Am. J. Hum. Genet. 50:56-64, 1992

Mapping of 262 DNA Markers into 24 Intervals on HumanChromosome I IAkira Tanigami, * Takashi Tokino, * Shuya Takiguchi, * Masaki Mori, * Tom Glaser,t J. W. Park,1Carol Jones,$ and Yusuke Nakamura*

*Division of Biochemistry, Cancer Institute, Tokyo; tCenter for Cancer Research, Massachusetts Institute of Technology, Cambridge; and tEleanorRoosevelt Institute, Denver

Summary

We have extended our mapping effort on human chromosome 11 to encompass a total of 262 DNA markers,which have been mapped into 24 intervals on chromosome 11; 123 of the markers reveal RFLPs. Theseclones are scattered throughout the chromosome, although some clustering occurs in R-positive bands (p15.1,p11.2, q13, and q23.3). Fifty-two of the markers were found to contain DNA sequences conserved inChinese hamster, and some of these 52 also cross-hybridized with DNA from other mammals and/or chicken.As the length of chromosome 11 is estimated at nearly 130 cM, the average distance between RFLP markersis roughly 1 cM. The large panel of DNA markers on our map should contribute to investigations of hereditarydiseases on this chromosome, and it will also provide reagents for constructing either fine-scale linkage andphysical maps or contig maps of cosmids or yeast artificial chromosomes.

Introduction

Human chromosome 11 contains genes responsiblefor several genetic diseases, including Beckwith-Wiedemann syndrome on pter-*15.4 (Ping et al.1989), familial atopy on ql2-13 (Cookson et al.1989), multiple endocrine neoplasia type 1 on q13(Larsson et al. 1988; Nakamura et al. 1989; Bale etal. 1991), mental illness on q21 (Clair et al. 1990),ataxia telangiectasia on q22- '23 (Gatti et al. 1988),tuberous sclerosis on q23 (Smith et al. 1990), andsome hematopoietic diseases (Tsujimoto et al. 1985;Griffin et al. 1986). Aberrations in chromosome 11have also been reported in some types of tumors (Scra-ble et al. 1987; Hopman et al. 1991). Furthermore,amplification of the region around the hst-1 and int-2genes at qi3 has been observed in several types ofcancers: esophageal carcinoma (Tsuda et al. 1989),hepatocellular carcinoma (Hatada et al. 1988), breastcancer (Zhou et al. 1988), melanoma (Adelaide et al.

Received July 10, 1991; revision received September 4, 1991.Address for correspondence and reprints: Yusuke Nakamura,

M.D., Ph.D., Division of Biochemistry, Cancer Institute. 1-37-1Kami-Ikebukuro, Toshima-ku. Tokyo 170, Japan.X 1992 by The American Society of Human Genetics. All rights reserved.0002-9297/92/5001-0006$02.00

1988), and squamous-cell carcinoma of the head andneck (Somers et al. 1990). Deletions of constitutionalmaterial from the short arm of chromosome 11, de-tected, by RFLP markers, as loss of heterozygosity(LOH), have been detected in breast cancer (Theilletet al. 1986; Ali et al. 1987; Mackay et al. 1988),hepatocellular carcinoma (Wang and Rogler 1988;Fujimori et al. 1991), and bladder cancer (Fearon etal. 1985; Tsai et al. 1990). The observations citedabove have implied that several tumor-suppressorgenes exist on chromosome 11. Construction of ahigh-density map ofDNA markers represents a crucialearly stage in the process of identifying these genes.The map reported here will be a useful guidepost forthe eventual construction of a physical map of overlap-ping DNA fragments (contigs) from clones of yeastartificial chromosomes (YACs) or cosmids.

Material and Methods

Construction of Genomic LibraryWe constructed a cosmid library from a Chinese

hamster x human hybrid cell line which containedhuman chromosome 11 as its only human component.Four thousand clones containing human DNA insertswere identified by hybridization of colonies with la-

56

Mapping of Markers on Chromosome 11

beled total human DNA; this number of cosmid clonescorresponded to one haploid-genome equivalent. DNAsamples from 380 of these clones were prepared eitherby the cosmid minilysate procedure (Sambrook et al.1989) or by means of an automated DNA preparationmachine, PI-100 (Kurabo, Tokyo), and were exam-ined for RFLPs among six unrelated individuals asdescribed in our previous report (Tokino et al. 1991).

Somatic Hybrid Cell Lines

To map the DNA markers on chromosome 11, weused a panel of somatic hybrid cell lines which eachcontained a part of this human chromosome. The pan-els are composed of 15 cell lines: R304-A2, P3-27A,R229-3, and R28-4D, and 11 of theJ1 series (J1-1,-44, -35, -8, -10, -4B, -1, -7, -9, -23, and -24) reportedby Glaser et al. (1989). Chromosome 11 breakpointsin each hybrid are indicated in figure 1. These deletionpanels permit division of chromosome 11 into 24 in-tervals (A-X on fig. 1).

Cross-Species HybridizationTo define well-conserved sequences, genomic DNAs

from pig, mouse, rat, and chicken were digested withEcoRI and were transferred to nylon membrane afterelectrophoresis in an agarose gel. Hybridization withradiolabeled human chromosome 11 probes was donein 10% SDS and 7% polyethylene glycol (PEG) over-night at 65C; the filters were then washed in 0.1 xSSC (15 mM NaCl, 1.5 mM sodium citrate) and 0.1%SDS at 500C. Autoradiograms (KODAK XAR films)were exposed at - 70'C for 2 d, with intensifyingscreens (Dupont Cronex Lightning Plus).

Results

Of 380 cosmid clones tested for RFLP, 123 (32.4%)revealed polymorphisms with one or more enzymes.For example, cCI11-506 (Dl1S589) identified poly-morphisms with MspI, TaqI, and BglII (fig. 1, arrow-heads). The MspI RFLP, the lower TaqI RFLP, and

cCIII-506 (D11S589)

M123456

(kb)

4.4a32.32.1

11

4-

Msp I Taq I BgI II

Figure I Autoradiogram of Southern blots hybridized with cCI11-506 (Dl 1S589) used as a probe. Lymphoblastoid cell line DNAsderived from six unrelated Caucasians were digested with the restriction enzymes indicated. Arrowheads indicate polymorphic bands. LaneM of the MspI digest contains a size marker.

57

Table I

Sixty-One New RFLP Markers on Chromosome II

ALLELE 1 ALLELE 2

CLONE NAME(locus symbol) ENZYME

cCI11-363 (D11S546) ... TaqIcCI11-368 (D11S547) ... RsaIcCI11-374 (D11S548) ... TaqIcCI11-377 (D11S549) ... PvuIIcCI11-378 (D11S550) ... PstIcCI11-385 (D11S551) ... MspIcCI11-386 (D11S552) ... PvuIIcCI11-387 (D11S553) TaqI

cCI11-388 (D11S554) ... MspIcCI11-394 (D11S555) ... PvuIIcCI11-396 (D11S556) ... PstIcCI11-400 (D11S557) ... MspIcCIll-404 (D11S558) MspI

cCI11-410 (D11S559) ... PvuIIcCI11-411 (D11S560) ... RsaIcCI11-414 (D11S561) ... TaqIcCI11-415 (D11S562) TaqI

cCI11-417 (D11S563) ... TaqIcCI11-419 (D11S564) MspI

cCI11-422 (D11S565) ... BglIIcCI11-425 (D11lS566) . .. MspIcCI11-431 (D11S567) ... RsaIcCI11-432 (D11S568) ... PvuIIcCI11-434 (D11S569) ... TaqIcCI11-438 (D11S570) ... TaqIcCI11-439 (D11S571) ... TaqIcCI11-440 (D11S572) ... PvuIIcCI11-442 (D11S573) ... TaqIcCI11-444 (D11S574) ... MspIcCIll-445 (D11S575) BglII

cCI11-446 (D11S576) ... TaqIcCI11-447 (D11S577) ... MspI

PstIPvuII

cCIl1-451 (D11S578) PvuII

cCI11-453 (D11S579) ... MspIcCI11-460 (D11S580) ... BglII

PvuIIcCI11-465 (D11S581) MspI

BglIIcCI11-468 (D11S582) ... RsaIcCI11-470 (D11S583) ... BglIIcCI11-471 (D11S584) ... MspIcCI11-473 (D11S585) ... TaqIcCI11-481 (D11S586) ... BglII

PstIcCI11-484 (D11S587) ... PvuIIcCI11-502 (D11S588) ... TaqI

PvuIIcCI11-506 (D11S589) ... MspI

TaqITaqIBglII

Size(kb) Frequency

5.64.15.73.38.03.24.42.93.22.17.44.24.44.43.35.14.43.34.97.53.90.83.07.92.45.12.33.53.96.37.74.93.93.43.25.44.92.14.74.32.14.45.06.27.84.24.5

13.73.43.74.43.35.3

.42

.67

.17

.17

.70

.33

.75

.50

.25

.67

.10

.67

.42

.67

.58

.33

.50

.75

.67

.67

.33

.70

.40

.67

.25

.17

.33

.50

.75

.67

.33

.25

.60

.25

.50

.75

.67

.17

.42

.42

.33

.50

.25

.50

.25

.30

.50

.75

.50

.75

.50

.75

.25

Size(kb)

4.93.53.03.27.42.24.22.21.61.57.03.53.83.13.23.04.03.23.26.62.90.72.86.91.73.72.13.22.95.47.24.53.82.92.24.54.71.94.43.82.03.82.63.17.63.42.6

8.4 + 5.32.33.34.03.05.0

Frequency LOCATION

.58 ql3.1-13.3

.33 q13.3-21

.83 q23.2- 23.3

.83 pll.2-12

.30 p15.1

.67 pl5.5

.25 q21- 22

.50 q13.1-13.3

.75 pl 1.2 >12

.33 q23.2-23.3

.90 p1l.2

.33 q13.3-21

.58 q21-22

.33 ql3.1->13.3

.42 q21-22

.67 q21-22

.50 q24-25

.25 q23.2-23.3

.33 plS.l

.33 pl1 1.212

.67 q21-22

.30 q13.3-21

.60 q13.3-21

.33 p15.1

.75 q23.2-23.3

.83 q21-22

.67 plS.2-1S.3

.50 q23.2-23.3

.25 plS.l

.33 ql3.1-13.3

.67 pl5.5

.75 q23.2- 23.3

.40

.75

.50 pl 1.2 12

.25 q13.3-21

.33 q23.2-23.3

.83

.58 q23.2-23.3

.58

.67 pl3-14

.50 q21-22

.75 q21- 22

.50 ql3.1 -13.3

.75 q21-22

.70

.50 plS.l

.25 p15.1

.50

.25 q21- 22

.50

.25

.75

(continued)

Mapping of Markers on Chromosome 11

Table I (continued)

ALLELE 1 ALLELE 2

CLONE NAME Size Size(locus symbol) ENZYME (kb) Frequency (kb) Frequency LOCATION

cC11-508 (D11S590) ... BglI 3.8 .75 3.6 .25 q21-22cCI11-512 (D11SS91) ... TaqI 3.3 .33 3.1 .67 q13.3-21

PstI 5.5 .30 4.7 .70cC111-514 (D11S592) ... MspI 5.7 .67 3.1 .33 pl4-15.1

TaqI 3.6 .17 3.3 .83cC111-517 (D11S593) ... TaqI 4.6 .58 4.3 .42 q24-25cC111-519 (D11S594) ..........Pvull 3.7 .75 3.6 .25 q12 13.1cC111-524 (D11S595) ... BglII 4.6 .50 4.1 .50 q13.1-13.3cC111-529 (D11S596) ... TaqI 4.0 .42 3.6 .58 p14-15.1cC111-530 (D11S597) ... TaqI 5.9 .67 3.3 .33 q21-22cC111-539 (D11S598) ... RsaI 4.2 .50 2.7 .50 q24-25cCI11-558 (D11S599) ... TaqI 3.0 .83 2.6 .17 q13.1-13.3cC111-560 (D11S600) ... PstI 7.0 .80 6.6 .20 p15.1cCI11-565 (DllS601)..........MspI 2.1 .50 1.4 .50 plS.4-15.5cC111-568 (D11S602) ... PvuII 3.7 .25 3.3 .75 p15.1cC11l-569 (D11S603)... MspI 4.4 .42 2.8 .58 pl1.2-12cC111-574 (D11S604) ... TaqI 5.0 .42 3.3 .58 p15.1cCI11-588 (D11S605) ... PstI 4.3 .60 2.3 .40 pll.2-12cCI11-593 (D11S606) ... MspI 3.7 .50 2.2 .50 q24-25

NOTE. -Markers shown exclude those previously reported by Tokino et al. (1991).a Estimated from typing of 6-12 unrelated individuals.b Localized by hybrid cell panel.

the BglII RFLP correlate with each other, which maysuggest an insertion/deletion polymorphism, and theupper TaqI RFLP is independent of other RFLP sys-

tems. Several clones also revealed two RFLP systemswith one enzyme. Table 1 characterizes the RFLP sys-

tems that have not been reported elsewhere (Tokinoet al. 1991 ). Thirty-five of the 123 polymorphic clones(eight in the present series) revealed RFLPs with twoor more enzymes (two-system RFLP, 28; three-systemRFLP, 6; four-system RFLP, 1), and four were theVNTR markers (Nakamura et al. 1987) reported else-where (Tokino et al. 1991). Of 162 RFLP systemspresent in these cosmids, more than halfwere detectedwith MspI or TaqI. Table 2 shows the number ofRFLP systems detected with each enzyme.

Figure 2 indicates the localization of 262 DNAmarkers, including 139 nonpolymorphic clones, intoone of 24 intervals on chromosome 11, by hybridiza-tion experiments in each of the somatic hybrid celllines. Ninety-one (44 of them were RFLP markers)were localized on the short arm; 170 clones (79RFLPs) were on the long arm; and one was mapped

to the centromeric region. No clone at region J wasobtained. The DNA markers were otherwise scatteredthroughout chromosome 11, although some cluster-ing was observed on R-positive bands, especiallyp15. 1, p 1.2, q13, and q23.3. In physical length, esti-mated cytogenetically, q13.1--13.3 and q23.3 ac-count for approximately 15% of the total length of

Table 2

Number of Clones Revealing Polymorphism withEach Enzyme Testeda

Enzyme (restriction site) No.

TaqI (TCGA)............................. 49MspI(CCGG) ............................. 39PvuII (CAGCTG)............................. 23PstI (CTGCAG)............................. 21RsaI(GTAC) ............................. 17Bg1II (AGATCT) ............................. 13

Total for all systems ......................... 162

a Includes all non-VNTR RFLP markers reported by Tokino etal. (1991).

59

Somat ic llybrid Ccl I

15.5

15. 4

15.3

15.2

15.1~~~~~

14

13

12

11.2

11.111.1I1

12

13.113.213.313.413.5

14.114.2

14.3

2122.122.222.3

23.123.2

23.3

24

25

U I

Pane l

A: E

RFLP markers

J ,385,446*Non-fFLP markers

W55B :37l .253,289,565 395,469,479

:C: 516,546: :__ ____489E :1*t280-.,440 421,583,598

F:14.35.38.310.314.378.419,434, 428 449,444.484,502.560*q.568,574 .8.3

CG:242*.,514,529 370.397*.443*,456.461.491,552 564

H: 536

I :25.468 376.393- .458.464,475,482.570,585,604K: s5o

._L: 511*11: 474N 34052297.2850*.260.282.312*.3175 256.321.360.391*.408,448,457.493.540,606345,377.388,422*.451 .569*, 5880 :396 496P: 382

494

R :202.222.519 518.521,542,557*

S : ] .8,44.219*,231,247*,254* 207.228.234.261.355,356.364*.366,367.369.398259*.283,288*,297.318,319.363* 426*.429*,454.462.466.467.501,504,505*.515387,410*. 445,473*.524,558* 532*.534.545*.559.572*.580,591,605.608.745*

T:270.368a.400.431.432: .453.512 17.279.352.362.402.416.486.507*.566

U:131^.3745.218,273* 325.357* 372.384.405,420.430,433.485386.404.411.414,425.439,470 535.543.556.561.567.607.610471. 481. 506,508. 530

V:1:.204.303 276,375,483*.526,544.551

V:2,6,g. 18*.31,43*.220.268.299304.320.374,394,417.438*.442 3,26,301,313.361,373,379,390,406.407.427417.460,465 450,463,480,488*,497.525*.547*.571,576

X:36.465.2455, M .415*,5175394593 365.371.455,498.503.554*.578

11Figure 2 Mapping of 123 RFLP markers and 139 nonpolymorphic DNA markers on chromosome 11. Boldface vertical lines indicatethe portion of the human chromosome that each hybrid cell line contains. Boxes indicate the four VNTR markers, and asterisks indicateclones that contain one or more sequences hybridizing to Chinese hamster DNA under stringent hybridization conditions. The hybrid cellpanel divides chromosome 11 into 24 intervals, A-X. Region J, which separates region I into two subregions, is indicated by horizontallines within the "I" segment. None of our probes hybridized in region J. (All DNA probes will be available freely through the JapaneseCancer Research Resources Bank (JCRB), 10-35, Kamiosaki 2-chome, Shinagawa, Tokyo 141, Japan.)

Mapping of Markers on Chromosome 11

chromosome 11. However, more than one-third (90)of our clones were mapped to these two regions.

Several clones distinguished breakpoints in some

hybrid cell lines that we had not been able to separate

with theDNA markers reported previously. For exam-ple, cCI11-590 (D1 1S740) was mapped between twobreakpoints ofJ1-9 and J1-24; cCI1 1-511 (D1 1S702)was between those ofJ1-24 and J1-10; and cCI1 1-396(D1 1S556) and 496 (D1 1S694) were between those ofJ1-8 and J1-7.

Fifty-two (20%) of the 262 mapped clones con-

tained DNA sequences that were conserved well inChinese hamster. Nearly half (25) of them were local-ized on bands at q13.1-13.3 (region S) or q23 (re-gions V and W). It is interesting that 17 (one-third) ofthe 51 clones on qi 3.1 13.3 contained conservedsequences. However, only 3 of 33 clones on q21->22(region U) showed cross-hybridization with DNAfrom Chinese hamster. Seventeen clones, mainly on

q13, were further investigated to determine howwidely they were conserved (table 3). All 17 containedsequences that were conserved in pig, mouse, and rat;

two clones showed cross-hybridization with DNAfrom chicken, as well as with DNA from mammals,as shown in figure 3. In particular, all eight EcoRIfragments of cCI1 1-410 (D1 1S559) were conserved inthree kinds of mammalian DNA and showed pluralbands in one species.

Discussion

The 123 RFLP markers on chromosome 11 that are

documented here and in our previous report (Tokinoet al. 1991) correspond to nearly one RFLP markerper 1-cM interval. More than half of the total of 162RFLP systems were detected with MspI or TaqI. Barkeret al. (1984) noticed that methylated deoxycytidinesat CpG frequently underwent transition to TpG. Re-striction sites of both MspI and TaqI carry one set ofCpG (table 2); those of PvuII and PstI each containone set of TpG and one set of CpA, which is comple-mentary to TpG.

Several markers detected RFLPs with more than oneenzyme and will be more informative. For example,cCI1 1-460, -502, and -514 showed 67% heterozygos-ity by using multiple enzymes among 12 individuals(data not shown). However, some of them, such as

cCI1 1-506, did not increase informativeness by multi-ple enzymes, because of complete disequilibrium.We have now mapped a total of 262 cosmid clones

into 24 intervals, separated by somatic hybrid cell lines

Table 3

Conservation of Human Chromosome I ISequences in Four species

CONSERVATION OF HUMANCHROMOSOME 11 SEQUENCES INa

CLONE NAME(locus symbol) Pig Mouse Rat Chicken

cCI11-18 (D11S434) .... +++ +++ + + +cC111-219 (D11S449)... + + +cCI11-247 (D11S457)... + + + + + +cCI11-254 (D11S460)... +++ + + + + +cCI11-259 (D11S461)... + + + + +cCI11-288 (D11S469)... + + + +cCI11-363 (D11S546)... + + +++ + + +cCI11-364 (D11S633)... + + + + +cCI11-410 (D11S559)... +++ +++ + + +cCI11-426 (D11S658)... +++ +++ + + +cC111-429 (D11S661)... + + + + + + +cCI11-473 (D115S85)... + + + + + +cC111-532 (D11S710)... + + +++ + + +cCI11-545 (D11S718)... + + + + + + +cC11-558 (D11S599)... +++ + + + + +cCI11-572 (D11S734)... + + + + +cCI11-745 (D11S749)... + + + + + + +

a + + + = Strongly hybridized; + + = moderately hybridized;and + = weakly hybridized.

which contain parts of chromosome 11. These cloneswill be useful guideposts for construction of either ahigh-resolution physical map or a contig map ofYACs. The density of clones in two regions (51 atq13.1--13.3 and 39 at q23.3) suggests that they aredistributed every 200-300 kb; these clones ought tobe valuable for analyzing these regions in particular.The clones are relatively evenly distributed, al-

though some clustering on R-positive bands was ob-served. A similar bias has been reported by others(Gardiner et al. 1990; Yamakawa et al. 1991). Thereason for this bias is still unclear; it might be relatedto staining or to conformation of the chromosomeand/or the methylation pattern of DNA. This ques-tion remains to be answered when comprehension ofthe human genome is complete.To identify genomic regions containing expressed

sequences is one of the important goals of the HumanGenome Project. Searching well-conserved sequencesin other species is an established method for obtainingessential housekeeping genes. Using that strategy, weidentified 52 clones that contained conserved se-quences. Nearly half of them were located on ql3 andq23, where genes involved in many disorders havebeen mapped by linkage analysis. Isolating genes ei-

61

Tanigami et al.

H P M R C...,,:I

1.9kb 1.Okb 0.5kb

cC111-410 (D11S559)

4PMRr- HPMRC I

> 10kb 6kb 3.3kb 0.3kb

cCIII-558 (D11S599)Figure 3 Conservation of chromosome 11 sequences. Cosmids cCI11-410 and -558 were digested with EcoRI, and each fragmentwas hybridized with DNA from five species: lane H, human; lane P, pig; lane M, mouse; lane R, rat; and lane C, chicken. The size of eachfragment is shown at the bottom of the autoradiogram.

ther by screening cDNA libraries with these genomiccosmid clones or by means of the exon-trappingmethod (Duyk et al. 1990) may facilitate studies on

these genetic diseases.In addition, the RFLP markers on chromosome 11

will contribute to investigations of molecular oncol-ogy. LOH, which results in dysfunction of a tumor-suppressor gene, has been observed on the short armof chromosome 11 in tumors of several types. Thereported frequencies of LOH were 46% (6/13; Fuji-mori et al. 1991) and 36% (5/14; Wang et al. 1988)in hepatocellular carcinoma, 42% (5/12) in bladdercarcinoma (Fearon et al. 1985), and 27% (14/51;Theillet et al. 1986) and 22% (14/65; Mackay et al.

1988) in breast cancer. A dense map containing a largenumber ofRFLP markers will be useful both for defin-ing the commonly deleted regions where tumor-suppressor genes exist and for detecting other aberra-tions in tumors.

AcknowledgmentsWe acknowledge with thanks technical assistance from

Kiyoshi Noguchi and secretarial assistance from KazuyoOda. This work was supported in part by grants from theJapanese Science Technology Agency of the Japanese Minis-ter of Education and Culture and from the Cancer Leagueof Colorado.

62

Mapping of Markers on Chromosome 11 63

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