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Home , Chromosome 12, Chromosome 14, Chromosome 6, FUCA2, ME2 (gene), Phosphoglucomutase 3

J Med Genet: first published as 10.1136/jmg.24.11.649 on 1 November 1987. Downloaded from

e-one mapping and medical genetics

Journal of Medical Genetics 1987, 24, 649-658

The molecular genetics of 6 VINCENT CUNLIFFE AND JOHN TROWSDALE From the Human Immunogenetics Laboratory, Imperial Cancer Research Fund, PO Box 123, Lincoln's Inn Fields, London WC2A 3PX.

SUMMARY contains several clinically important markers as well as classical loci, proto-oncogenes, and a growing number of anonymous DNA restriction fragment length polymorphisms (RFLPs). It is also of unique interest because of the location of the major complex (MHC) on the short arm, at 6p21-3. The MHC is one of the most detailed areas of the human genetic map to date and many important diseases, some of a sus- pected autoimmune aetiology, are associated with it. General Fragile About 70 well characterised genetic loci have been markers sites RFLP r mapped to human chromosome 6 (fig 1). Consider- vI 25 copyright. able interest has been focused on those of the HLA 24 system, located on the short arm at 6p213. This 23 I PYHGS UF12 TUBB multigene complex, otherwise termed the major >>FR A 6A 2222-3 histocompatibility complex (MHC), encodes class I p 22.1 I. D6S7 and class II HLA molecules as well as some com- IHLA 21.3 , _D6S8IS 9 plement components and is involved in defence 21.2 PIMG I KRAS 11 D659 I I against a variety of diseases. Particular alleles of 21.1 GLOK PRL D6S101 some HLA loci are associated with hereditary pre- 12 MERM1lG dispositions to diseases, for example, insulin depen- 1: http://jmg.bmj.com/ dent diabetes mellitus (IDDM), , anky- 13 IMEI 6DS5 losing spondylitis, , and Hodg- 13 PGM3 *FRA6 14 D6S11 kin's lymphoma. The HLA complex spans over 3 x 15 GA 106 bp and to date contains more than 20 expressed 16.1 Ic . The considerable knowledge that has accum- 16-3 I ulated concerning the organisation, structure, 21 SOD2 regulation, and functions of the q I genes in this linkage 22-1 on September 30, 2021 by guest. Protected group forms a paradigm for studies of the molecular 22.2 biology of a complex region of the human 22.3 MYB D6S1 and- it will be covered in detail in this article. 23.3 Chromosome 6 is already known to encode a large 24 number of enzyme and surface loci, several proto-oncogenes, and at least six , four I TCP * FRA 6B of which have been assigned close to, or within, the HLA In 27 region. addition, there are several fragile 6 PLG sites involved in translocations, inversions, and dele- tions which are aetiologically linked to some lym- FIG I Regionally localised markers on human I chromosome 6. Thisfigure is mostly based on data collated phoid and other malignancies. The genetic markers in the 8th Human Mapping Workshop. The of chromosome 6 are summarised in fig 1 and are HLA complex is shown in detail in fig 2 and the markers are referenced in the table. explained in the table. Vertical bars indicate the Received for publication 18 May 1987. (approximate) extents ofthe boundaries within which Accepted for publication 21 May 1987. a particular marker is located. 649 J Med Genet: first published as 10.1136/jmg.24.11.649 on 1 November 1987. Downloaded from

650 Vincent Cunliffe and lb Trowsdale TABLE Markers oni chromosome 6.

Getne sYmbol Locationi Descriptioni Reference anid remark-s ADCP 6 Adenosine de.tminase compiexing I 1. 17 ARGI 6 . lister 15. 62 ASSP2 6 Argininosuccinaite svnthetase pscudogene 2 4. 5. 31. 32 BEVI 6 Baboon M7 sirus integration site 6. 84 BKMAI 6q2l Banded krait minor satellite DNA-I 85. 101 CA21HA 6p2l 3 Congenital adrenal hyperplasia (21 -hydroxylase deficiency) A HLA region. CA21 HB 6p2l '3 Congenital adrenal hvperplasia (21-hydroxylase deficiency) B see fig 2 CGA 6q12-q2l Chorionie gonadotrophin. Ct polypeptide 45. 85 cscI 6 Corticosterone sideehain isomerase 42-44. 82-84 D6S7 6p2 l-pter Anonymous DNA segment from p7H4 19. 83 D6S8 (6p2l Anonymous DNA segment from p2C5 18. 83 DHFRP2 6 Dthvdrofolate reductase 2 34. 77 ER 6 Oestrogen receptor 17. 59. 60, 98 F12 6p23 Clotting factor XII (Hageman factor) 14. 15. 47. 48 F13A 6pl3--qter Clotting factor XIII. A subunit 16 FEA 6 Fg embrvonic antigen 14. 92 FRA6A (sp23 Fragile site, folic acid type. rtre. fra(6)(p23) 12. 72 FRA6B 6p25.1 otr 6q216 Fragile site, aphidicolin type. common. fra(6)(q25l1 or q26) 12. 72 FRA6C 6p22.2 Fragile sitet aphidicolin type, common. fra(6)(p222) 12. 72 FRA6D 6q 13 Fragile site, aphidicolin type, common. fra(6)(ql3) 12. 72 FTHL 6mp2l -3-~pl2 Ferritin-like sequence. heavy polvpeptide 12. 87. may be in HLA region. see note, fig 2 FUCA2 6 Ct- l-fucosidase2 13. 49 GLO I 6p2l 2I-.p2 1i Glyoxalase I 6-8. 17- 19 HFE 6sp2l1.3 Ha1emochromaitosis 211 88. may be in HLA region. strongly associated with HLA-A. see fig 2 HLA and comple- ment components C2' C4. BF bp2 13 See detailed map. fig 2 1. 44. 91 (this contains a discussion of HLA class I. class II. and class III genes and diseases associated with the region) 61 INFR 6q ct interferon receptor 57. copyright. INSL 6p23--q12 Insulin-like sequence. AGB6 38. 78 KRASI 6p23--ql2 Proto-oncogenes. c-Ki-ras- I processed pseudogene 21-23. 35-37 LQT 6 I.ong 0T (Romano-Ward syndrome) 24. 93 MEI 6q 12 Malic enzvme 1. soluble 11. 25 ME2 6 Mailic enzvme 2. mitochondrial 1(). 26 MCF3 6q 16- q2-2 Proto-oncogene MCF-3 71. 102 MRBC 6 Monkey red blood receptor 27. 57 MSK28 6 Antigen identified by monoclonail MG2 28. 53 MSK29 6 Antigen identified by monocionail antibody A42 28. 53 MYB hql45-q4 Asian myeloblastosis viral (v-mnrh) oncogene homologue 13. 29-31. 67-7(1 NDF 6 Neutrophil differentiation faictor 15. 94 NEU 6p2 1.3 Ncuraminidaise 1 sialitosis 15. 91) http://jmg.bmj.com/ p 6 P blood group (globoside) 32. 33. 55. 56 PGKIP2 6p2l- pl2 Phosphoglvcerate kinase 1. pscudogene 2 2(1 28-3(1. 34. 35. 102 PGM3 6q 12 3 12. 13. 37. 38 PIM Proto-oncogene pint 54. 56. 64 65 PLG 6p25.-qter Plasminogen 39. 4(1. 5(). 51 PRL 6p3-~q12 Prolactin 39. 79 PUTI 6 Polypeptide m44p in lymphocyte membraine 42. 52 PYHG5 bpter-p2I Protein spot in 2D gels (MWN' 90K) 43. 95 ROS 6q16-.ql2 Proto-oncogecne ros 59. 63 RPL32P bp2 13 Ribosomal protein L32 pseudogene 33. 76 SCA 6 Spinocerebellar ataxia 45. 46. 80. 81 on September 30, 2021 by guest. Protected SOD2 6q2 2. mitochondrial 14. 61 SRBC 6 Sheep red blood cell receptor 48. 58. M Brown. personal communication. 1987 S5 6 Surface antigen 5 (MW 45KD) 49. 54 TCPI 6q23-'-qter T complex polypeptide I 5. 24. 103 TNFA 6p2-3--q12 Tumour necrosis factor a 18. 78. 79. 97 TNFB Tumour necrosis factor )5. } TRM I 6p2.3--ql12 Methionine tRNA initiator I 5 TRM2 6p23-~qI12 Methioninc tRNA initiator 2 TS546 6 Temperature sensitivity complcmentation. ts546 19. 97 TUBB 6pter-.p2 4. 52 YES2 6 Yamaguchi satrcoma viral )v-vt-s-2) oncogene homologue 2 53. 66

Correlating the formal genetic map with the along human undergoing at molecular genetic map of chromosome 6 the pachytene stage. Using data taken from a large number of chromosomes they constructed a map Morton et a12 mapped the distribution of chiasmata which charted the frequenicy of crossovers per unit J Med Genet: first published as 10.1136/jmg.24.11.649 on 1 November 1987. Downloaded from

Gene mappinv- id medical genetics 651 length of ch1 - - ome. On chromosome 6 this some substance to the notion of a human equiva- frequency was-ui,- variable, particularly near the lent. 24 and, therefore, inconsistencies between In view of this, and the restricted expression of the molecular map and the formal genetic map are the human and mouse isoenzymes to the testis,27 it to be expected. seemed plausible that this human PGK might T'Iere are estimated to be about 52 chiasmata per be linked to HLA. A human genomic clone was iso- human meiosis. The genetic length of the human lated containing PGK sequences and mapped to is therefore 52/2 x 100 = 2600 cM (divi- 6p23-*p12.28 However, sequence analysis of this sion by two is necessary because only two of the four DNA identified a PGK processed pseudogene strands in a bivalent are involved in the chiasma; (PGKIP2) lacking all introns, flanked by 11 nucleo- multiplication by 100 gives the length in centi- tide direct repeats, punctuated by a premature in morgans). Chromosome 6 was estimated to consti- frame termination codon.29 Recent evidence from tute 2.5% of the total length of 2600 cM, a different source has indicated that the intron-less that is, 65 cM.2 However, Francke and Pellegrino3 PGK2 gene has a complete open reading frame and estimated that chromosome 6 made up more a testis specific pattern of expression.10 As such it like 6% of the haploid complement, which gives a would be a rare example of a functional processed much greater value of 150 cM. In the next few years, cellular (pseudo)gene. It is likely that both groups as more RFLP data accumulate, it will be possible to have studied the same genomic locus and, if this is generate detailed molecular maps of sections of so, discrepancies between their sequences have yet chromosome which are saturated with markers. The to be resolved. A third study showed the cosegrega- HLA region is ideal for this kind of analysis. tion of a PGK sequence with in a panel of human-rodent hybrid cell lines. Moreover, , surface , and pseudogenes sequencing of the DNA suggested that it encoded the autosomal testis specific PGK isoenzyme The combination of enzymatic activity assays, DNA 30

(PGK2). copyright. hybridisation on Southern blots, and segregation Recent isolation of a genomic clone containing analysis in somatic cell hybrids have localised genes the HSP70 gene facilitated its locus assignment to for fi tubulin (TUBB),4 two different tRNA initi- chromosome 6.7 This gene encodes a 70K protein ator methionine genes (TRMI, TRM2),5 glyoxalase whose synthesis is induced in response to a variety of (GLOI), " soluble and mitochondrial malic en- physiological stresses, most notably heat shock. It is zyme (ME], ME2),9-1" extremely well conserved between phyla; this prob- (PGM3), 12 13 mitochondrial superoxide dismutase ably reflects its essential role in minimising the (SOD-2),' liver arginase (one of two expressed damaging effects of such stresses. genes, ARGI),'5 fucosidase (FUCA2),'6 adenosine A cDNA probe for the functional, http://jmg.bmj.com/ deaminase complexing protein (ADCPI), 17 and linked argininosuccinate synthetase gene was used numerous pseudogenes. to identify 10 or more homologous sequences that The glycolytic enzyme I were dispersed throughout the genome, with a panel (PGKJ) is coded for by a gene located on the X of somatic cell hybrids.3' 32 Since a deficiency at the chromosome at q13, close to one of its processed chromosome 9 locus results in citrullinaemia, the pseudogenes (PGKIPI, Xq 1 1-q13). Deficiencies at other sequences, including that on chromosome 6 the functional locus can result in haemolytic (ASSP2), are likely to be non-functional pseudo- on September 30, 2021 by guest. Protected anaemia.'8 The murine homologue also lies on the genes. Generation of processed pseudogenes is be- .'9 There is, however, a PGK iso- lieved to depend on the activity of endogenous enzyme expressed exclusively in the testis that has reverse transcriptase in germline cells acting on an autosomal location.2" In the mouse, this locus is cellular RNAs and converting them into cDNAs on , close to both the major histo- capable of inserting into accessible regions of the compatibility (H-2) complex and the T/t complex.2' genome. Providing that insertion does not abrogate There is homology of synteny between human the expression of essential functions, these insertion chromosome 6 and mouse chromosome 17, largely events are likely to persist. A processed pseudogene within and adjacent to the MHC.22 There are also of the ribosomal protein L32 (RPL32PJ) has been some reports of developmental defects in the axial found in an intron of the DP,B1 gene.33 By using a skeleton23 and male transmission ratio distortion panel of human-rodent somatic cell hybrids, a effects, cosegregating with HLA, as well as recom- processed pseudogene of dihydrofolate reductase bination suppression between some extended HLA (DHFRP2) has been mapped to chromosome 6. haplotypes.21 Such phenomena are reminiscent of An assignment to 6pl2- pll has also been made for the behaviour of the mouse T/t complex26 and lend a sequence with homology to the functional Kirsten- J Med Genet: first published as 10.1136/jmg.24.11.649 on 1 November 1987. Downloaded from

652 Vincent Cunlliffe and *: ."Tn-Towsdale ras proto-oncogene (KRASI).3-37 Between 6p23 Chromosome 6 and neoplasia and 6q12 lies a 13 kb insulin-like sequence AGB6 (INSL) expressed in fetal brain.38 This interval The link between genetic aberration and cancer was also contains the prolactin gene (PRL).39 An associ- first established by the oberservation of a peculiarly ation between HLA-B8 and the development of small chromosome in the leukaemic cells of patients prolactin secreting adenomata has been described,4M with chronic granulocytic leukaemia. Abnormalities so it would be of interest to determine the dis- as conspicuous as gross chromosomal rearrange- tance between the HLA region and the prolactin ments and as subtle as single point mutations can be gene. equally potent causes of neoplasia. Such lesions can In the mouse, the level of corticosteroid side chain activate proto-oncogenes and thereby change the isomerase is under the control of a single locus growth characteristics of the cell. Deletions, trans- linked to the H-2 complex. Furthermore, both H-2 locations, and inversions of chromosome 6 material and HLA are associated with differential sensitivity have been observed in many types of leukaemia. to glucocorticoids.41-44 Other rearrangements of this linkage group have Human chorionic gonadotrophin has two sub- been shown in retinoblastoma, malignant mela- units, a and P. The a subunit is also a component of noma, and colon carcinoma and adenoma. The luteinising hormone, thyroid stimulating hormone, ROS,63 PIM,64 65 YES,66 MYB,67-70 and MCF371 and follicle stimulating hormone, and is encoded by proto-oncogenes all reside on chromosome 6. ROS a single gene (CGA). In situ and filter hybridisation and MCF3 are, in fact, the same locus which has have localised CGA to 6ql2-*q21.45 Other studies, been transduced twice by retroviruses to generate however, have concluded that the gene is on chro- the v-ros and mcf-3 viral oncogenes. Aberrant mosome 18 at pI1.46 expression of any of these genes, as a consequence Recent cloning of the gene coding for the oes- of any chromosomal rearrangement (including trogen receptor has enabled its cytogenetic assign- amplifications)70 in which they are involved, could ment to this autosome,59 68 and an analysis of explain the aetiology of tumours possessing such somatic cell hybrids showed that the a/J interferon lesions. copyright. receptor gene was also located on chromosome 6.61 Fragile sites are regions of particularly Interestingly, the synteny of the a/f3 interferon prone to deletion or translocation and four such sites receptor and mitochondrial superoxide dismutase lie on chromosome 6: FRA6A, FRA6B, FRA6C, gene on 6q is recapitulated by synteny of the y and FRA6D (table). Deletions covering some of interferon receptor and cytoplasmic superoxide them have been observed in malignant lymphoma, dismutase gene on . This may well acute myeloid leukaemia, acute lymphoblastic reflect a conservation of linkage between sequences leukaemia, and adult T cell leukaemia.72 now on chromosome 6 during evolution. http://jmg.bmj.com/ Defects in coagulation can be caused by lesions The major histocompatibility complex (MHC) in three loci that map to chromosome 6. Clotting factors XII (Hageman factor)47 48 and XIII16 map The MHC consists of a cluster of at least 30 genes to 6p23-*qter by deletion mapping and the - covering about 3 million base pairs (3 mega bp or ogen gene resides in the 6q25--qter region.49-51 3 mbp) of DNA. It is divided into three regions, Segregation analysis has been particularly useful containing class I, class II, and class III genes, as

in mapping the loci of cell surface antigens, several shown in fig 2. There is also a fourth category on September 30, 2021 by guest. Protected of which lie on chromosome 652-56 (see also the containing all those genes which are not comple- table). The gene encoding CDII, a T cell differentia- ment or HLA related and therefore include the tion antigen, was thought to reside here.57 58 How- 21-hydroxylase gene and the loci for TNF a and P. ever, recent molecular cloning of its gene facilitated The MHC has been mapped by conventional link- in situ and filter hybridisation that placed the locus age analysis and, more recently, by pulsed field gra- at lpl3 (M Brown, 1987, personal communication). dient gel electrophoresis.9"10 These two tech- Some cystic fibrosis (CF) patients have recently niques are in broad agreement on the positions of been noted to have deficiencies of vasoactive intes- the subregions, assuming that 1 cM is roughly tinal peptide. Chromosomal assignment of the locus equivalent to 1 mbp. The maps in fig 2a and b are of the gene encoding this hormone was essential to based on these data as well as on information both establish if it coincided with the CF locus defined by from overlapping cosmid clones and from B cell RFLP analysis on . Somatic cell hy- deletion mutant lines. There are several recent brid analysis regionally localised this gene to reviews of the HLA complex that should be 6p21-*qter and refuted the hypothesis that defects consulted for detailed information (cited in reference at this locus were the primary cause of CF.62 91). J Med Genet: first published as 10.1136/jmg.24.11.649 on 1 November 1987. Downloaded from

Gene mi , "d medical genetics 653

I SPiSCAebeo? 1cM H rSpinocerebellor1 lmbp l ataxia J

l D6S8J [D6S7J -PGK2-o AGB6 GLO1 PIM1 HLA 2C5 7H4

- 17 genes 100kb copyright. Class II Class III Class I r~~ I I DP DZ DODX DQ DR C4B BF I,In n-nn r I 21-OHB \ / ,cxaoto3x kd3o a \\ // B C A P ...... 4- +44 IVIII T v a + +'1* -91-9 1" -+ 2211 11m111 21-OHA http://jmg.bmj.com/ DV3 TNF-o+3

FIG 2 Map ofthe region ofhuman chromosome 6 around the HLA complex. The HLA region has been compiled using data from a number ofsources as described in the text. The complement (class III) is shown orientated as in mouse although this has not yet been established in . "" The tumour necrosis factor (TNF) a and a genes are thought to map within this complex from studies ofdeletion mutants. In the mouse these genes are proximal to on September 30, 2021 by guest. Protected H-2D and so may also be located between the complement region and HLA-B in man. The PIMJ oncogene is also positioned centromeric to the HLA complex in view ofits position in the mouse (A Berns, 1987, personal communication).

THE HLA CLASS I REGION unlinked to HLA, given the recent assignment to Serological analysis established that this region con- of a set of HLA class I related se- tains multiple related genes. The best characterised quences, the CD1 family.74 One of the best esti- expressed loci are HLA-A, HLA-B, and HLA-C mates of the number of class I genes comes from which express glycoprotein chains of approximately gene cloning from a haplotype loss mutant LCL 721 43 000 Daltons, associated with P2-micro- (H T Orr, 5th International H-2 and HLA Cloning globulin at the cell surface. There are other class I Workshop) and suggests a minimum of 17. loci which may be equivalent to the mouse Qa and At least six of these genes, by sequence analysis, TL loci. However, such human homologues may be are pseudogenes. All of the functionally defined J Med Genet: first published as 10.1136/jmg.24.11.649 on 1 November 1987. Downloaded from

654 Vincent Culnliffe and dale class I sequences isolated so far map to the same using sets of overlapping cosmid clones. It contains HLA region, largely at the HLA-A end of the genes for complement components C2, factor B, MHC. Other genes may reside between the HLA-A and C4.75 21-hydroxylase (CA21H) is located very and HLA-C loci. close to C4. Some persons contain a tandem duplica- tion of the C4 and 21-OH genes. Hereditary defects in the 21-OH gene result in the disease congenital HLA CLASS II GENES adrenal hyperplasia.76 The class III region is The HLA class II products are heterodimeric glyco- separated by several hundred kb from both the class present on the surface of antigen presenting I and class II region (D Campbell, 1987, personal cells consisting of an a chain of about 33 kd and a communication). 13 chain of about 28 kd. Typically the genes for both partners in the heterodimers are close to each other, OTHER GENES LINKED TO THE MHC for example, DQa and 13 are adjacent as are DPa Fig 2a indicates the positions of some markers that and P. Evidence from transfection experiments flank the HLA region. GLOJ, PIMI, and CA21H show that heterodimers of mixed isotype may form, have homologous locations on mouse chromosome for example, DPa coupling with DQ13, and similar 17. The genes encoding tumour necrosis factor a events have been documented for the equivalent (TNFA) and lymphotoxin (TNFB) both map within mouse Ia genes (R Sekaly, 1986, personal communi- the murine and human MHC.77 The two murine cation). At the centromeric end of the class II re- genes are directly arranged in tandem, separated by gion is a stretch of 100 kb containing four DP genes, only 1 kb, and lie 70 kb centromeric to the H-2D two a and two P, arranged in the order: centromere- locus.78 Both human genes are contained on a single DP132(pseudogene)-DPa2(pseudogene)-DP13-DPal. 42 kb cosmid.79 Filter hybridisation to a series of The arrangement of these genes was determined by haplotype deletion mutants derived from a B cell mapping of overlapping cosmid clones. The first lymphoblastoid line, showed that they reside on 6p intron of the DP13 gene contains a processed either centromeric to HLA-B or centromeric to pseudogene of ribosomal protein L32 (RPL32PJ). HLA-DP.77 79 They may be in an analogous posi-copyright. A gap of at least 125 kb separates two genes of tion to the mouse, namely centromeric to HLA-B unknown function, DZa and DO1, and this could (H-2D in mouse).l''" contain other genes. Both DZa and DOfi are tran- The murine T/t complex is characterised by two scribed, but so far no transcripts have been found large inversions.26 Chromosomal abnormalities of for the DX genes. DXa and P3 are closely related this type could explain many of the associated by sequence to the next two genes, DQa and P, phenotypes and although this structural rearrange- which encode the serologically defined HLA-DQ ment may be peculiar to the mouse, it is still plau- product. sible that syntenic loci therein have a homologoushttp://jmg.bmj.com/ The DR region contains one a chain gene, DRa, location on human chromosome 6. The murine one or two expressed 13 chain genes, and a variable TCPI gene is contained within the T/t complex, but number of pseudogenes. Notably DRI persons con- its human homologue was recently mapped to tain only one expressed gene whereas most of the 6q23-*qter in humans.'"3 other DR types contain two. There is a considerable Spinocerebellar ataxia (SCAI) maps within 12 gap, probably over 300 kb (D Campbell, 1987, per- cM of the MHC by conventional linkage analy- sonal communication), before the class III region. sis.80 xl Localising unique DNA sequences to speci- The recently discovered HLA class II gene DV1 fic positions within the genome is invaluable in on September 30, 2021 by guest. Protected remains to be placed on the map but is probably mapping genetic disorders, especially if RFLP data near DX (H Inoko, 1987, personal communication). exist, and assists the detailed analysis of chromo- some structure. Levine et a182 recently showed that HLA CLASS III GENES AGB6 mapped between PGKIP2 and HLA, using Conventional linkage analysis established that this mutant cell lines that were deleted for GLO1 but region lay between the HLA-D and HLA-A,B,C positive for PIMJ. AGB6 is 7 cM away from GLOI, regions. Although the order of the genes in the class which in turn is 6 cM away from HLA. III region has been established, the orientation of Anonymous DNA markers on the telomeric side the complex vis a vis the neighbouring class II and of the HLA complex include D6S8 and D6S7, class I regions has not been determined. It might be which are 4 cM and 45 cM away from HLA, respec- predicted that the order is the same as in mice, '(' tively.83 The BEVI locus maps to chromosome 6,84 given the general structural similarities of the two and it is of interest that the BKMA satellite homologous chromosomes. sequence, which is a characteristic of the sex deter- The class III region has been mapped in detail mining chromosome in the heterogametic sex of J Med Genet: first published as 10.1136/jmg.24.11.649 on 1 November 1987. Downloaded from

Ge - nd medical genetics 655 other vertebrates, shows an 80% concordance with techniques agrees more or less with the recombina- chromosome 6.85 tion data (assuming 1 cM is roughly equivalent to Southern blot analyses of human-rodent cell hy- 1 mbp). However, now that restriction fragment brids identified sequences homologous to a ferritin length polymorphisms (RFLPs) of unique sequences heavy subunit cDNA probe on at least eight chro- have been described in most regions, it would be mosomal locations, one of which mapped to valuable to revise the serologically determined re- 6p21-3cen (FTHL).86 87 However, only a sequence combination frequencies, particularly for DP, where that mapped to appeared to be ex- typing has previously been both arduous and inac- pressed in the hybrids. A family study of sibs affec- curate. ted with hereditary haemochromatosis analysed re- combination data which placed the haemochroma- EVOLUTION OF CHROMOSOME 6 tosis locus (HFE) between HLA-A and HLA-B.88 As more genetic markers are mapped in human, rodent, and other species, and chromosome banding DISEASES ASSOCIATED WITH MHC techniques become more sophisticated, it appears As well as haemochromatosis and congenital adre- that relatively large linkage groups may be con- nal hyperplasia there are some 200 diseases that served between species.22 In the primates, chromo- show a statistically significant association, though somal evolution has been relatively conservative and often weak, with the MHC.96 The more detailed homologies between the different species are easy to studies considered insulin dependent diabetes melli- discern. Almost all of the chromosomes of the pri- tus (IDDM), rheumatoid arthritis (RA), myasthenia mates were conserved intact throughout 12 million gravis, Graves disease, , and narco- years of evolution. lepsy. The autoimmune aetiology suspected for Comparison of human chromosome 6 with the many of these diseases implicates the HLA class I or from chimpanzee, gorilla, class II genes directly in the susceptibility, although or orang-utan indicates almost identical banding there is no direct evidence for this. A disease such as patterns.9

narcolepsy is not obviously of the autoimmune type, In rodents, on the other hand, there have been copyright. yet it is almost exclusively associated with a parti- obvious chromosomal rearrangements, such that cular HLA-DR allele, DR2. A new gene closely complete linkage groups are not conserved. The associated with the DRfi chain gene may be HLA linkage group, extending as far as the GLO invoked, although DR2 itself may be one of a marker, is conserved in man and mouse, as well as number of factors that together cooperate to other species including rabbits, hares, dogs, and produce the pathology. Bare lymphocyte syndrome rats. However, HLA-GLO linkage is not observed and some types of severe combined immuno- in chickens.9' deficiency (SCID) are characterised by the absence of low levels of HLA class II and sometimes class I Conclusions http://jmg.bmj.com/ products on lymphocytes. They are caused by lesions in unlinked genes coding for trans acting Human chromosome 6 contains one of the most de- factors which normally promote expression of the tailed areas of the human gene map to date, the HLA-D genes.89 MHC, and its structural analysis will be invaluable The recent report of a patient with combined defi- in the effort to understand the behaviour of the ciencies of and 21-hydroxylase lends , particularly recombination, in the credibility to the argument that the NEU gene lies at context of a detailed molecular map. Moreover, it on September 30, 2021 by guest. Protected 6p213 between HLA-A and GLO.9' will help to establish the genetic basis of many HLA associated diseases and provide material for analy- RECOMBINATION IN THE MHC sing the regulation and function of the MHC in the Having a closely linked set of markers permits de- immune response. The rest of this autosome con- tailed analysis of recombination in the HLA region. tains relatively few markers, a situation that will There is evidence for recombination hotspots that change radically over the next few years. separate the DQ-DR3 region from the rest of class II, since DX and class III markers do not exhibit a We wish to thank Dr Peter N Goodfellow for useful strong association with DO-DR. A recombination discussions and critical reading of this paper, and we hotspot is defined as a region at which recombina- are grateful to Kim Richardson for typing the manu- tion occurs at a frequency higher than the average script. (for a discussion see reference 1). Different haplo- types* may differ in the location of these hotspots. *Haplotype is a term used to refer to the collection of the HLA markers on The new HLA region map generated by physical one chromosome, for example. HLA-Al. B8. DR3 is a common haplotype. J Med Genet: first published as 10.1136/jmg.24.11.649 on 1 November 1987. Downloaded from

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