Since the demonstration of the correct number of chromosomes in man 
in 1956 and the discovery of the first chromosomal disease in man  in 1959,
human cytogenetics has developed in an explosive way during the early 'sixties
and has since settled down to a steady growth rate.
Since 1965 the number of new syndromes discovered each year has
gradually diminished and fears were expressed that cytogenetics had passed
direct from infancy to senescence. The reason for this was that whereas the
early successes were wan easily and rapidly, the techniques remained quite
unchanged except for minor refinements.
Even autoradiography, which registered encouraging advances in the study
of the X chromosome and, to a lesser degree, in the field of acrocentrics,
failed to break new ground in chromatid analysis.
In 1968 a new era was opened when Caspersson et al.  observed a
peculiar pattern of fluorescence in the chromosomes of Vicia faba and Trillium
erectum following quinacrine mustard staining activated by UV light.
Apparently the importance of the findings was not fully grasped by
researchers in human cytogenetics and it was only when Caspersson & Zech
 revealed the whole human karyotype where every pair was clearly
distinguishable that the rush on chromatid fine structure analysis started all
over the world.
Although the fluorescence pattern is still the most accurate analytical
tool, its technical difficulties prompted research into other procedures more
amenable to routine exploitation.
The diversity of tortures inflicted upon chromosomes in order to force
them to divulge their inner information is really amazing. Boiling them ,
digesting them , burning them with alkali  or salts (8), even
intoxicating them before fixation  - all these maltreatments have been treed
I do not intend here to review all the available techniques, as I am
personally aware of more than 20 variants. I will merely cite some of the more
immediate achievements that have resulted from the analysis of the fine
structure of chromatids.
Impact on Clinical Cytogenetics
To quote all the improvements in syndrome analysis brought about by
the new techniques, whether fluorescence or denaturation, would be an enormous
task. I will nevertheless run the risk of missing some of the important
improvements by concentrating art only a few of then.
Confirmation of previously established
New techniques have made refinements in the recognition of
chromosomal error in all trisomies and all deletion syndromes.
For instance, in the case of a deletion of the short arm of a group
B chromosome, tedious clinical comparisons and painstaking autoradiographic
investigation  had already led to a distinction between 4p- and 5p- for
"cri du chat") syndromes. With chromatid analysis this distinction was now
elucidated and definitely established (11).
A curious feature is that the two clinical syndromes, although
clearly distinct, are to same extent apparently related, just as chromosomes 4
and 5 exhibit same similarities. Such a consequence could be extremely
significant, since it will be encountered repeatedly.
For the medium-sized chromosome, clinical demonstration of a
particular C-trisomy has been confirmed by fluorescence identification of pair
8 by de Grouchy et al. [ 12], and now confirmed in at least six cases by our
heat denaturation technique , Trisomy 8 is the only C-trisomy hitherto
individualized but, as we shall see later, partial trisomy 8 can also be
In the case of acrocentrics, chromatid analysis has established the
syndrome of trisomy 13 beyond doubt and there are good prospects of
individualizing the clinical consequences of trisomy 14 and trisomy 15,
together with the partial trisomies for these elements.
For the E group, only trisomy 18 and syndromes 18p- and 18q- have
been fully investigated and no new syndromes for the F group have yet been
recorded [19, 20].
For the small acrocentrics, highly important data have been
gathered. Primarily, the Y chromosome can be detected by its remarkable
fluorescence, even in the resting nuclei. This technique possesses the same
accuracy for Y diagnosis as does the Barr bodies count for the X
For pairs 21 and. 22, their first separation by Caspersson &
Zech led to unexpected results. The Ph1 chromosome, marker of granulocytic
leukemia, was long supposed to be a deleted 21. The fact that this tiny element
looks much more like a deleted 22 was a surprise (13), in view of the
long-known association between trisomy 21 and acute childhood leukemia.
This again raises the question: Can chromosomes resembling each
other control organs or functions of the same "kinship".
However, it is in the analysis of chromosomal rearrangement that
fine structure analysis refined most of the old observations.
Improved analysis of chromosomal
Rearrangements between acrocentrics:
The detection of each element involved in centric fusion or, more
precisely, in reciprocal translocation in the centromeric region of
acrocentrics, has confirmed the previously anticipated possibilities.
Hence, in a case of G-G translocation carrier, it is easy to
distinguish between a 21-21 and a 2I-22 translocation. In view of the fact that
21-21 translocation leads only to trisomy 21 or to unviable monosomy, this
recognition is of the utmost importance for genetic counselling.
The same is true of D-G translocation. A demonstrable 22-15
translocation, for example, would be considered a relatively tolerable burden,
since neither possible trisomies nor possible monosomies are compatible with
late embryonic development, according to our present knowledge.
A systematic study of the D chromosome involved in D-21
translocation is not yet available, yet it could very well be that the
malsegregation risk of a carrier is not always the same, depending on whether
the D involved is a 13, a 14, or a 15. If one category had a much more stable
meiosis than the others, it might explain the curious fact noted by some
workers  that some D-G translocations seem to be carried by families
without apparent damage, whereas other families exhibit the now-classical
one-in-five risk if the mother is the carrier, or one-in-fifty if it is the
Here again, if a systematic study could possibly relate each type
of translocation to a particular meiotic behaviour, possibly different in the
two sexes, this would give a hint as to how to prevent malsegregation.
Besides these classical centric fusions, chromosome 21 can suffer
ordinary translocation. We have thus observed a mother carrier of a 21q- 18p+
translocation in which the terminal segment of the 21 could be detected on the
top of the short arm of the 18. The 21. trisomic child had a complete trisomy
with two no.21 chromosomes, free and normal, and a third present in two pieces:
the deleted 21 and its end part translocated to chromosome 18.
There have been other instances showing partial monosomy of
chromosome 21, in particular a patient  with 45 chromosomes who apparently
lacked a whole 21. Half of the long arm of the 21 (terminal part) was
translocated on the short arm of chromosome 9. This type of case was thus a
partial monosomy for the juxtacentric portion of 21 and the translocation was
undetectable with ordinary staining. Thus all alleged cases of monosomy 21 need
to be reanalysed with the new techniques.
Rearrangements between other chromosomes
The clearest demonstration of the resolving power afforded by the
new techniques is evidenced by the demonstration of trisomy for the short arm
of chromosome 9.
The syndrome was isolated at our Institute by M.-O. Rethoré ,
who carefully compared the clinical analyses and chromosomal pictures of four
cases of translocation involving the short arm of a C chromosome. Recognition
of the donor chromosome as a no. 9 was based on the observation of the
secondary constriction which, in some cases, passed over to the carrier
As exemplified in various translocations studied by denaturation
the short arm of no. 9 remains detectable in each instance and
gives definite proof of the clinical entity (fig 1).
In addition to these confirmations, the new techniques have
already led to the isolation of new syndromes.
Fig. 1. A case
of trisomy for short arm of chromosome 9 (trisomy 9 p). (Right) the parental
translocation: one of the 9 is amputated of its short arm and one of the 19 has
received this fragment; (left) the child has received two normal 9 and the 19
carrier of the short arm of 9.
Discovery of new syndromes
Among the expected possibilities, trisomy 22 has not yet been
detected by the new techniques. On the other hand, cases with an extra G-like
chromosome have turned out to be something else, as already seen in a karyotype
of the (9p) trisomy syndrome.
Curiously, we have detected, in two apparently unrelated families, a
peculiar translocation which would have escaped detection with the old
techniques (and had indeed escaped us).
Here the entire long arm of chromosome 22 is transferred to the long
arm of no.8 and, reciprocally, the terminal pardon of chromosome 8 is
transferred to the centromeric region of no. 22.
The exchanged segments being of equal length, this translocation
could not be detected by conventional staining .
The children, carriers of an extra G-like chromosome, are trisomics
far the distal portion of the long arm of chromosome 8. This type of reciprocal
translocation of equal length had been anticipated long ago , but awaited
new techniques for confirmation.
There is little doubt that ether examples will be discovered,
leading eventually to the detection of chromosomal imbalance in abnormal
children already classified as "normal karyotype" with the old techniques. This
implies that every negative chromosomal examination of the last 10 years must
be reinvestigated with the new techniques, not to mention all the positive
Analysis of abnormal cells
Although very impressive studies have been devoted to chromosomal
changes in neoplastic cells, further cytogenetic analysis was soon blocked
because of the impossibility of defining precisely the identity of rearranged
Application of the new techniques can radically change this state of
affairs and I would like to remark in passing that with: Mlle Venuat and Dr
Dutrillaux we have been able to observe, in a quasi-diploid malignant strain, a
characteristic aberration of chromosome 6, together with a curious streakiness
of this element farming pseudo-dicentrics .
If the general theory of clonal evolution of the karyotype has any
validity, chromatid fine structure analysis should soon provide the evidence by
demonstrating "common variants" for some classes of cancer.
Eventually this approach could tale immediate advantage of the
enormous wealth of information already gathered by cell hybridization
techniques , The chromosome maps thus established could give a glimpse of
the relationships between gene dosage and metabolic pathways as postulated in
the hypothesis of "combinaisons interdites" .
No doubt the cytogenetics of tumours will change so rapidly in the
next few years that any review of this field is actually impossible.
Impact on Non-human Cytogenetics
Extension of chromatid analyses to animal karyotypes was indeed very
attractive and many of us have, fortunately, not resisted that temptation. It
is well known that the karyotype of the anthropoid apes orang-utan, gorilla,
and chimpanzee, had an "air de famille" and had an obvious resemblance to the
human karyotype. A puzzling feature was that although all the elements of the
chimpanzee karyotype, for example, shared similarities with the human (apart
from the difference in number-48 in the chimpanzee), there was no full metric
agreement between recognisable elements of the two species.
As proposed by de Grouchy & Turleau , this curious situation
might be explained by a number of rearrangements, especially pericentric
With Dr Rethoré and Dr Dutrillaux, we have studied two closely
related chimpanzees: Pan troglodytes (the variety generally seen in zoos) and
Pan paniscus (the pygmy chimp), thanks to the courtesy of M. Nouvelle (Paris)
and M. Vandenbergh (Liege).
The reason for this choice was the earlier finding by Hamerton 
and by Chiarelli  that P. paniscus differed. from P. troglodytes in that a
small acrocentric pair in Paniscus was replaced by a small metacentric
Curiously enough, the expected translocation was not found. All pairs
are identical in both species but for the no. 22, acrocentric in Troglodytes
and metacentric in Paniscus.
By comparing the results of heat denaturation, fluorescence, and
enzymatic denaturation, it appears that the metacentric pair is not an
isochromosome. The long arm is similar to that of no. 22, whereas the short arm
has a very peculiar chromatid structure, highly fluorescent, extremely faint in
denaturation but for its telomeric region, and extremely swollen after
Here, it seems that a particular heterochromatic region constitutes
the real distinction, as if Paniscus had amplified enormously a short segment
of the short arm of no. 22. Hence the difference in the two species seems to be
an increase in material-a de novo synthesis of one part of a chromatid (fig.
If these highly fluorescent regions are related to repetitive DNA and
act essentially in the regulation process, what we see at work here is the
chromosomal picture of a regulatory system.
Besides chromosomal rearrangements, these comparative studies of
chimpanzees have also shown how similar some chromatids can be in man and in
If we count only the very typical structures, and reject the less
conspicuous chromatids, it seems difficult to avoid the conclusion that at
least the long arm of no. 7 as well as of 10 and 11 are identical in both
species. A less precise identity is highly probable for 1, 3, 8, X, 16, 19, 20,
21 and 22, but more speculative for others.
Two remarks are apt here:
(1) Some chromatid structures in primates have remained unchanged for
10 million years at least if we accept morphological similarity as proof of
common origin, i.e. if we disregard a possible convergence.
(2) Chromosomal shift by multiple rearrangement is enormous, but
reshuffling seems to occur more within a chromosome than between different
Hence, every heterozygote step must have suffered from a very severe
segregational load, a proposition contradictory to the progressive mutational
evolution of the neo-Darwinian school. A possible alternative to this paradox
is the reduction of the reproductive group, even to the size of a unique couple
It is also possible that the permanence of some chromatids is not
fortuitous, but may signify that some combinations are highly preferential,
either for positional effect between genes or for regulatory opportunities. For
example, it could very well be that an equilibrium exists inside a chromosome,
in the sense that a trisomy for one arm could be equivalent to the monosomy of
the other, since we have already encountered such a situation in an 18-16
translocation in man .
The impact of chromatid analysis on the speciation theory will no
doubt prove to be enormous, even if only to exclude some forms from some
groups, as is already the case with the Gibbon, which we propose to expel from
the primates, for its lack of chromatid structure similarities to man.
Fig. 2. Analysis of the chromosome 22 of Pan paniscus (pigmy
Chimpanzees) and Pan troglodytes (ordinary chimpanzee). The chromosome 22 has a
greatly enlarged short arm in Pan paniscus (three different individuals) A, B
and C compared with the small arm found in Pan troglodytes (individual D). This
enlarged short arm of 22 in Pan paniscus seems rather "euchromatic" by
conventional staining (Aa, Ba and Ca). Controlled denaturation by heat
demonstrates a heterogeneous structure (Ab, Bb and Cb). Quinacrine fluorescence
shows a very brilliant segment (Ac). Enzymatic treatment confirms the
heterogeneous nature of this short arm (Cd).
Impact an Chromosomal Mechanics
The way chromosomes behave in the intimacy of the cell is quite
difficult to understand from fixed preparations but fine structure analysis can
be used to test hypothetical explanations. Three simple examples can be
Following the lead of McClintock  I have proposed that the
aberrations observed in ring chromosomes could be related to chromatid
exchanges before the separation of centromeres . Theoretical models showed
that, if this were true, double-sized dicentric rings would have a peculiar
structure, in the sense that the sequence of the genes in the two segments
between centromeres would run in the same order but be opposed by their ends.
Secondly, the reduction in size would result essentially from loss of the
central part of the ring and not from loss of the juxtacentromeric segments.
Although this theoretical model was recently challenged by a double breakage
hypothesis , chromatid analysis revealed that these previsions are indeed
confirmed by observations (fig. 3).
For example, as expected, a ring of chromo-some 13 showed
distinctly the dark juxtacentro-meric region and the dark juxtatelomeric
region, after rejoining of the short arm and the end of the telomeric region to
form a ring. In dicentric rings, the sequence can be observed in both
chro-matids which are opposed by their ends. Similarly, in small rings the
middle segment is lacking.
Fig. 3. Some examples of a ring 13.
Note that the small ring is restricted to the dark portions of chromosome 13,
the juxtacentromeric one and the juxtatelomeric. On double-sized dicentrics the
dark juxtacentromeric region remains separated from the dark telomeric region
by a a pale region. It can be seen that the sequence of the bands runs in
opposite direction in the two chromatids and are opposed by their ends.
Selective endoreduplication :
This curious chromosomal misdemeanour is exceedingly rare but very
interesting. In some cells a distal portion of a chromatid is replicated twice,
as we observed nearly 10 years ago. . Curiously, this happens especially
often for the terminal segment of chromosomes which exhibits a, structural gap
at a fixed point. This point is constant for the affected individual and this
chromosomal peculiarity can be inherited as a familial dominant trait .
Sometimes the distal endo-reduplicated segment has a moniliform
appearance and it can be shown that the sequence of these exceptional
structures reproduces, with finer details, the denaturation picture. Hence the
possibility that the event involves an abnormal replication which, in turn, may
be due to the absence of some chemical required to hold together the
Remarkably enough, in some exceptional instances, it is not the
distal part which is present twice but the other arm and the adjacent
centromeric region, as if the real aberration were at the weak point detected
on these chromosomes.
The exact significance of these phenomena regarding the fine
mechanics of the chromosome is not yet certain.
"Aneusomie de recombinaison"
Among the possible origins of chromosome imbalance, the eventuality
of "anosomie de recombinaison"  still lacks definite demonstration in man.
The logic of the argue gent was that some rearrangement could, at meiosis,
produce unbalanced gametes, even without an apparent change of metrics, if only
a chromatid exchange had taken place in a particular exchanged segment. The
simplest instance is an insertion, for a crossover inside the inserted segment
could produce unbalanced chromosomes in meiosis of a heterozygote carrier.
No such type of chromatid exchange has yet been demonstrated, but
the existence of insertion is now certain. Six months ago we found the first
case, a piece of short arm of chromosome 3 inserted in the distal third of the
long arm of chromosome 7.
With ordinary staining, the appearance was that of a reciprocal
translocation, but chromatid analysis reveals the insertion beyond any
Recently, Grace et al.  reported another insertion of part of
long amp of 7 inside the long arm of 3, and Gray et al.  showed an
insertion of the short arm of 1 in the long arm of 4.
In other complex rearrange ments, pericentric inversion can also be
recognised and we have recently analysed one in chromosome 2.
At least the topological conditions for "aneusomie de recombinaison"
do exist in man and the eventual occurrence or absence of this aberration would
increase our knowledge of meiotic mechanisms.
Direct meiotic studies have not yet fully taken advantage of the new
techniques, although, from preliminary observation, Dutrillaux thinks that the
position of chiasmata could have a curious correlation with the banding
Finally, the systematic study of break paints in various
rearrangements will be statistically feasible with the steady increase of data.
In a preliminary study of 28 independent translocations , found in
different families (with no cases of centric fusion in this sample), we could
show that of 56 breaks, 18 were in the centromeric zone, 20 were in the
telomeric zone, and. only 18 occurred somewhere in between the two.
Although the definitions of centromeric and telomeric zones are
quite arbitrary it can be safely assumed that the "in between" is at least ten
times longer than both of then together.
Besides this tendency to break at both ends of chromosome arms, no
case of translocation was recorded in which both breaks could be demonstrated
to be in the intermediate region in these 28 instances.
Hence it could very well be that breaks themselves are not purely
random, but correspond to some peculiarity of chromosomal structure.
This leads us to the last but not the least paint of impact of the
new techniques. What kind of structure is revealed by the various pictures we
can obtain of a chromosome?
Impact on the Knowledge of Chromosome
This last point is of outstanding importance and is to be discussed
more fully later. I shall therefore touch upon this subject with great
To comment bluntly on the present state of observation, we can say
that all techniques available are consistent, although they do not all show the
If we take the four categories now studied, we can compare the
so-called Q-bands (after treatment with the quinacrine mustard staining of
Caspersson et al.), the R-bands (after treatment with the controlled heat
denaturation of Dutrillaux & Lejeune), the E-bands (after treatment with
the enzymatic digestion of Dutrillaux, de Grouchy & Lejeune), and the
G-bands (produced by various Giemsa techniques).
The correlation is as follows:
|Q-band ||R-band ||G-band ||E-band
Since the sequences obtained for a given chromosome are perfectly
comparable we are positive that each technique acts on the same structural
The first impression from the Q-band observation was that quinacrine
could attach specifically at some base-pair of DNA and G-C was considered the
most likely . Hence, the banding would result from the preferential
reaction of quinacrine mustard with portions of DNA especially rich in G-C.
Such an enormous (at the molecular level) concentration of monotonous
formula was disconcerting.
With heat denaturation, this DNA-related banding was less obvious,
because with the temperature (87°C) and the time used, preferential
denaturation of DNA according to its base sequence is not very likely and only
immediate renaturation could occur.
But with the demonstration of the enzymatic bands, the pure DNA
hypothesis is even less tenable. Actually, Couturier  has systematically
used many different enzymes and obtained the same pattern with all the
proteolytic enzymes, but not with others (especially DNase and RNase). More
precisely, he showed that the best conditions for revealing the banding were
the exact pH and temperature conditions optimal far the proteolytic activity of
each enzyme studied.
Thus we are forced to accept the fact that the enzymatic banding
pattern can be related to protein differences along the chromatids.
How do these differences relate to the DNA-specific sequences? What
kind of polypeptide sequence do they represents? Why are some of them more
readily "digested" than others? All these questions remain to be answered.
But the DNA hypothesis and the acid protein hypothesis are not
necessarily conflicting. Of necessity, both DNA, and protein must be sterically
and chemically related to each other so as to build the entity we call a
chromosome. With increasing knowledge of the precise mechanism of each staining
technique, it could very well appear that all of there reveal a peculiar
configuration resulting from DNA/protein interaction and no pure DNA or pure
protein properties alone.
In this line of thought, a structural hypothesis for which Dutrillaux
is mainly responsible, suggests that chromosomes have special relationships
with the nucleoplasm and that banding patterns correspond to these paints of
interaction between chromatids and nucleoplasm.
In other words, chromosomes would no longer be noodles floating in a
bowl of nuclear juice, but would be organelles having definite and localizable
molecular interactions, with a structurally non-homogeneous nuclear content.
Although it is difficult to interpret such a picture completely, it would be
particularly appealing if some meiotic behaviour were found to be related to
Despite all the satisfaction that cytogeneticists have experienced
with chromatid fine structure analysis, one disappointment has been keenly
felt. A bending pattern is, for a geneticist, immediately associated with the
remarkable "topography" of polytenic chromosomes. Curiously enough,
fluorescence studies of giant chromosomes of Dipterae have not yielded any good
correlation with the well known maps of these chromosomes, although ordinary
mitotic chromosomes of this species have a recognisable fluorescent banding
Cold it be that the two banding types correspond to two separate
physiological functions of chromatid segments? This question really is well
worth investigating, for the induction of polyteny in cultured cells would be
another milestone in cytogenetics.
To conclude these introductory remarks on the scientific impact of
chromatid analysis on the recent development of cytogenetics, it can be stated
that the discovery of banding patterns not only gave new impetus to research,
but has actually rendered all previous findings obsolete.
In view of what we have learned with these techniques during two
years, the old preparations seem like a Palaeolithic research tool. Yet as
scientific progress makes rapidly obsolete the keenest refinements of today, it
can be ventured and indeed hoped, that at another meeting such as this, ten
years hence, the present developments under discussion at this symposium will
appear to our successors as neolithic technology.
Fig. 4. A
case of insertion. The middle part of short arm of chromosome 3 is inserted in
the distal portion of long arm of chromsome 7. (a) Actual karyotype of the
individual; (b) cut-out of the chromosomes to show artificially the inserted
piece; (c) the amputated chromosome 3 at left and the long chromosome 7 at
right are the original ones (as shown in a). The amputated chromosome 3 at
right and the long 7 at left are reconstituted by patching together the cut out
fragments seen in (b).
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