferon regulatory factor 1, IRFl, regulates a member of the cytokine family, type 1 interferon (IFNa, IFNP) via binding to elements of the IFN gene promoter as well as to the interferon response sequences of IFN inducible promoters (Miyamoto et al., 1988). GABRGB encodes a y-aminobutyric acid receptor subunit that interacts with the subunit GABRAl (Moss et al., 1991), and GLRl encodes the first human glutamate receptor cloned (Puckett et al., 1991). FGFR4, fibroblast growth factor receptor 4, is a member of the family of cell surface receptors binding fibroblast growth factor (Partanen et al., 1991). FLT4 is an fms-like tyrosine kinase receptor expressed in human placenta, lung, heart, and kidney (Aprelikova et al., 1992). Finally, EGRl encodes an early growth response gene, the mRNA levels of which increase during cardiac and neural cell differentiation (Sukhatme et al., 1988). Data from our previous map provided a framework that enabled us to easily place these additional genes on

803 All

Copyright 8 1992 rights of reproduction

O&38-7543/92 $5.00 by Academic Press, Inc. in any form reserved.

804

WARRINGTON

TABLE

1

Locus EGRl FGFR4 FLT4 GABRGS GLRl IL9 IRFl NKSFl

Primer CcAccTcTTAggTcAgATggAAg TccATggcAcAgATgcTgTAc CTgAgAgcTgTgAgAAggAg CAgcATccTcAggTAggAAg cgcccAgggAcAgcTgTAcTg gccTgTccTgcAAgcgTcTgg gATTcAgATAcTTATcAAccAc ATgggTTTTAcTgATATggTTc CATcccAAAcccTTcAgTgc AcTcTAcTcTcAgAgAcAcAgg CTAATgcAgAgATTTAgggc gTggTgTAAAgAcTgcATAg CTcTAggcAAgcAggAccT cATAccAAggcgcTcAcAc TgcAgTgTTcTgATAccAgTgc gggAAcTAgcATcTTgTTcTcc

Annealing temperature (“Cl

337

57

1000

56

540

62

104

55

249

63

127

60

650

66

124

61

the radiation hybrid map using the polymerase chain reaction (PCR). MATERIALS

AL

also computes 0, the estimated frequency of breakage (analogous to recombination frequency), and lod scores (logarithm of the likelihood ratio for linkage) (Cox et al.. 1990). The odds favoring one order of four markers over another was calculated by four-point analysis (Cox et al., 1990).

Primer Sequences, Product Sizes, and Annealing Temperatures

Product (bp)

ET

AND METHODS

Isolation and characterization of radiation hybrids. The isolation and characterization of the radiation hybrids have been described (Warrington et al., 1991). The isolation and characterization of the human-CHO cell hybrid, HHW 661, which is the irradiated parent of the radiation hybrids, has been described by Wasmuth et al. (1986). This cell line retains a derivative human chromosome 5 [der(5)t(4;5)(5qter -* 5p15.1::4p15.1)] as its only detectable human DNA. The nonirradiated Chinese hamster cell parent, UCW113, is an HPRT-deficient derivative of V-79 Chinese hamster lung (CHL) fibroblasts. Irradiation of the cell hybrid and fusion to the nonirradiated Chinese hamster cell parent were performed as previously described (Cirullo et al., 1983). Polymerase chain reaction. The presence or absence of each of the markers in the radiation hybrids was determined using the PCR. Each marker was tested separately; none were multiplexed. The PCR primer sets for IL9, IRFl, EGRl, GLR~, NKSFl, FLT4, FGFR4, and GABRGB were designed from published sequence data (Polymeropou10s et al., 1991; Maruyama et al., 1989; Sukhatme et al., 1988; Puckett et al., 1991; Wolfe et al., 1991; Aprelikova et al., 1992; Armstrong et al., 1992; Wilcox et al., 1992). The primer sources for DRDl, GABRAl, GRL, CD14, FGFA, ADRBZ, CSFlR, IL3, IL4, and IL5 have been described (Warrington et al., 1991). Each PCR was carried out in a total volume of 25 ~1 using 0.25 pg DNA in 67 mM Tris-HCl (pH 8.8), 6.7 mM MgCl,, 16.6 mM ammonium sulfate, 10 mM /3-mercaptoethanol, 1.25 mA4 each dNTP, 25 pmol each primer, and 1 unit Thermus aquaticus DNA polymerase. The initial denaturation was at 94°C for 4 min. The primer sequences, product sizes, and annealing temperatures are shown in Table 1. Radiation hybrid mapping. Radiation hybrid mapping was used to determine the order and the distance between the specific loci based on the cosegregation of human markers in somatic cell hybrids following irradiation, as described by Cox et al. (1990). The distances between marker pairs were computed using a two-point linkage analysis program (Cox et al., 1990) and are reported in centirays (CR). Because the RH map distances stem from the dose of irradiation used to fragment the chromosome, it is necessary to note the dosage used when reporting the distances, which in this case is 6500 rads. This program

RESULTS A set of 109 radiation hybrids containing fragments of 5q, which has been described elsewhere (Warrington et al., 1991), was screened by PCR with primer sets representing IL9, NKSFl, IRFl, GLRl, GABRG2, FGFRI, FLT4, and EGRl. Each of the markers was nonselectively retained in l&-21% of the 109 radiation hybrids containing human DNA. The retention frequencies of the newly mapped loci are IL9, 19%; NKSFl, 21%; IRFl, 15%; GLRl, 20%; GABRGS, 19%; FGFR4,20%; FLT4,17%; and EGRl, 18% and are comparable to the retention frequencies (16-28%) for the loci previously mapped with these hybrids (Warrington et al., 1991). RH map analysis was performed using the program of Cox et al. (1990). Distances between pairs of loci, twopoint distances, which are based on observed marker segregation, are reported in centirays, cRGsM,where 6500 rads indicates the dosage of X rays used in the irradiation of the hybrids. Table 2 summarizes the two-point linkage information and shows the estimated distances between pairwise combination of loci, CR,,,, as well as lod scores. Data are listed only for those marker pairs that had a lod score > 3.0. In addition, a panel of five cell hybrids that retain naturally occurring deletions of 5q helped to orient the new loci along the cytogenetic map (Fig. 1). Information acquired from the natural deletion panel compliments the RH mapping information. For example, both GABRGB and GABRAl are present in hybrid HHW 1138, whereas FGFR4 and DRDl are absent in HHW 1138. Linkage between DRDl and GABRA1 and between DRDl and FGFR4, but not between FGFR4 and either of the GABA receptor subunits, enabled us to place DRDl proximal to FGFR4. The order of these loci relative to those previously mapped was determined by arranging them so that the sum of the distances between adjacent markers were minimized. Comparisons of the relative likelihood of one order versus another, for any set of four markers, aided the process of ordering (Cox et al., 1990). As shown in Fig. 2, the predicted order of the loci in q22-q35 is IL5, IL4, IRFl/IL3, IL9, EGRl, CD14, FGFA/GRL, ADRBB, CSFlR, GLRl, NKSFl, GABRAl/GABRGB, FLT4/DRDl, FGFR4. Comparisons of the likelihood of one order versus another, for any set of four markers, aided the process of ordering. Odds comparing the likelihood of a given order versus the likelihood of the order in which a given pair is inverted identified pairs for which unequivocal order could not be determined (Fig. 2). RH mapping was unable to define order in regions that are very close together, for example, FGFA/GRL, IRFl/ IL3, and GABRAl/GABRGB. RH mapping was able to predict some orders with a significant ratio of likeli-

RH

MAP

OF

GROWTH

FACTORS

TABLE RH Map Analysis Number

Marker A GABRG2 NKSFB IL4 NKSFB IL3 CD14 ADRBZ FGFA FGFA IL3 CD14 GLRl GRL CD14 CD14 GLRl CD14 GLRl IL4 FGFR4 GLRl FGFA FGFA GLRl FLT4 IL9 ADRBB CSFlR FGFA FLT4 IL5 IL3 GLRl GLRl FLT4 FLT4 DRDl NKSFP IL5 IL9 GABRAl DRDl NKSF2 GRL GABRAl GABRG2 DRDl NKSFB CD14 GABRGX ADRB2

B GABRAl GABRAl IRFl GABRGB IRFl FGFA CSFlR ADRBB GRL IL4 EGRl CSFlR ADRBB EGRl GRL NKSFP ADRBB ADRB2 IL5 DRDl GABRAl EGRl CSFlR GABRGL GABRAl EGRl DRDl DRDl EGRl GABRGB IRFl IL5 FGFR4 DRDl DRDl CSFlR GABRAl FLT4 EGRl EGRl ADRB2 NKSFP ADRBP CSFlR CSFlR ADRBZ GABRGB CSFlR CSFlR CSFlR EGRl

++ 19 19 13 11 13 16 23 19 15 13 13 17 16 13 12 14 16 16 12 13 13 11 15 12 11 11 14 13 11 10 9 10 11 11 9 11 11 10 9 9 14 11 14 12 13 13 10 13 12 12 12

+0

2 4 4 3 2 5 2 6 3 6 2 2 6 6 6 3 4 7 6 I 10 6 8 6 8 12 11 10 7 8 7 8 8 I 5 9 10 9 9 7 9 I 6 7 6 10 7 6 6 16

of Hybrids of clones

AND

2 and Calculated

Distances

observed

-+ 80 76 17 76 78 77 68 71 76 76 79 71 71 77 76 72 70 69 74 66 73 75 67 74 73 75 66 66 73 74 74 75 68 70 71 68 69 70 76 76 66 67 64 67 66 67 70 64 67 67 67

2 2 1 2 2 5 4 8 3 6 3 10 11 5 6 7 12 12 6 7 8 4 11 7 9 I 6 7 6 8 6 8 8 9 9 14 9 7 I I 14 9 14 14 14 15 8 14 15 15 6

Note. Only those marker pairs with lod scores of 3 or greater are shown. marker A and marker B, +- indicates that marker A is retained and marker marker B is retained, and -- indicates that neither marker A nor marker B two markers; cRGsoo, the estimated map distance between two markers; the

hoods. For instance, the order for the markers IL9, EGRl, CD14, GRL had a ratio of likelihoods greater than 10,OOO:l (Fig. 3). The relationship between a cRGsoO and actual physical distance in kilobases of DNA for several loci on 5q is

805

RECEPTORS

Sum

s

RH map units (CR,,)

101 99 95 99 96 100 100 100 100 98 101 100 100 101 100 99 101 101 99 92 101 100 99 101 99 101 98 97 100 99 97 100 95 98 96 98 98 97 101 101 101 96 99 99 100 101 98 98 100 100 101

0.06 0.12 0.18 0.19 0.19 0.22 0.23 0.27 0.29 0.31 0.31 0.33 0.36 0.36 0.40 0.40 0.41 0.43 0.44 0.44 0.46 0.46 0.47 0.48 0.49 0.50 0.50 0.51 0.51 0.51 0.52 0.52 0.53 0.54 0.55 0.56 0.56 0.56 0.57 0.57 0.56 0.57 0.57 0.57 0.57 0.58 0.58 0.58 0.59 0.59 0.61

6 13 20 21 21 25 26 31 34 37 37 40 45 45 51 52 53 57 57 58 61 62 63 65 68 69 69 71 71 72 13 74 75 78 79 81 82 83 83 83 83 84 85 85 85 86 87 87 89 89 94

Lod score 17.79 15.31 10.66 12.46 10.63 11.22 12.90 10.79 9.36 8.13 8.33 8.75 7.96 7.23 6.18 6.64 6.99 6.48 5.70 5.77 5.45 4.97 5.46 5.01 4.50 4.55 4.71 4.28 4.20 4.00 3.77 4.04 3.92 3.75 3.18 3.44 3.45 3.34 3.32 3.32 3.87 3.35 3.74 3.49 3.48 3.64 3.06 3.35 3.22 3.22 3.08

For each pair, ++ indicates the number of hybrids retaining both B is not retained, -+ indicates that marker A is not retained and is retained. t? denotes the estimated frequency of breakage between lod score, a measure of the likelihood that two markers are linked.

being determined. The markers pairs IRFl and IL4, which are 20 CR apart on the RH map, are both present in a 400-kb YAC (D. Saltman, M. Lovett, unpublished results). This gives a distance correlation of approximately 20 kb per CR. The markers GABRAl and

806

WARRINGTON

ET

AL.

16.2

15.2 15.1

r-l

14 IS.3 IS2 19.1 12 1111 11.2

12 19.1 192 IS.2

14

I5

21

IL!3 EGR1 CD14 FGFA/ GRL ADRBP CSFl R GLRl NKSF2 GABRAIl GABRG2 FLT4i DRDl FGFR4

22 29.1 232

26 40

ias

31.1

-r

312

\

L

31.3

52

92

13 6

3s: 3s.s

72 79 /-56

34 [

95

FIG. 1. Radiation hybrid map of the distal portion of the long arm of human chromosome 5 aligned with the chromosome 5 natural deletion mapping panel. The deduced RH map is shown on the left with centiray distances separating markers. (*) No linkage. (-) The breakpoint represented in the natural deletion panel. (/) Indicates marker pairs whose order may be inverted. The cytogenetic regions to which sets of markers are assigned are indicated by lines extending to the brackets to the left of the idiogram. The idiogram depicts a normal chromosome 5. The bars depict the region of 5 retained in each hybrid cell line. The hybrid HHW 105 retains an intact chromosome 5 as its only human material. Five loci (IL5, IL4, IRFl, IL3, IL9) were present in all cell lines except HHW 1118 (SRO q22-q31.1). EGRl, CD14, FGFA, GRL, ADRBZR, CSFlR, GLRl, NKSFl, GABRAl, and GABRGZ were present in all six cell lines (SRO 5q31-5q33.2). FLT4, DRDl, and FGFR4 were absent in HHW 1138 but present in all other hybrids (5q33.3-5qter).

GABRGB, which are 6 CR apart on the RH map, are both in a 450-kb YAC, giving a distance correlation of 75 kb per CR (Wilcox et al., 1992). In fact, it was the prediction of close physical association suggested by the RH map that prompted screening of an IL4 YAC with IRFl and the screening of a GABRAl YAC with present

GABRGS. Alternatively, an estimate of the distance correlation based on a comparison of the physical distance from q31.2 to qter (approximately 3 X lo4 kb), a region which has a contiguous RH map (586 CR), provides an estimate of 51 kb per 1 CR. We are currently determining the exact distance between many other

RH

MAP

OF

GROWTH

FACTORS

AND

A ________ B _______ C _______-D

marker pairs on 5q to be able to more precisely calibrate the relationship between an RH map unit and kilobases of DNA and to determine how consistent this relationship is over the length of 5q.

IL9 Marker

DISCUSSION

The order of and relative distance between 18 growth factor, growth factor receptor, hormone receptor, or neurotransmitter receptor genes on the distal portion of 5q were determined by RH mapping. The presence or absence of markers in cell hybrids that retain naturally occurring 5q deletions also helped in ordering the loci. A combination of these methods enabled us to construct a map of these loci spanning a physical distance of approximately 35 million bp from 5q22 to 5q35. The clustering of growth factor, growth factor receptor, neurotransmitter receptor, and hormone receptor genes raises the interesting possibility that the distal portion of 5q contains other genes encoding novel growth factors or receptors that have arisen by duplication and divergence during evolution. Similar clustering of growth factor, growth factor receptor, or hormone receptor genes has been recognized in the mouse genome. Comparative mapping studies of syntenic groups have placed IL5, IL4, IL3, and ADAlR on mouse chromosome 11 and GRL, ADRBB, CSFlR, PDGFRB, and CD14 on

1~ T IL3 IL9 EGRl CD14 FGFA/ i GRL ADRB2 CSFl R GLRl NKSF2 GABRAil

5 x id:1

5x109 1 x lo!1 4x loa:1 4 x Id:1 224:l

I-

6 x lo":1

6x10:1

Ir

3 x lo':1 1 x 106:1 3x 1OB:l

807

RECEPTORS

FIG. 3. Four-point marker order (A) IL9, likelihood greater than of those four markers.

EGRl

CD14

GRL

Order

Odds

ABCD

1

BACD

10827

BCDA

14607

CBAD

312643

ABDC

569599

BADC

9o8002

ACBD

5 x 10’

BCAD

8 x 10’

ACDB

1 x 108

CABD

3 x 109

ADBC

4x109

BDAC

6 x 1013

analysis

(B) EGRl, 10,OOO:l

of IL9, EGRl, (C) CD14, when compared

CD14,

and GRL. The has a ratio of any permutation

(D) GRL with

mouse chromosome 18 (Davisson et al., 1990; Ferrer0 and Goyert, 1988). The RH map of 5q22-5q35 will aid in the identification of several disease genes that have been localized to this region by linkage studies including diastrophic dysplasia, Treacher Collins syndrome, an autosomal dominant form of limb girdle muscular dystrophy, and hereditary startle disease (hyperexplexia) (Hastbacka et al., 1991; Dixon et al., 1991; Jabs et al., 1991; Speer et al., 1992; Ryan et al., 1992). Polymorphic loci known to flank the disease genes can easily be placed on the RH map to identify loci that lie within the candidate region for each disease. Any newly isolated gene or DNA fragment thought to be near the region of interest can quickly be placed on the RH map without the need to identify polymorphisms. For purposes of quickly determining whether or not new genes or anonymous fragments of DNA are within or outside the candidate gene regions, this is very useful. If a DNA fragment in question clearly lies outside a region of interest, it can be excluded from further study. Thus, considerable time and effort to develop polymorphisms and place markers on linkage maps can be avoided, while loci within the region of interest can be focused on. ACKNOWLEDGMENTS

FIG. 2. Radiation hybrid map with the odds of the given order versus inverted order for adjacent pairs. The odds compare the likelihood of the given order versus the likelihood of the order in which a given pair is inverted. Four-point analysis was performed on each set of four markers, and the odds for any two middle markers were compared with the odds where the order of those markers was inverted. The odds for the flanking markers, IL5-IL4 and DRDl-FGFR4, were determined using the set of the four most proximal and distal markers, respectively, and inverting the positions of the two most flanking markers.

We thank Richard Montellano for technical assistance. J.A.W. was supported by Carcinogenesis Training Grant NCXT32CA09054-17. This work was supported in part by NIH Grant HG00320 to J.J.W. and NIH Grant HG00368 to M.L.

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