Bioscience Reports, Vol. 6, No. 4, 1986
Llypothesis
The Chromosome Territory of Human
Oncogenes
A. Lima-de-Faria 1'3 and Felix M i t e l m a n 2
Received 7 February, 1986
KEY WORDS: chromosome territory; oncogene
The prevailing view of the chromosome of higher organisms is characterized by
randomness. Genes are believed to be located at random and mutations and most
structural rearrangements are likewise supposed to occur at random (1-4).
During the last few years the molecular organization of the eukaryotic
chromosome has been subject to intensive investigation but the evidence has been
mainly on single DNA sequences and their immediate neighbours. Most molecular
findings, such as the split gene, the pseudo-genes, the transposable elements, and the
enhancers, are relatively short DNA sequences and do not furnish information on the
organization of the large structure that is the eukaryotic chromosome considered as a
whole. It is the relative position of DNA segments within the chromosome as a unit that
is the subject of this paper. Every chromosome arm is well delimited by a centromere
and a telomere. It has been established long ago that chromosome arms cannot survive
without centromeres and without telomeres (5). An extensive analysis of the position of
specific DNA segments in a wide number of species has shown that their position
within the chromosome arm is related to the location of the two main regions: the
centromere and the telomere. These results led to the concept of the chromosome field
(6-8). The validity and usefulness of this approach has been shown by the fact that it has
led to predictions on gene location and gene function. An example is the location of the
genes for 28S and 18S ribosomal RNA that can be predicted within reasonable limits
independently of the phylogenetic position of a species and of the length of a
chromosome. An analysis of 165 species (including plants, worms, amphibians and
humans) showed that the ribosomal DNA sequences display two organizatory
features: (i) In 90.5~ of the cases they are located in the short arm, i.e., the one in which
the number of nucleotide pairs between the centromere and the telomere is lowest and
1 Institute of Molecular Cytogenetics, University of Lund, S-223 63 Lund, Sweden.
2 Department of Clinical Genetics, University Hospital, S-221 85 Lund, Sweden.
3 To whom correspondence and requests for reprints should be sent.
349
0144-8463/86/0400-0349505.00/0 9 1986Plenum PublishingCorporation
Lima-de-Faria
350
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Fig. 1. The 136 nucleolar chromosome arms from 92 species of plants
belonging to the family Ranunculaceae showing the location of the DNA
sequences for ribosomal RNA (black circles). All the arms are distributed
according to their length with all the centromeres building a vertical line (C).
The telomeres are marked T and arms of the same length occupy identical
positions (dots on the right). The ribosomal genes show a well-defined
chromosome territory and are located near the telomere irrespective of the
variation in arm length. Of the 136 genes, 125 are located within one micron
from the telomere, and only 11 are outside this region. This means that 91.9%
have a telon territory.
(ii), in 85.2~o of the cases they are located near the telomere, i.e., as the arm length
increases they are successively displaced m a i n t a i n i n g the same relative distance to the
telomere (9) (Figs..1 and 2). O t h e r D N A sequences also display an optimal c h r o m o s o m e
territory. This has made it possible to classify them into centrons, m e d o n s a n d telons,
depending on whether they show a tendency to appear near the centromere, in the
middle of the arms or near the telomeres, respectively. It is this a p p r o a c h that led us to
investigate the distribution of h u m a n oncogenes within the centromere-telomere field.
Of the oncogenes k n o w n , not all of them have been localized on h u m a n
c h r o m o s o m e s at specific bands. Table 1 shows 17 retroviral a n d three n o n - r e t r o v i r a l
oncogenes a b o u t which there is i n f o r m a t i o n of their location at a single or in a
restricted group of bands. N o i n f o r m a t i o n o n c h r o m o s o m e o r g a n i z a t i o n becomes
evident from this data. However, if the centromere-telomere field concept is applied,
order emerges from the data. This is achieved by using the simple arm frame method.
Chromosome Territory of Oncogenes
351
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3
microns
Fig. 2. Location of the DNA sequences for 28S and 18S
ribosomal RNA (black circles) in three species of mammals:
human, gorilla and guinea pig. The arms of the nucleolar
chromosomes which form the nucleolus (diploid number) are
distributed according to their length, the centromeres (C)
building a vertical line. The telomeres are marked T. The
ribosomal RNA genes show the same telomere territory as
those of plants and form a straight line parallel to that of the
telomeres.
All the c h r o m o s o m e a r m s of t h e h u m a n c o m p l e m e n t (or a n y o t h e r species) are a l i g n e d
after t h e i r l e n g t h (irrespective o f the c h r o m o s o m e to w h i c h t h e y b e l o n g ) w i t h all t h e
c e n t r o m e r e s o n a v e r t i c a l line.
It b e c o m e s e v i d e n t t h a t m o s t o n c o g e n e s h a v e a t e n d e n c y to be d i s t r i b u t e d n e a r t h e
t e l o m e r e s (Fig. 3). T o find o u t w h e t h e r t h e i r d i s t r i b u t i o n was r a n d o m a K o l m o g o r o v S m i r n o v test was e m p l o y e d (10). F o r the 17 r e t r o v i r a l o n c o g e n e s the v a l u e s are
D = 0.387, p < 0.01. T h e d e v i a t i o n fi'om r a n d o m n e s s is d u e to t o o m a n y of t h e
o n c o g e n e p o s i t i o n s lying in the t e l o m e r i c half o f t h e c h r o m o s o m e a r m s , in p a r t i c u l a r in
Table 1. Nomenclature, origin and chromosomal localization of human oncogenes
Oncogene
symbol
Origin
Chromosomal
localization
I. Retroviral
src-2
ski
raf-1
fms
myb
erb-B
mos
myc
abl
H-ras-1
ets
K-ras-2
los
fes
erb-A
src-1
sis
Rous chicken sarcoma
SKV 770 avian virus
3611 murine sarcoma
McDonough feline sarcoma
Avian myeloblastosis
Avian erythroblastosis
Moloney murine sarcoma
MC 29 avian myelocytomatosis
Abelson murine leukemia
Harvey murine sarcoma
Avian E26 leukemia
Kirsten murine sarcoma
FBJ murine osteosarcoma
Snyder-Theilen feline sarcoma
Avian erythroblastosis
Rous chicken sarcoma
Simian sarcoma
lp36
lq23
3p25
5q34
6q22 2a
7pll 12
8q22
8q24
9q34
1lp15
11@3-24
12p12
14q21 31
15q26
17@1-22
20q13
22q13
II. Non-retorviral
N-ras
N-myc
met
References (17-19).
Human neuroblastoma
Human neuroblastoma
Human osteosarcoma
lpl I-I3
2p23-24
7q22
352
Lima-de-Faria
S rc "1
K-ras-2, sis
-
-
~
H-ros-1
erb-B
erb-A
.
9
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yp
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20q
12p. 2 2 q
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ets, f e s
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N - m y c , raf-1
",
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..
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o
2p,3p
',
I
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11q.15q
I
myb
N-ras, s r c - 2
ski,fins
11p
.
6q
Ul
4
lp
lqSq
I
2q
T
i
i
|
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i
0
1
2
3
4
i
5
6
6
microns
Fig. 3. The chromosome arms of the human complement
(1 - 22 + x + Y = 48) have been distributed according to their
length irrespective of the chromosome to which they belong. The
centromeres (C) occupy a vertical line and the telomeres are marked
T. The 17 retroviral oncogenes (black bars) and the 3 non-retroviral
oncogenes (white bars) of Table 1 have been localized in specific
bands. The middle point of these bands is indicated by a vertical
dash. On the right side of the graph are dots which mark the number
of arms (arms of the same length occupy the same position in the
graph). Also to the right is the designation of the shortest (Yp) and
longest arm (2q) and of the arms in which oncogenes appear.
the distal fifth of the arm. If one takes b o t h the retroviral a n d n o n - r e t r o v i r a l oncogenes
(all the 20 positions of T a b l e 1) the result is 0.01 < p < 0.05 which still represents the
same type of d e v i a t i o n from r a n d o m n e s s . These results show that oncogenes have an
o p t i m a l c h r o m o s o m e t e r r i t o r y a n d that their preferential l o c a t i o n is in the telomere
region, i.e., they can be classified as telons (Fig. 4).
A n o t h e r aspect of the o n c o g e n e d i s t r i b u t i o n is that they tend to be a b s e n t from the
shortest arms (seven arms which are one m i c r o n or shorter) (Figs. 3 a n d 4). This is m o s t
p r o b a b l y n o t accidental since it agrees with the b e h a v i o u r of other D N A sequences t h a t
we have s t u d i e d previously a n d which also a v o i d the shortest arms, a l t h o u g h there is
plenty of r o o m for t h e m to occur in these arms (9).
The a m o u n t of D N A of the h u m a n d i p l o i d g e n o m e is 5.6 x 109 nucleotide pairs
(11). The length of the h a p l o i d h u m a n c o m p l e m e n t has been e s t i m a t e d to be at
m e t a p h a s e of mitosis 157.1 m i c r o n s (12). Thus, one m i c r o n of a h u m a n m i t o t i c
c h r o m o s o m e c o r r e s p o n d s to a b o u t 18,000 K b of D N A . O f the 20 oncogenes, 14 t u r n
out to be l o c a t e d in the region which extends one m i c r o n from the telomere. This means
that the c h r o m o s o m e t e r r i t o r y of m o s t oncogenes is in a region 18,000 K b from the
telomere.
These results lead us to c o n c l u d e that m o s t oncogenes (retroviral a n d n o n retroviral) so far localized in h u m a n c h r o m o s o m e s turn out to be telons.
Chromosome Territory of Oncogenes
353
3
O~
C
T
I,.
I
I
I
I
I
0
1
2
3
4
5
m icrons
I
6
Fig. 4. Blackarea covers the distribution of
all 20 oncogenes(Table 1)with the exceptionof
erb-B and N-raswhich have a centron location.
Experimental evidence on the interaction between centromeres, telomeres and
other regions of the chromosome has been available for some time (8, 13), but now this
interaction is being found at the D N A and messenger RNA levels. Molecular evidence
is now available which shows that telomeres participate in the expression of genes that
are located in their territory. The protozoan Trypanosoma is a parasite which evades the
immune system of the host. It can switch on new genes that code for its surface antigens.
In this way it rapidly changes the properties of its surface coat. These variable genes are
expressed when two events occur: (i) an extra copy of the gene is produced and (ii) it is
translocated to a telomere region. Only the copy that is located near the telomere
produces the messenger RNA of the new glycoprotein. The gene may have different
positions along the chromosome but the telomere sequences are necessary for
expression (14). This result strongly supports the concept of the chromosome field,
since it demonstrates that the molecular function of a specific D N A sequence depends
on the relative position of the sequence within the centromere-telomere segment.
Moreover, its significance in connection with retroviral oncogenes is twofold. (i) The
human oncogenes are telons like these genes. (ii) The oncogenes of vertebrates are
known to be regular components of the genome of many species, playing a central role
in normal cellular processes, and changing their expression (i.e., become malignant)
when they recombine with a retroviral genome (15, 16). Hence, in both cases there is a
structural rearrangement involved and a telomeric territory.
This information leads us to suggest that: (i) Oncogenes ought to be dependent on
the properties of telomere sequences (or of D N A sequences present in the telomere
region) for their expression. (ii) The oncogenes, which at present do not show a strict
telomere territory (i.e., six cases out of the 20), ought to have different properties or a
different organization of their D N A sequences. (iii) Oncogenes which will be discovered
in the future should mainly be located within the 18,000 K b region from the telomere,
but if they do not have this distribution it means that they should belong to a different
class with diverging properties.
354
Lima-de-Faria
ACKNOWLEDGEMENTS
W e w o u l d like to t h a n k Prof. Bengt-OUe B e n g t s s o n , I n s t i t u t e of Genetics,
U n i v e r s i t y of L u n d , for k i n d l y p e r f o r m i n g the statistical analysis. T h i s w o r k was
s u p p o r t e d b y g r a n t s from the Swedish N a t u r a l Science R e s e a r c h C o u n c i l a n d the
S w e d i s h C a n c e r Society.
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