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Home , Chromosome 19, Ferritin light chain, Gene

J Med Genet: first published as 10.1136/jmg.23.1.2 on 1 February 1986. Downloaded from Review article

Journal of Medical 1986, 23, 2-10

Gene mapping and 19

D J SHAW, J D BROOK, A L MEREDITH, H G HARLEY, M SARFARAZI, AND P S HARPER From the Section of Medical Genetics, University of Wales College of , Heath Park, Cardiff CF4 4XN.

SUMMARY is currently the most fully mapped of the smaller , with about 40 loci assigned to it (HGM8). Major inherited disorders on this chromosome include and familial hypercholesterolaemia. Other loci include five blood groups, a cluster of , and the receptors for and polio . A number of cloned genes and random DNA sequences identify polymorphisms which, together with blood group and other polymorphisms, have been used to establish a framework for ordering the loci and estimating genetic distances. lines allow loci to be assigned to one of eight different regions and a detailed genetic map of the chromosome will be possible in the near future. copyright.

Chromosome 19 is currently the best mapped of the suggested, though not conclusively, linkage with Lu smaller chromosomes, with more than 30 and this was subsequently confirmed by the studies distinct loci assigned to it, quite apart from of Renwick et at6 and Harper et al. 7Thus, by 1972, a anonymous DNA fragments. It also has the longest well defined group of linked loci had been identi- mapping history of any , although this has fied, containing a major and only become apparent in the past four years, with showing a clear sex difference in recombination http://jmg.bmj.com/ the assignment of an already well established rate. The data had even been analysed by a linkage group to the chromosome. For both these multipoint computer programme to give most likely reasons, and on account of the important diseases order. involving it, chromosome 19 can be seen as a Despite all these advances, the linkage group paradigm for the mapping of the human . remained unassigned for a further 10 years, until The first detected in man was that linkage was shown for both Lu and Se with the reported between the Lutheran and Lewis blood (C3). This extended the groups by Mohr in 1951.' 2 Although this was later linkage group significantly, since C3 was already on September 27, 2021 by guest. Protected reinterpreted as linkage between Lutheran and the known to be linked to the disorder familial Secretor , Lewis was subsequently shown to hypercholesterolaemia.9 Even more importantly, it form part of this linkage group.- provided a chromosomal assignment for the entire As early as 1965, these loci revealed another group, since hybrid cell studies had localised the C3 fundamental aspect of genetic linkage when Cook4 gene to chromosome 19.1) Thus, the early work on showed a marked sex difference in the Lu-Se what are now regarded as 'classical' chromosome 19 recombination rate, with female recombination markers was carried out in complete ignorance of twice that seen in males. the chromosomal localisation. An additional 'first' was the localisation of a serious autosomal genetic disorder to this linkage Inherited disorders and other major loci (table 1) group. Mohr's original work included data on myotonic dystrophy, using Danish families previous- MYOTONIC DYSTROPHY ly studied and reported by Thomasen. The data As already mentioned, this was the first human autosomal disorder for which genetic linkage to Received for publication 17 October 1985. Accepted for publication 24 Octobecr 1985. another marker was demonstrated. Since no basic 2 J Med Genet: first published as 10.1136/jmg.23.1.2 on 1 February 1986. Downloaded from

Gene mapping and chromosome 19 3

TABLE 1 Major genetic loci on chromosome 19. relationships with other diseases or markers on the chromosome. Polymorphic Genetic disorders Myotonic dystrophy (DM) This requires a brief mention as a disorder thought Familial hypercholesterolaemia (FHC) + Mannosidosis (a mannosidase) to be on chromosome 19 that has now been excluded. Close linkage with myotonic dystrophy Blood groups Lutheran (Lu) + was considered possible on the basis of coinheri- Lewis (Le) + tance of the disease in two kindreds,17 18 with a total Secretor (Se) + H antigen lod score exceeding 3. However, study of neuro- Landsteiner-Wiener (LW) + fibromatosis families with polymorphisms known to and be linked to myotonic dystrophy (Se, C3, Peptidase D (PEPD) + APOC2) has given such strongly and uniformly Glucose isomerase (GPI) negative results'9 that other mechanisms are re- Lysosomal DNAse Creatine , muscle type (KMM) quired to explain the association. Phosphoglycerate kinase 2 (PGK2) Other FAMILIAL HYPERCHOLESTEROLAEMIA (FHC) Complement C3 This important disorder, one of the major identifi- (INSR) heart disease, LDL receptor (LDLR) able genetic causes of early coronary (APOE) follows autosomal dominant inheritance with occa- Apolipoprotein Cl (APOCI) sional severely affected homozygotes recorded. Apolipoprotein C2 (APOC2) Chorionic gonadotrophin. beta subunit (CGB) Family studies have shown definite though loose Luteinising hormone, beta subunit (LHB) linkage between this condition and C3.'° Since chain (FTL) results for other markers in the linkage group, such as Se and Lu, have been negative, this suggested that the FHC locus might be on the opposite side of copyright. protein or cellular defect is yet known for the C3 to the other markers. condition, its localisation has remained dependent Studies on familial hypercholesterolaemia (FHC) on family studies, a major drawback for a relatively have been greatly helped by the identification of uncommon disorder. The linkage with Se, Le, and defects in the low density lipoprotein (LDLR) Lu, though fully established, remains rather uncer- receptor as the cause.21 The gene for this receptor tain as regards precise distance and order of loci, has recently been cloned,22 and this has allowed largely because they are not expressed in cultured more detailed studies to be carried out on both the http://jmg.bmj.com/ cells, show , and are not as polymorphic physical localisation in cell lines and on the linkage as is desirable. The clinical application of these relationships. These show the LDL receptor to be markers in prediction has been correspondingly on the short arm (p13.2-p13-1).23 The question as limited, even though Se is detectable prenatally.' 12 to whether the locus is distal or proximal to the C3 Hopes that the C3 linkage might be more useful in locus remains uncertain, with linkage data from this respect were raised by the discovery of a C3 FHC families favouring the former,24 but hybrid cell

gene probe showing a number of polymorphisms,'3 lines suggesting that it is proximal.25 on September 27, 2021 by guest. Protected but while this locus shows moderately close linkage with myotonic dystrophy in male meioses, there is E, Cl, and C2 frequent recombination in females. The precise localisation of the myotonic dystrophy gene has re- It is now known that a group of at least three loci quired the development of additional DNA probes determining apolipoproteins exists on chromosome as described more fully below. 19, quite separate from the locus for familial hypercholesterolaemia. Apolipoprotein E (APOE) MANNOSIDOSIS shows a protein which was found to This rare lysosomal storage disease, due to deficien- be linked to C3 by family studies.26 The APOC2 cy of the a-mannosidase was localised to gene has been cloned27 and also shows polymorph- chromosome 19 by means of rodent-human cell isms which suggest close linkage with APOE28 29. hybrid studies on this enzyme. 14 Subsequent work neither are measurably linked to FHC or the LDL has shown the locus to be in the central region of the receptor. The original reports showed no recom- chromosome (pI3-*q13),'5 16 but since the enzyme bination between APOE and APOC2, but recom- is not polymorphic and no specific gene probe has binants have now been detected both with the yet been isolated, nothing is known about its linkage APOC2 probe3" and in a kindred with J Med Genet: first published as 10.1136/jmg.23.1.2 on 1 February 1986. Downloaded from

4 D J Shiaw, J D Brook, A L Meredith, H G Harley, M Sarfarazi, and P S Harper

APOC2 deficiency,3' so the loci may be around been cloned and localised to the long arm of 3 cM apart. Gene probes for both APOE and chromosome 19.4' Among the non-enzymatic pro- APOCI also exist, but currently show no poiy- teins is the B subunit of chorionic gonadotrophin morphismns. However, direct molecular studies have and luteinising hormone4" (the gene has been cloned shown the two D)NA sequences to be only about but no morphisms detected) and the ferritin 15 kb apart.32 light chain4 (the heavy chain is separately located Both APOC2 and APOE are now known to be on ). closely linked to myotonic dystrophy. Shaw et a!33 An important gene recently characterised and showed a distance of 4 cM between DM and assigned to chromosome 19 is that for the insulin APOC2, with a lod score of 7.8, and this has been receptor.48 This gene is located relatively distally on 35 confirmed by two other groups,34 bringing the the short arm and shows polymorphisms with to total lod score to over 20. APOE has been shown several restriction enzymes. Its relationship to diffe- have around 10% recombination with myotonic rent forms of diabetes has yet to be defined. It might dystrophy in a large French-Canadian kindred.3" also have been considered as a 'candidate gene' for myotonic dystrophy, in which hyperinsulinism is a Blood group loci consistent finding, but the different regional loca- lisation and the occurrence of recombination be- The blood groups that form a linkage group on tween the loci in families rule this out (D J Shaw et chromosome 19 have been the subject of extensive al, unpublished data). studies over many years, though there are some doubts as to the interpretation of some of the early surface receptors (table 2) data. In addition to Secretor, Lewis, and Lutheran, Cell there is also the 'H' locus determining ABO Several cell surface receptors are coded for by genes specificities, as well as the newly recognised on chromosome 19; those already mentioned in- Landsteiner-Wiener (LW) group, 37 giving a total of clude the low density lipoprotein receptor (LDLR)copyright. loci. To what extent their coexistence on five and the insulin receptor (INSR). The receptor for chromosome 19 reflects functional or evolutionary poliovirus is located on chromosome 19,49 as are the factors is not clear at present. Until the underlying baboon virus M75" and RD114 virus receptors.5' genes are cloned it will not be easy to determine are at three monoclonal their precise physical distances and ordering. There least which have been raised to cell surface antigens Enzyme and other protein loci encoded by chromosome 19.52 53 These loci, mostly less well defined than those discussed above, may http://jmg.bmj.com/ The importance of the complement C3 locus, which well prove to be of considerable functional import- shows polymorphisms at both the protein and the ance, but their relationships are as yet not well DNA level, in mapping chromosome 19 has already understood. been mentioned. The only enzyme on chromosome 19 that currently shows significant polymorphism is Repair loci peptidase D,38 and even this polymorphism is so its use in gene Two genes, ERCC154 and RCC,55 which correct infrequent as to seriously limit on September 27, 2021 by guest. Protected mapping. Cook et at39 suggested the possibility of defective DNA repair in Chinese hamster cells have linkage with Se, but it was not until PEPD had been been assigned to chromosome 19. located on chromosome 19 by hybrid cell studies that its linkage relationships were reassessed. loci on chromosome 19. O'Brien et a!411 showed close linkage with myotonic TABLE 2 Other genetic dystrophy in two families (no recombinants in 14 Gene Regional localisation opportunities). Unfortunately, no subsequent (where known) informa- myotonic dystrophy families have proved Poliovirus receptor (PVR) tive, and the precise ordering in relation to other Cell surface antigen MSK 19 recombination has been Cell surface antigen MSK 2(0 loci is uncertain, though Cell surface antigen MER 5 q 13-3 shown between PEPD and APOC2. DNA repair gene (RCC) Non-polymorphic enzymes include glucose phos- DNA repair gene (ERCC-1) ql32- ql3-3 RD114 virus receptor (RDRC) phate isomerase (GPI),4' one form of phospho- Baboon virus M7 receptor (M7VI) glycerate kinase (PGK2),42 the muscle specific form (CYPI) q13 2 as Beta subunit of transforming of creatine kinase,43 and a lysosomal DNAse,44 growth factor (TGFB) q 13 1-ql 33 well as cytochrome p450, the gene for which has J Med Genet: first published as 10.1136/jmg.23.1.2 on 1 February 1986. Downloaded from

Gene mapping and chromosome 19 5 DNA polymorphisms tions, has given valuable evidence on the localisa- tion of specific genetic disorders, notable examples For chromosome 19, as for other chromosomes, the being the retinoblastoma locus on 13q and Duchenne detection of restriction fragment length polymorph- on the short arm of X (). isms (RFLPs) based on DNA is now making a Chromosome 19 is morphologically a somewhat substantial contribution to the overall gene map, as featureless chromosome, with a band structure that well as to more specific studies of major loci, such as is considerably less distinctive microscopically than myotonic dystrophy. Some polymorphisms are de- would appear from conventional diagrams. The tected by specific gene probes (for example, C3, predominantly pale staining with Giemsa may re- APOC2, LDLR), while others are defined by flect the presence of a relatively large number of anonymous DNA sequences localised to chromo- functional genes. Centromeric polymorphism can be some 19 by hybrid cell studies. Table 3 lists those recognised with C banding techniques and is begin- RFLPs identified so far, together with their approxi- ning to be utilised in linkage studies,35 though mate localisation. centromeric DNA probes are likely to be more The first sequence to be isolated, 1J2, was specific in this respect. produced from a flow sorted chromosome 19 and 20 Trisomy 19q has been reported,57 but without enriched DNA library, while succeeding sequences features that can be related to known loci on the have been isolated from a library constructed from chromosome. So far, no deletions or monosomies the cell line 'WILF' mentioned below (probes p17-1 have been available for molecular study. A number and p4-1), from a further flow sorted library of instances of balanced rearrangements have been (p BAM 47) (R Bartlett, 1985, personal communi- recorded, mostly without clinical abnormalities. Cell cation) and from a library (cos 1-13).56 lines from such persons have formed the basis for These probes all show useful polymorphisms and, constructing hybrid cell lines which are proving a although linkage data are still preliminary for most valuable independent source of information on gene 16 of them, their physical localisation suggests that they localisation and order.'5 copyright. are already sufficient in number to provide a Hybrid cell lines containing only one copy of framework for mapping most of the chromosome, chromosome 19 and lacking various specific regions especially when considered together with the of this chromosome have now been constructed and classical protein polymorphisms. have been used as a panel both to localise specific genes and other markers to chromosome 19 and to Cytogenetic and hybrid cell evidence give a regional localisation on it.

This type of evidence is particularly valuable for http://jmg.bmj.com/ The study of human chromosomal disorders, in localising those loci that are not polymorphic and particular small deletions and balanced transloca- which thus cannot be studied by genetic linkage analysis. It is also an important independent approach for ordering loci already defined in linkage TABLE 3 Cloned DNA sequences on chromosome 19. groups, especially where linkage data are equivocal or contradictory, and where the loci are infrequently Regional Polymorphic localisation separated by crossing over. (where known) Using a panel of hybrid cell lines, Brook et al'5 on September 27, 2021 by guest. Protected Specific gene probes defined the direction of the C3-PEPD/DM-Lu C3 pl3.3-3pl3.2 + linkage group and have placed a number of other APOE cen-*q13-2 loci in its framework. Subsequent work has ex- APOC1 cen-q13-2 APOC2 cen-iq13.2 + tended the number of loci with a defined localisation LDL receptor pl3-2-.pl3-1 + and fig 1 shows the current situation. One point of Insulin receptor pl.3-3pl3-2 + q13 3-q13.4 uncertainty until recently has been the position of CGB q13 3 the in relation to the various loci. Phosphoglycerate kinase 2 Creatine kinase (muscle) Preliminary results using a cell hybrid line with a Cytochrome p 450 ql3-1 gql3 3 + centromeric breakpoint, allowing a clear separation of loci on long and short arms, have now been Anonymous DNA sequences IJ2 (D19S9) p13 2-ql3-2 + reported,58 and suggest a long arm localisation for Cos 1-13 (D19S11) pl3-2-cen + APOC2. Since this locus shows clear linkage with P Bam 34 (D19S6) q133-3qter + P.B. 47 (D195) pl3-1 -cen + C3 on the short arm, it seems likely that the 17-1 (D19S8) pl3-1-cen + C3-Se-DM-Lu linkage group spans the centromere, 4-1 (D19S7) pl3-2-ql3 2 + and that recombination in this region may be OL5 (D 19S4) relatively infrequent. J Med Genet: first published as 10.1136/jmg.23.1.2 on 1 February 1986. Downloaded from

6 D J Shaw, J D Brook, A L Meredith, H C Harley, M Sarfarazi, and P S Harper

INSR must still be regarded as tentative. This is in part because of the limited size of most families, requir- 13.3 C3 ing the combination of numerous data sets and often the extrapolation of indirect assignments

p 13 2 LDLR to achieve the maximum information from the data. A further factor is the marked sex difference in 13 1 p4-1 recombination. cos 1-3 Sherman et at24 have recently constructed a 12 linkage map based on all available published data up 1 1 p17. 1 to 1984. Although no single order could be consi- 11 APO Cl dered definitive, they found a most likely linkage 12 APO C2 (from p to q) of: FHC-(Le-C3)-(LW-PEPD-DM)- Se-(APOC2-APOE-Lu). Fig 2 is an attempt to APO E 13 1 combine this with further data from DNA poly- morphisms reported at the 1985 Human Gene GPI q Mapping Workshop, in particular, the strong evi- 13 -2 PIJ2 dence for close linkage between DM and APOC2, ERCC I while table 4 gives details of some of the linkage 13 3 distances between the various markers and myoto- CGB nic dystrophy. The hybrid cell studies discussed 13 4 FTL earlier make it likely that the linkage group extends onto the long arm, rather than being confined to the FIG 1 Regional localisation of chromosome 19 markers. short arm as suggested by Sherman et al.24 There The bracket on the right hand side indicates regions within still remains considerable scope for rearrangement, which the precise order of markers is unknown. is but there little doubt that the orientation andcopyright. approximate sequence are now correct. Sherman et a124 found the overall recombination More detailed localisation using hybrid cell lines in female meioses to be three times that in males, has been attempted using a line 'WILF' which suggesting that while the total genetic length of the contains chromosome 19 as its major human chromosome in males is around 100 cM, it may component.25 Using a series of subclones from this, approach 300 cM in females. This striking difference each of which contains a different fragment of

will also have practical implications for the use of http://jmg.bmj.com/ chromosome 19, it has been possible to identify a linked markers in the prediction of genetic disorders series of overlapping fragments that may give more such as myotonic dystrophy. detailed localisation than is currently possible using Computer programmes allowing multipoint link- hybrids based on naturally occurring rearrange- age analysis of the data should help in establishing ments. However, the possibility of internal rear- the relative order of the various loci,6" particularly if rangements within the chromosome 19 fragments the linkage data are tested on suitably structured means that this type of evidence must be regarded reference families, such as those currently being with caution at present. on September 27, 2021 by guest. Protected Direct cytogenetic studies of in chromo- some 19 are few and so far confined to males.59 A TABLE 4 Peak lod scores (Z) and recombination fractions chiasma is usually seen on each arm, and the between DM and seven RFLPs. localisation of chiasmata is frequently more terminal than proximal, which would support the relative Male Femnale Combined infrequency of recombination in the centromeric C3 -1 0(45 0(30 region, with a greater recombination between physi- 7 2-69 -0(19 0(14 cally close loci nearer the ends of the chromosome. p17-1 (D19s8) 0(05 ( 1 (0 1( 7 0-66 2 09 2-98 Direct observation of female meioses will be of APOC2 0(1 0-05 0(05 considerable interest in view of the pronounced sex Z 1-6 5-63 6-52 p4-1 (D19s7) () 10 030 0(20 difference shown for loci on chromosome 19. Z 1-56 0(41 1-47 Cos 1-13 (D19sl 1) 0 25 0-45 03(0 Z 0-88 -0()6 0-54 Genetic linkage distances on chromosome 19 pIJ2 (D19s0) 0 0-M0)45 0(15 7 189 -(0(9 0(87 with the structural map of loci shown LDLR 6 0(20 020 015 By comparison Z 0(53 0)48 1 65 in fig 1, the genetic linkage map of chromosome 19 J Med Genet: first published as 10.1136/jmg.23.1.2 on 1 February 1986. Downloaded from

Gene mapping and chromosome 19 7 made available from Paris and Utah. However, cloned gene into cultured cells or family studies remain an insensitive method of could be studied. Any or all of these techniques, as determining order for closely linked loci, and the well as others still being developed, could be applied precise order may well remain uncertain until direct to myotonic dystrophy, and, for that matter. to any methods of scoring large numbers of meioses of the many other human diseases whose molecular become available. basis is still unknown. Molecular approaches to isolation of the myotonic References dystrophy gene Mohr J. Estimation of link-age betwcen the LuLthcran a(nd the Lewis blood groups. Acta Pathol Scand 1951;29:339-44. 2 Mohr J. A stuids, of litnkage ini ,nant. Copenhagen: Munksgaard. Until now, the techniques of 1954. have been used principally to construct gene probes 3 Grubb R. Zur Genetik des Lew%is-svstems. NVaturiissenscha/ften for relatively well characterised proteins on chromo- 1953;21:56(-1. some 19, and to increase the availability of polymor- 4 Cook PJL. The Lutheran-secretor recombination fractioni in man: a possible sex differcncc. Annii Hlonl Geniet 1965;28:393-7. phic markers for mapping in the form of anonymous Thomasen E. Msotonia. Aarhus: Universitctstorlaget. 1948. cloned DNA sequences. For serious genetic dis- Renwick JH. Bundey SE. Ferguson-Smith MA. Izatt MM. orders such as myotonic dystrophy, the information Confirmation of the linkagc of the loci for myotonic dystrophy available on localisation of the gene now makes it and ABH secretion. J Med Geniet 1971:8:407-16. 7 Harper PS. Rivas ML. Bias WB. Hutchinson JR. Dvken PR. potentially feasible to approach the isolation and MeKusick VA. Genetic linkage confirmcd between the locuIs for characterisation of the gene itself, despite our myotonic dystrophy and the ABH-secretion and the Lutheran present almost complete ignorance about the blood group loci. Ain J Hum Geniet 1972:24:310-6. of its likely product. Eiberg H. Mohr J. Niclscn LS. Simonsen N. Genetics and linkage relationships of the C3 polymorphism: discoverN of the Because of the limited accuracy of the linkage C3-Se linkage and assignment of LES-C3-DM-Se-PEPD-Lu approach to , it will not be possible svntcnyr to chromosome 19. Clitn Gentet 1983:24:159-70. to define points nearer than a few million base pairs Berg K. Heiberg A. Linkagc studies on familial hypercholcstcr- copyright. olcmia with xanthomatosis: normal lipoprotein malrkers anld the to a disease gene by family studies alone. Such C3 polymorphism. Birtlt Defects 1976:XII:266. lengths of DNA are far too large to clone by "'1 Whitehead AS. Solomon E, Chambers S. Bodmer WvF, Povev S. conventional techniques, and so new methodologies Fev G. Assignment of the structural genc for the third are being developed for the isolation and character- component of human complemcnt to chromosome 19. Proc Nati isation of million DNA fragments. These Acad Sci USA 1982;79:5021-5. 6 Harper PS. Bias WB. Ilutchinson JR. McKuIsick VA. ABII include the use of somatic cell hybridisation to sccretor status of the foctus: a( genctic markcr identifiaible bv propagate human sub-chromosomal fragments, and amniocentesis. J Med GectiZI 1971:8:438-40. http://jmg.bmj.com/ a new form of gel electrophoresis involving periodic 2 Schrott HG. Omenn GS. Mvotonic dystrophy: opportunitics for alterations in the electrical field direction, to analyse prcnatal prediction. Neurologys (inneap) 1975:25:789-91. 13 Davies KE. Jackson J. Williamson R. et al. Linkage analysis of and isolate large DNA fragments (orthogonal field myotonic dystrophy and sequenccs on chromosome 19 using a alteration gel electrophoresis).62 6 cloned complcment 3 genc probe. J Med Geniet 1983:20:2'59-63. Having isolated a length of DNA of a few million I4 Ingram PH. Bruns GAP. Rcgila VM, Eiscnmain RE, Graild base pairs, within which the disease gene is thought PS. Expression of cx-D-mannosidasc in man-hamster somnatic cell hybrids. Biochlem Getnet 1977:15:455-76. to be located, a number of experimental approaches ' Brook JD. Shaw DJ, Meredith L. Bruns GAP. Harper PS. are possible. The fragment could be cloned as a Localisation of genetic markers and orientation of the linkage on September 27, 2021 by guest. Protected 'mini-library' and a complete restriction site map group on chromosome 19. Hum Geniet 1984:68:282-5. constructed. Probes could then be selected from any '6 Martinvik F, Ellenbogen A. Hlirschhorn K. Hirschhorn R. Further localisation of the genes for human acid alpha glucosi- site for further study. The positions of expressed dase (GAA), peptidase D (PEPD), and alpha mannosidase B gene sequences could be deduced by hybridisation (MAN B) by somatic cell hybridisation. Humn Getnet with mRNA or by direct selection of protein coding 1985;69:109-1 1. regions.64 Alternatively, RFLPs could be investi- 17 Ichikawa K. Crosley CJ. Culebras A. Wcitkamp L. Coincidence of neurofibromatosis and myotonic dystrophy in a kindrcd. J gated for linkage disequilibrium with the disease. Med Genet 1981;18:134-8. This based approach should allow one to 18 Rivas ML, Di Liberti JN. Genetic linkage between myotonic detect very closely linked markers in a way that is dystrophy and neurofibromatosis. Birth Defects 1984:20:570. not possible with family studies. 'Candidate' disease '9 Huson SM. Mcredith AL, Sarfarazi M, Shaw! DJ, Compston DAS, Harper PS. Linkage analysis of peripheral neurofibroma- genes could then be investigated in several ways: for tosis (Von Rccklinghauscn disease) and chromosome 19 mar- example, to study differences in expression in kers linked to myotonic dystrophy. J Med (;enlet 1986:23: various tissues from patients and normal control 55-7. subjects; or to determine their complete base 2i( Bcrg K, Borresen AL. Hciberg A. Maartman-Moc K. Study of the linkagc rclationships betwccn APOE and familial hypcr- sequence and relate this to the structures of genes of cholestcrolacmia with xainthomattosis. Cv togeiet Cell Getiet known function; or the effect of introducing the 1984:37:4 18. J Med Genet: first published as 10.1136/jmg.23.1.2 on 1 February 1986. Downloaded from

8 D J Shaw, J D Brook, A L Meredith, H C Harley, M Sarfarazi, and P S Harper

FIG 2 Observed recombiniation fractions and maximum lod scores (in paretntheses) for various polymorphisms O,]n

M: 0-50 (O-00) 1 LE F: 0-02 (0-08)

M: 0- 19 (1 74) M: -04 (7-91) C3 F: 0-25 (1-50) F: 0-21 (1-44)

MO 18 (0-78) M: 0-01 (3-40) LW F: 0-43 (0-0) F: 0-20) (0 55)

M: 0-01 (0-09) M: 0-21 (1-63) PEPD F: 0-32 (0-20)

M: 0-19 (0-53) M: 0-50 (0-00) M: 0-06 (3-73) M: 0(X) (2-96) DM F: 0-20 (0-48) F: 0-50 (0-00) F: 0-38 (0-21) F: 0(05 (0(78)

SE M: 0-02 (0-08) M: 0-32 (0-32) M: 0(-19 (4-17) M: 0- 15 (1-99) M: 0-03 (3-40,' F: 0-50 (0-00) F: 0-50 (0-00) F: 0-32 (0-36) F: 0-50 (0-00) F: ((-5(1 (0-00) F: 0-06 (1-54)

M: (-01 (0-18) M: 0-17 (5-24) APOE F: 0-50 (0-(O) F: 0-41 (0-13) F: 0-10 (7-17)

M: 0-26 (0 82) M: 0-50 (0-00) M: 0()19 (2-23) M: 0-04 (3-68) M: 0-25 (((-49) M: 0-50 (-(X)) LU F: 0-50 (0-00) F: 0-50 (0-00) F: 0-43 (0-09) F: 0-34 (0-15) F: 0-41 ((1-()1) F: 0-10 (1-21)

M: 0-50 (0-00) M: 0-25 (0-05) M: (1-26 (0-84) M: 0-(06 (3-17) M: 0-(X) (10-61) APOC2 F: 0-30 (((-17) F: 0-00 (0-87) F: 0-31 (((-30) F: 0-34 ((1-11) F: 0-03 (8-79)

M: 0-01 (0-49) M: 0-01 (0-68) M: 0-01 copyright. (1-55) IJ2 F: 0-50 ((-(X)) F: ((-29 (6-38) F: ((-50 (0(X))

M: 0-27 (0-05) M: 0-01 (0-56) M: 0-06 (0)-67) 17-1 F: 0-01 (((-28) F: ((-18 (()-11) F: ()-09 (2-(9)

4-1 M: 0-50 (0-00) M: ()()-1 (1-65) M: ()1( (1-56) F: 0-50 (0-00) (F: -5(1 (0-00) 0129F: (0)41) http://jmg.bmj.com/ FHCILDLR LE C3 LW PEPD DM

21 Goldstein JL, Brown MS. The familial hyperlipoproteinemias. map to human chromosome 19 the gene for apolipoprotein CII. In: Stanbury JB, Wyngaarden JB, Fredrickson DS. Goldstein Proc Natl Acad Sci USA 1984;81:2945-9. JC, Brown MS, eds. The metabolic basis of inherited disease. 5th 28 Humphries SE, Berg K. Gill L, et al. The gene for apolipopro- ed. New York: McGraw-Hill, 1983:672-712. tein C-II is closely linked to the gene for apolipoprotein E on on September 27, 2021 by guest. Protected 22 Yamamoto T, Davis CG. Brown MS. et al. The human LDL chromosome 19. Clin Genet 1984;26:389-96. receptor: a cysteine-rich protein with multiple Alu sequences in 29 Myklebost 0, Rogne S, Olaisen B, Gedde-Dahl T, Prydz H. its mRNA. Cell 1984;39:27-38. The locus for apolipoprotein CII is closely linked to the 23 Naylor SL, Lalouel JM, Shaw DJ. Report of the committee on apolipoprotein E locus on chromosome 19 in man. Hum Genet the genetic constitution of chromosomes 17, 18 and 19. Human 1984;67:309-12. Gene Mapping 8 (Helsinki Conference) 1985. Cytogenet Cell -3 Berg K, Pedersen JC, Borresen AL, Heiberg A, Solaas MH, Genet (in press). some 19 markers in 24 Humphries S. Concerning chromosome Sherman SL, Ball SP, Robson EB. A genetic map of chromo- families with hypercholesterolemia with xanthomatosis. Human some 19 based on family linkage data. Ann Hum Genet Gene Mapping 8 (Helsinki Conference) 1985. Cytogenet Cell 1985;49:181-7. Genet 25 Brook JD, Shaw DJ, Thomas NST, Meredith AL, Cowell J, (in press). 3' Cox Little Harper PS. Mapping genetic markers on human chromosome 19 DW, McAlpine PJ, Phillips S, Maguire GF, JA. using sub-chromosomal fragments in somatic cell hybrids. Linkage analysis of apolipoprotein CII (APOC2) and other Cytogenet Cell Genet (in press). chromosome 19 markers. Human Gene Mapping 8 (Helsinki 26 Olaisen B, Teisberg P, Gedde-Dahl T Jr. The locus for _ Conference) 1985. Cytogenet Cell Genet (in press). 32 apolipoprotein E (apoE) is linked to the complement compo- Davison PJ, Talmud P, Norton P, et al. The genes for nent C3 (C3) locus on chromosome 19 in man. Hum Genet apolipoprotein E (APOE) and APOCI are less than 15 kb apart 1982;62:233-6. on human chromosome 19. Human Gene Mapping 8 (Helsinki 27 Jackson CL, Bruns GA, Breslow JL. Isolation and sequence of a Conference) 1985. Cytogenet Cell Genet (in press). human apolipoprotein CII cDNA clone and its use to isolate and 33 Shaw DJ. Meredith AL, Sarfarazi M, et al. The apolipoprotein J Med Genet: first published as 10.1136/jmg.23.1.2 on 1 February 1986. Downloaded from

Gene mapping and chromosome 19 9 dcromosome 19. Based on data of Sherman et al24 with additional data from HGM8.

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4X Yang-Feng TL. Franckc U. Ullrich A. Gene for human insulin 57 Lange M, Alfi OS. Trisomy 19q. Ann Genet (Paris) 1976;19:17- receptor: localisation to site on chromosome 19 involved in 21. pre-B-cell leukemia. Science 1985;228:728-31. 5X Lusis AJ, Heinzmann C, Sparkes RS, Geller R, Sparkes MC, 49 Miller DA, Miller OJ. Dev VG, Hashmi S. Tantravahi R. Mohandas T. Regional mapping on human chromosome 19: Human chromosome 19 carries a poliovirus receptor gene. Cell apolipoprotein E, apolipoprotein CII, low density lipoprotein 1974;1: 167-72. (LDL) receptor, peptidase D. glucose phosphate isomerase. 5" Brown S. Ole HK, Gazdar AF. Minna JD. Franeke U. Human Gene Mapping 8 (Helsinki Conference) 1985. Cytogenet Requirement of human chromosomes 19, 6 and possibly 3 for Cell Genet (in press). of hamster X human hybrid cells with hahoon M7 59 Hult6n MA. Chiasma distribution at diakinesis in the normal type C virus. Cell 1979;18:135-43. human male. Hereditas 1974;76:55-78. 51 Schnitzer TJ. Weiss RA, Juricek DK, Ruddle FH. Use of VSV Ott J. Genetic linkage in man. Baltimore: Johns Hopkins pseudotypes to map viral receptor genes: assignment of RD114 University Press. 1985. receptor gene to human chromosome 19. J Virol 1980;35:575- 61 Weis JH, Nelson DL, Przyborski MJ. et al. Eukarvotic 80. chromosome transfer: linkage of the murine major histocompa- '2 Rettig WJ, Dracopoli NC, Goetzger TA, et al. Somatic cell tibility complex to an inserted dominant selectable marker. Proc genetic analysis of human cell surface antigens: chromosomal Natl Acad Sci USA 1984;81:4879-83. assignments and regulation of expression in rodent-human 62 Carle GF, Olsen MV. Separation of chromosomal DNA hybrid cells. Proc Natl Acad Sci USA 1984;81:6437-41. molecules from yeast by orthogonal-field alteration gel elec- 53 Palmer DK, Morse HG, Jones C. Assignment of a gene trophoresis. Nucleic Acids Res 1984;12:5647-64. encoding a cell surface antigen to human chromosome 19. 63 Schwartz DC, Cantor CR. Separation of yeast chromosome- Human Gene Mapping 8 (Helsinki Conference) 1985. Cytogenet sized by pulsed field gradient gel electrophoresis. Cell Cell Genet (in press). 1984;37:67-75. 54 De Wit J, Hoeijmakers JHJ, van Duin M, et al. Assignment of 64 Weinstock GM, Ap Rhys C, Berman ML, et al. Open reading the DNA repair gene (ERCC-1) to human chromosome 19. frame expression vectors: a general method for antigen produc- Human Gene Mapping 8 (Helsinki Conference) 1985. Cytogenet tion in E coli using protein fusions to B-galactosidase. Proc Natl Cell Genet (in press). Acad Sci USA 1983:;80:4432-6. 5S Thompson LH, Moorey CL, Burkhart-Schultz K, Carrano AV, Siciliano MJ. Correction of a -excision repair muta- tion by human chromosome 19 in hamster-human hybrid cells. Correspondence and requests for reprints to Profes- Somatic Cell Mol Genet 1985;11:87-92. sor P S Harper, Section of Medical Genetics, copyright. 5 Litt M. Buroker NE, Bufton L. DNA polymorphisms via cosmid probes. Human Gene Mapping 8 (Helsinki Conference) 1985. University of Wales College of Medicine, Heath Cytogenet Cell Genet (in press). Park, Cardiff CF4 4XN. http://jmg.bmj.com/ on September 27, 2021 by guest. Protected