In spite of the recent accumulation of data on changes in autosomes,
very little is known about the actual causes of these aberrations and about the
mechanism by which they modify the phenotype.
From the apparently chaotic stage of present knowledge, a few
indications are emerging concerning the factors which predispose to those
accidents. Also, a hypothesis can be proposed concerning the consequences of
We will try to summarize briefly the available data related to these
1. Predisposing factors
In 1895, it was shown by Shuttleworth that the mothers of
21-trisomic children were older, at the birth of the defective child, than
mothers of normal children.
Amply demonstrated since, and shown to be independent of the
father's age or of the birth rank, by Penrose (1934), this effect of the
maternal aging is the most striking predisposing factor for the typical
Remarkably enough the same trend is found in the two other trisomic
syndromes which are well established as cytogenetic entities. From current data
(Lejeune, 1963) the mean maternal age of 25 cases of (17-18) trisomy was 35.2
± 3.8 and of 13 instances of (13-15) trisomy it was 33.4 ± 1.7. These two
means differ statistically from the general mean of the population.
A possibly analogous observation has been made on somatic cells.
From the observations of Jacobs et al. (1961 and 1963) who analysed
more than 10,000 mitotic figures in the leucocytes of more than 200 patients,
it appears that the frequency of the loss of a chromosome is higher the older
is the individual. Selective elimination of the X in women and of the Y in men
seems statistically probable.
This effect of aging on the stability of the genome, either in
somatic or in germcels, is poorly investigated in experimental animals. Only
after X-irradiation did Patterson et al. (1932) find an increase of
non-disjunction with the aging of the egg. It was recently confirmed by Uchida
(1963) that this aging effect does not exist in non-irradiated eggs.
In the case of the abnormal X chromosome (ring-X) Hannah (1955) has
amply demon strated an effect of egg aging on the loss of this ring-X, during
early embryonic cleavages. No affect is detectable on meiosis itself.
B. Peculiarities of the Chromosomes
In the overwhelming majority of chromosomal interchanges involving
acrocentric chromosomes, it seems that, even if an observational bias is likely
(Turpin and Lejeune, 1961), the groups (21-22 and 13-15) run a special risk of
rearrangement. The presence of satellites on those chromosomes, and the
relations of these bodies with the nucleoli, predispose them to that
Mitotic association of acrocentrics (Ferguson-Smith and Handmaker,
1961), and risk of translocation between them (Ohno et al., 1961) or of
mechanical disturbance of segregation, could explain the frequency of the
21-trisomy and 13-trisomy syndromes as well as rearrangements of the 21 ~ 13
type or 21 ~ 21 type. Also, similar timing in DNA synthesis of pairs 21 and 13
as reported by Gilbert et al. (1962) points in the same direction. It is also
worth mentionimg in this context that chromosomal changes produced by the .V.
40 virus in human tells, as reported by Shein and Enders (162) and Yerganian et
al. (19b2), are more frequent in pairs 21 and 13 than in others.
The tentative conclusion that acrocentric satellited chromosomes are
more prone to anomalies than other pairs can be drawn from all these data.
C. Structural Rearrangements
The existence of a structural change in an individual (even if
genetically balanced) increases greatly the probability of the occurrence of an
autosomal disorder in his progeny.
The well substantiated case of the 21 ~ 13 type of translocation in
families with more than one case of the 21 trisomy tan be taken as an
Normally in the progeny of a carrier, having 45 chromosomes and a 21
~ 13 translocation, the free 21 should migrate to the pole opposite to the
hybrid chromosome. Thus, two balanced gametes would be produced, one entirely
normal, the other carrying the translocation. But, if the chromosomal change
impairs the meiotic process, the free 21 could migrate to the same pole as the
translocated chromosome, leading thus to two types of unbalanced gametes, one
nullo-21, the other diplo-21.
The same error could involve the free chromosome 13 as well, but,
possibly by its greater mass 13 dues not seem to be so often affected as the
From the four possible types of children : normals with 46
chromosomes, normals but carriers of the translocation with 45 chromosomes,
21-trisomics with 46 chromosomes due to the translocation and haplo-21, only
the first three are known. The haplo-21 condition is probably incompatible with
embryonic development although compatible with somatic survival (see
A summary of the published data relating to 98 children born from
translocated mothers (Lejeune, 1963) shows that the children are quite equally
partitioned between the three classes : normals, carriers and 21-trisomics. The
implication is that in the meiotic process of the mothers carrying the
translocation, the free 21 migrates quite at random, going one in every two
meioses to the same pole as the translocated chromosome.
Curiously enough this does not seem to be the case in the progeny of
carrier fathers, who barely seem to have 21 trisomic children.
Other instances, like a 21 ~ 22 translocation, conform to this
scheme (Lejeune, 1963), but the 21 ~ 21 type is the most severe of all, giving
rise to only two types of gametes, nullo 21 or diplo 21. Here the progeny of
carriers is only composed of 21-trisomics or of miscarriages.
Two other trisomic syndromes tan also be produced by translocation :
trisomy 13 (Oikawa et al., 1962) and trisomy 17 (Brodie and Dallaire,
D. Chromosomal Interaction
Besides this action concerning the chromosome involved in the
change, it becomes more and more evident that translocation increases the risk
for abnormal segregation of other chromosomes.
Three cases of association between sex aneuploidy and autosomal
translocation have been observed in our laboratory.
One is a XXY Klinefelter carrying a 13 ~ 13 translocation (Lejeune
et al., 1960) ; another XXY Klinefelter was also carrier of a 21 ~ 13
translocation, which he received from his father (normal XY) (Institut de
Progénèse, No. 293). Finally an haplo-X Turner had a 2 ~ 22 translocation,
received from her mother, and was followed in three generations of this family
(Institut de Proggénèse, No. 420).
It is difficult to believe that these associations were purely
In Drosophila also, structural changes in autosomes increase the
frequency of abnormal segregation of the X (Sturtevant, 1944), especially if
the X themselves show structural heterozygosity (Cooper et al., 1955). Also
non-random segregation of the Y can be induced by autosomal rearrangements
This interchromosomal effect seems applicable to for autosomes, as
shown by a few examples.
A 21-trisomic with 47 chromosomes is reported by Moorhead et al.
(1961) to have been born from a mother who was a carrier of a 22 ~ 13
translocation, while the affected child had not received the translocation
A mother of three 21-trisomic and of two normal children was
reported by Shaw, (1962) having an apparent deletion of the small arms and
satellites of one of the small acrocentrics. This marker was transmitted to one
21-trisomic and one normal and not to the others. The same author also reported
another family in which the mother of two typical 47 chromosomes 21-trisomics
exhibited an excess of genetic material on one of the big acrocentrics (partial
A less substantiated possibility is that structural changes increase
the risk of mis segregation also in the somatic cells. This seems likely for
the few first cleavages of the eggs, in the case of ring X chromosomes in
Drosophila, but whether this effect still occurs in adult life is an open
At least it seems an attractive hypothesis to suppose that
chromosomal interaction plays quite a role in accident of cell-division and
that many of these structural changes are rot detectable with the available
techniques. This could explain the accumulation of different chromosomal
diseases in various members of the same kindred. Also the coincidence of more
than one chromosomal change in the same individual should be taken into account
: XXY and 21-trisomy (Ford et al., 1959), XXX and 17-trisomy (Uchida et al.,
1961), 21-trisomy and 17-trisomy (Gagnon et al., 1961).
2. The time of occurrence
A. The Inborn Errors
In the relatively rare instances in which we can detect a
translocation as the cause of a trisomy, or in the case that a trisomic parent
reproduces, we can safely assume that the error occurred at the meiotic stage.
In most of the cases no inference of this type can be made and very often it
can be demonstrated that the error is posterior to fecundation.
In cases of mosaicism it is obvious that the variant cells appeared
after the zygote was constituted. The possibility of the fusion of two
different zygotes, simultaneously produced, has been observed by Garder et al.
(1962) and confirmed since by Beattle et al. (1963) and Grouchy et al. (1963
pers. comm.). This mechanism seems to he related to hermaphroditism and, quite
certainly, is not the cause of the most frequent mosaics.
In the exceptional cases of monozygous heterokaryotic twins (Turpin
et al., 1961, and Lejeune et al., 1962) the error has occurred at about the
same time as the cleavage of the zygote in two différent embryos.
The first report of these exceptional twins (normal XY boy and
XO-twin) has recently been found again by Dent and Edwards (1963, this
congress). Other examples are under investigation.
These accidents, have to be very early. The data of Russel and
Saylors (1961) in the production of XO mice by irradiation of the mother show
that the most sensitive stage is between the penetration of the spermatozoa in
the egg, and the first cleavage of it. It seems at least plausible that the
sudden union of the paternal and maternal genome is a very critical stage. It
could very well be that many of the congenital anomalies are not due to
defective gametes but to abnormal integration of the two genomes. Hence, these
diseases would be in fact acquired by the zygote; the earlier the accident, the
more important the variant population, and the greater the phenotypic
As far as very complex errors, like XXX, XXXX, XXXXY are concerned,
a mechanism of asynchronous duplication of one chromosome could explain the
actual facts math better than gametic errors, or even than the current theory
of the abnormal mitotic segregation. This particular phenomenon of asynchronous
duplication is possibly of real importance as we will see later.
B. The Late Errors
If chromosomal changes occur late in life, that is long after the
embryonic development has taken place, they can no longer give any "congenital"
affect. Nevertheless, the changed cells, if not at a selective disadvantage,
can survive inside the body and constitute a new population, a mutant
The relationship between the evolution of neoplasias and the
chromosomal changes in a clone is one of the most important questions of
The fact that inborn chromosomal errors increase greatly the risk of
certain types of neoplasia is well established. Thus, for example, 21-trisomics
are 20 times more insceptible to acute leukaemia than normal children (see
Stewart, 1961, and Holland et al., 1962), and 2.6 time more insceptible to
other cancers. Besides, a case of association between congenital leukaemia and
13-trisomy has been reported by Schade et al. (1962).
a. Granulocytic Leukaemia
The demonstration by Nowell and Hungerford (1960) of the
occurrence of a typical deletion of a short acrocentric (the Ph1 chromosome) in
cases of granulocytic leukaemia has been amply confirmed by numerous authors.
It is a basic fact that in the bone marrow of individuals affected by
granulocytic leukaemia, there is always a population of cells carrying this
The time at which the first cell carrying a Ph1 arises is not
precisely known but is probably largely prior to the clinical onset of the
disease as demonstrated in a case of Kemp et al. (1963). The normality of the
karyotype in somatic tissues other than blood and blood forming-organs,
demonstrates that it is not a constitutional abnormality.
Entire disparition of one acrocentric has been repeatedly recorded
in acute myeloblastic leukaemia (Ruffie and Lejeune 1962, Atkins and Taylor,
1962). The British authors Tough et al. (1963) consider that the loss involves
the Y chromosome. It remains possible that the missing one is a 21 or a 22
chromosome. This would mean a total deletion instead of the partial deletion
constituting the Ph1 chromosome.
In a case of congenital leucoblastosis in a 21-trisomic girl, we
were able to observe a clone with 54 chromosomes, together with the
intermediate steps between the basic number of 47 (21-trisomy) and the invasive
clone of 54 (Lejeune et al., 1963). The continuous series from 47 to 54
chromosomes, shows that the chromosomal shift was not purely random. Two main
restrictions were observed:
(1) Each karyotype of an immediately greater number contained ail
the supernumeraries found in the karyotype of the reference number. This
observation is very greatly in favour of a clonal derivation of the cells.
(2) Every new supernumerary was first doubled, that is put in
duplicata, before the acquisition of another one. This second fact pointed in
favour of a selective asynchronous duplication of the supernumerary.
That this mechanism can exist is shown by an observation made in a
normal tissue culture, not related at all with the leukaemic case just,
discussed. One tell exhibited 46 chromosomes, one of them only undergoing an
endo-reduplication. The result of such an aberration would be the occurrence of
two cells, both with 47 chromosomes. Thus the reciprocal 45/47 chromosome
repartition postulated in the case of a mitotic mis-segregatïon, would not be
a necessary corollary of the gain of an extra chromosome if this mechanism was
This could take account of the simple relationship found between
chromosomal number and type of aberration, in the case of leucoblastosis just
It is quite possible that this asynchronous duplication could be
of real importance in clonal changes, because it would explain the finding,
already quite common, that extra chromosomes are often found in duplicata,
- Two big acrocentrics in a malignant exudate (Sasaki, 1961).
- Two abnormal very long acrocentrics (Grouchy et al., 1963).
- Two mediocentrics looking like chromosome 3 (Vincent et al.,
Also as previously quoted, this asynchronous duplication could
explain the abnormal condition with many X and many Y chromosomes, without
postulating the highly improbable fusion of very exceptional gametes.
A discussion of autosomal disorders in cancers would be far
outside the intended scope of this brief report. It is sufficient to say that
the actuel data, at least in same instances of leukaemia, give an obvious
support to the clonal theory, first put forward by Hansemann in 1890, and
refined by Boveri (1918) and by Winge (1930). The relationship between
chromosomal aberrations and neoplastic changes is still a matter of
Even so, without going too far in this problem, it is possible to
state briefly which questions should be posed and answered before any judgment
can be proposed.
If the new properties of malignant cells are related to their
chromosomal changes, there must be a "common variant" in all neoplasias of the
same type. The Ph1 chromosome is a good illustration of this type of
Although a given karyotype has to be attained by any neoplasia of
a given type, the pathway should possibly not be entirely the same until the
typical variant is reached. For exemple, it could be that trisomy for a
medium-sized chromosome, is the common variant of the blastic change in
leukaemia, although some cases acquire this trisomy at once, and others after
having previously followed other steps.
Another possibility is that neoplastic cells require a certain
amount of "normality" to be viable. A possible correlation between the remnant
of the normal karyotype, the "normal invariant", and the abnormal is also
worthy of investigation.
The disagreement between those who consider that chromosomal shift
is the cause of cancer, and the others contending that karyotype instability is
the consequence of neoplasia, could thus possibly came to an end if the
preceding requirements could be observed. Then chromosomal changes would not to
be the cause or the consequence of the neoplasia, but the neoplastic process
3. The realization of the phenotype
One of the main problems offered to the geneticist by actual
observation is the following:
How can an otherwise normal set of genes induce severe abnormalities
if present in triplicate instead of the normal duplex condition?
Effectively, besides the haplo-X Turner syndrome, only overdosage of a
chromosome is now known, possibly because of the lethal affects of haplosomy.
The simplest hypothesis put forward to explain the deleterious action of the
21-trisomy was an extrapolation of the law "one gene one enzyme" (Lejeune,
1960). In quantitative terms a diploid would have two activity units of an
enzyme, and a trisomic three. The only point of agreement between this simple
theory and the observed facts consists of the alkaline phosphatase activity of
the polymorphs which is of the order of 3 in 21-trisomics, if the mean value of
normal individuals is taken as 2 (Alter et al., 1962).
Also the decrease of this enzymatic activity in the case of leukaemia
with a Ph1 chromosome fits rather well into the picture that a segment of the
21 chromosome controls the alkaline phosphatase activity; its triplication
raises the activity level in 21-trisomics and its haplosomy decreases it in
leukaemic cells. Experiments comparing the enzymatic activity of cloned cells
with their Karyotypes seem to point in this direction (Decarli, 1963) (this
This biochemical study of acquired chromosamal aberrations is more
promising as a mapping tool, than restriction to the particular inborn
abnormalities. Clonal prolifération can realize chromosomal constellations
which are forbidden by the embryology and are then a material of choice.
This field of cytogenetics is quite new, and it might not be too
surprising if detection of changes in neoplasia could help us to understand
some major biochemical effects of gene overdosage. Thus we might have for the
first time a reasonable hope of understanding the biochemical effects of
chromosomal errors, and eventually of controlling their deleterious
G. MONTALENTI (Italy): Concerning the interchromosomal interaction in
determining anomalies. I would like to know which arguments are in favor of the
hypothesis that the one anomaly is the result of a preceding one, against the
hypothesis that both are determined by the same condition of a spatial genotype
or of certain cells?
J. LEJEUNE (France): In the case of the transmission of a
translocation the interchromosomal affect seems the most likely. When there are
two anomalies in the same zygote it is possible that both are caused in the
same way. In conclusion both mechanisms are possible.
A. FRANCESCHETTI (Switzerland): Dont you think that in analogy with a
chromosomal anomaly influencing other chromosomes that the frequency of the
association of two genic affects can also be explained as the manifestation of
a recessive gene, for example another mutated gene?
J. LEJEUNE (France): Genic interaction seems to be quite a different
biochemical mechanism than chromosomal interactions. The latter represents, no
matter how we think about it at this moment, more an "accident of chromosomal
mechanism" than a biochemical affect in the strict meaning of this word.
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