. REPORT ON CHROMOSOME 6

- Prepared by:

 

W.F. BODMER, Oxford

with the help of

 

W. Bias, Baltimore M. Lewis, Winnipeg

H. Cann, Stanford E. Magenis, Portland

G. Cote, Winnipeg Ae D. Merritt, Indianapolis

J.H. Edwards, Birmingham N B. Olaisen, Oslo \
C. Falk, New York dg. Ott, Seattle

M. Ferguson-Smith, Glasgow M. Rivas, , wick PE nc.
T. Gedde-Dahl, Oslo E. Robson, London

BR. Giblett, Seattle B. Schacter, Baltimore

K.H. Grzeschik, Munster M. Smith, New York

J. Hamerton, Winnipeg L. Weitkamp, Rochester

L. Lamm, Aarhus

The fact that chromosome 6 is singled out for a' report on its own
shows that this is an area of increasing activity and interest,
stimulated by the assignment of the HLA region to chromosome 6.
This assignment is now fully confirmed by direct detection of HLA

13,24

segregation in man-mouse somatic cell hybrids’ Following

the recent 6th International Histocompatibility Testing Workshop
in Aarhus?“, the nomenclature of: the HLA region has been somewhat
revised to take account of the increasing number of loci being .

assigned to the region, as indicated in Table l.

An overall summary of the mapping data on chromosome 6, including
HLA fine structure, is given in Figure 1. The main advances since

the 2nd Human Gene Mapping Conference are:
Ee

>

(1)

(2)

(3)

BODME

tr
8
N

The assignment of GLO to this linkage group shel Ty a7
Combined lod scores for GLO-HLA are given in Table II.
Somatic cell data’ show only two exceptions (one clearly
due to chromosome breakage) to GLO and chromosome 6
segregation in 15 independent man-mouse hybrids and

no consistent segregation with any other chromosome.

The detection of linkage between PGM-3 and the
centromere using ovarian teratomas??. This provides
the first clue to the possible orientation of the HLA

region in relation to the centromere.

A great increase in knowledge concerning the fine
structure mapping of the HLA region, including
especially the assignment to it of genes controlling
the second’, fourth i and eighth?? complement
components and the Rodgers blood group®. The 6th
Histocompatibility Testing Workshop’, in addition
gave rise to a much better definition of the MLC
determinants controlled by the HLA-D locus. So far
it is only C2, C4 and C8 levels that are controlled
by genes in the HLA region, which leaves open the

question as to whether any of the relevant structural

on”

: Oo
Me for

genes are in the region. Only for C2 je the data good

enough to indicate a location for the relevant gene”

(see Figure 1) et Ch and Rg map near the HLA-B and C
loci, with some question as to how far to the left of

B is the BF locu Data on recombination between me,
BF, Cn ome R SS

three markers and HLA-A or B are given in Table V.

W

The Rg- allele is in strong linkage disequilibrium with
BODMER

B8 and in significant linkage disequilibrium with
BW40 (formerly W10) and pee 8. The Ch- allele is in
significant linkage disequilibrium with B12 and BW35

(formerly w5y2r28,

Further data have added to the lod scores between PGM-3 and HLA,
as indicated in Table III. A summary of some negative lod scores
for exclusion of linkage with HLA is given in Table IV. So far
there $F only very limited data on regional assignment of the
markers within chromosome 6, a deficiency which will surely soon

be remedied by the use of chromosome variants in hybrids.

Ww
TABLE I

New
Region name HLA
Loci ‘HLA-A
HLA-B
HLA-C
HLA-D

Other products or functions:

Chido

BODMER

Old

HL-A

LA or 1
FOUR or 2

AJ or 3

MLC-1, etc.

ww

(Ch) and Rodgers (Rg)
-~“eseme,

CA pica groups.

Bf, C2, C4, C8 - Complement functions.

Immune response, Disease susceptipity

—N "ra" Jontsens.

>
BODMER

TABLE IL

Lod Scores for HLA-GLO

Source 8 = 0.05 0.10 0.20 0.30 0.40
Rochester Paternal 1.98 2.91 2.86 1.92 0.75
Rochester Maternal 3.31 3.08 2.30 1.38 0.50

Sccttlr- Wea Patsmeh 0 +63 O75 066 Om ons

Seattle_Wpy mat 1 :
ea e P aterna oat ae D5E, erie peor”
0.18

Seattle—-wy. Intercross 0.58 0.70 0.46 . 0.04

 

 

Sources: This meeting, refs. 27,17,11.
TABLE IIT

BODMER

 

 

R NR €=0.05 0.10 0.20 0.30 0.40 6
Male 7 6.03 7.29 6.38 4.02 1.46 0.11
34 1.37. 5.10 6.59 5.35 2.83 oy
- - 1.94. ..1.44. 0.88 0.30
Sum 14.33. 14.41 10.25 4.59 ~0.15
Female - -9.73 5.07 1.39 -0.20 0.03 0.4
11 -12.39 6.74 2.14 -0.42 -O.11 0.43
- 1.31 -0.46 <-0.14 -0.22
i bo.
Sum -0.76 OrQ

Reference

10
BODMER

TABLE IV

 

At 0

0.05 : Co

0.10 : ADA, AK~1, AMY, El, Gm, Hb8, Inv, PGD, Pi, Pr

0.20 7 AcP-1, C3, ESD, Fy, Gc, GPT, GT, Hp, Jk, Kell, Le, Lu, P
0.30 3 ABO, MNSs, PGM-1, Rh, Se.

Sources ;: References 16, 17, 26 (This list is not exhaustive)
BODMER

TABLE V

 

Recombinants Non-recombinants References
Ch : HLA-B Oo 139 9, 18, 17
Rg : HLA-A, B or BE O 105 8
20
BE : HLA-B O 219 Lamm, L
(in press)
Bf ; HLA-A, B or C 3 120 23

0 44 1
BODMER

FIG, 1

Chromosome 6 Mapping

oe a
2, LI ,
Pairwise (centromere) O ————————PGM<-3 95% limits:7-34 : pP (22)
Linkages ~.. LO. :
GLO —~-———_-HLA lod = 7.4 F,S 3; C (11,17,27)
eed 20...
HLA ——————Pg-5 lod = 3.5 F: P (25,27)
poem-3 —L>-(male)izn 10d = 14.4 F, S: C (3,10,16)
Also on 6 : ME=-1, SOD-1 8S: C
Regional Exclusions

Localization (Deletion or 6pterw 6p22 ——O————- 6q27™Méqter (4,5,6)
translocation) °

 

 

Inclusion
(Inversion) 6p22 Coon «6923 (15)
Tentative GLO?
Map ¢
HLA region
Map

 

Than Gat so Cs- -WLA A racowbuwels
oR eav ©8-HLA- B reconianete ‘
BODMER

Footnotes to Fig. 1

(a) Map distances are given in cM.
(b) P = Provisional, C = Confirmed, F = Family, S = Somatic Cells.
(c) The arm of this linkage group cannot yet be determined.

The orientations of PGM-3,HLA, Pg-5 and the centromere

are based on the relative map distances, which are still
clearly subject to a substantial margin of error. Direct
mapping of HLA to the centromere using ovarian teratomas
should readily establish whether the given order is. correct.
The orientation of the HLA region with respect to PGM-3

is based on the data of Lamm et ali4a, The uncertainty

for GLO arises from a conflict between the data of Kompf
et ail4 , which shows substantial negative lods with PGM-3
and that of Weitkamp et al (this conference)?’, which
suggests, from HLA recombinants, that GLO is on the B side
of HLA.

(d) This BLA region map is a summary assessment from a number
of sources including especially, for Bf, Ch, Rg and C8

8, 9,19, 20

papers in this volume , for A, B, C, D and C4

papers in Histocompatibility Testing 197577, and for
C2, Fu_let al’. No attempt has been made to include
incompletely defined markers such as those for disease

association and immune response, ‘Ia' like antigens or

the proposed second 'weak' MLC locus.

Numbers in parentheses refer to relevant
references in this volume and elsewhere ,as listed at the end of

this report.
BODMER

References

a Sang. 27:382

l. ALLEN, F.H., Jnr. 1974 Linkage of HL-A and GBG (Factor B), Vox /

2. BENDER, Kv and GRZESCHIK, K.H. Assignment of the genes for human
glyoxalase I to chromosome 6 and for human esterase-D to chromosomel?:

(This conference)

3. BIJNEN, A.B., SCHREUDER, I., GILES, C.M., LOS, W.R.T.,
MECRA KHAN, P., VOLKERS, W.S., and VAN ROOD, J.J. A study
of genetic markers in families with a recombination in the HLA
region. P.77,Human Gene Mapping 2, Rotterdam Conference (1974)
Ed. D. Bergsma (Karger, Basel), 1975.

4, BORGAONKAR, D.S. and BIAS, W.B. HLAA loci and chromosome 6,
p. 67 New Haven Conference (1973)

5. EDWARDS, J.H., MACKINTOSH, L.P. and McDERMOTT, A. The‘ Hemde
Family: a 1/6 translocation. This conference (1975) .

6. FERGUSON-SMITH, M. This conference (1975)

7. FU, S.M., STERN, R., KUNKEL, H.G., DUPONT, B., HANSEN, J.A.,
DAY, J.K., GOOD, R.A. and JERSILD, C. MLC-determinants and C2
deficiency: LD-7a associated with C2 deficiency in four
families. J. Exptl. Med. (In press, 1975).

8. GEDDE-DAHL, T. and ROBSON, E.B. Rodgers blood group and the
HLA region. This conference 1975

9. GEDDE~DAHL, T., GILES, C.M., THORSBY, E., OLAISEN, B. and
ROBSON, E.B. Chido blood group and the HLA region. This
conference 1975.

10. GEDDE-DAHL, T., THORSBY, E., and OLAISEN, B. (unpublished)

11. GIBLETT, E.R. and LEWIS, M. Gene Linkage Studies on
Glyoxalase 1. This conference 1975 .

12. Histocompatibility Testing 1975. Ed. F. Kissmeyer-Nielsen
Munksgaard, Copenhagen.

13. JONES, E.A., GOODFELLOW, P., KENNETT, R.H., BODMER, W.F.

Independent Expression of HLA and B, Microglebulin on

Human-Mouse Hybrids. This conference 1975,
14.

l4a

i5.

16.

17.

18.

19.

20.

21.

22.

23.

BODMER

KOMPF, J., BISSBORT, S. and RITTER, H. Red Cell Glyoxalase I

(B.C. : 4.4.1.5 ) : Formal Genetics and Linkage Relations.
Humangenetik 28, 249-251. (1975) .

LAMM, l.U., KISSMEYER-NIELSEN, F., SVEJGAARD, A, BRUUN PETERSEN, G.,
THORSBY, E., MAYR, W. and HOGMAN , C. On the orientation of the

HLA region and the PGM 3 locus in the chromosome. Tissue

Antigens 2, 205-214 (1972).

LAMM, L.U., FRIEDRICH, U., PETERSEN, G.B., JORGENSEN, J., NIELSEN, J
THERKELSEN , A.J., and KISSMEYER-NIELSEN, F. Assignment of the Major
Histocompatibility Complex to Chromosome 6 in a Family with a
Pericentric Inversion. Human Heredity 24 273-284 (1974)

LAMM, L.U., THORSEN, I.L., PETERSEN, G. BRUUN, JORGENSEN,
HENNINGSEN, K., BECH, B. and KISSMEYER-NIELSEN, F. Data on

the HL-A Linkage Group. Ann. Human. Genet. 38, 383-390 (1975)
LEWIS, M. et al This conference (1975)

MIDDLETON, J., CROOKSTON, M.C., FALK, J.A., ROBSON, E.B.,

COOK, P.J.L., BATCHELOR, J.R., BODM:R, J., FERRARA, G.B.,
FESTENSTEIN, H., HARRIS, R., KISSMEYER-NIELSEN, F., LAWLER, S.D.,
SACHS, J.A. and WOLF, E. Linkage of Chido and HL-A. Tissue
Antigens, 4, 366~373 (1974).

MERRITT, A.D., PETERSEN, B.H., BIEGEL, A.A., MEYERS, D.A.,

BROOKS, G.F., HODES, M.E. Chromosome 6: Linkage of the

Eighth Component of Complement (C8) to the Histocompatibility
Region (HLA). This conference 1975.

OLAISEN, B., TEISBERG, P., GEDDE-DAHL, T. and THORSBY, E.

BF locus and the HLA region. This conference 1975.

OLAISEN, B., TEISBERG, P., GEDDE-DAHL, T., and THORSBY, E.

The Bf locus in the HLA region of chromosome 6 : Linkage

and association studies. Humangenetik (in press)

OTT, J., HECHT, F., LINDER, D., LOVRIEN, E.W., KAISER McCAW, B.,

)

Human centromere mapping using teratoma data. This conference 1975

RITTNER, C.H. et al in Histocompatibility Testing 1975.
24.

25.

26.

27.

BODMER

SMITH, M. et al This conference 1975

WEITKAMP, L.R. and TOWNES, P.L. Genetics of the Urinary

Pepsinogen Isozymes. Proc. 3rd Int. Isozyme Conf., New Haven 1974.

Ed. C. Markert.
WEITKAMP, L.R.

WEITKAMP, L.R.

Academic Press.
et al Human Heredity (in press)

et al This conference 1975