Rapports to Congress are conveniently planned to present an
authoritative survey of a particular field of research to specialists of other
Two dangers are then to be feared by the rapporteur: One is the
temptation of trying to be complete, an impossible task ending in a confuse
mass of truncated information; the converse is to choose a preferred topic,
ending with a terribly biased judgment on the relative importance of the
No safe way having yet been discovered, between these two pitfalls,
the most honest conduct is to face both risks. I'll then try deliberately to
summarize the general types of error known in man and, secondarily, focus on a
few mechanisms which could be of importance.
I. Excess or lack of same part of the genome
The simplest accident, and the first to be observed in our species is
the malsegregation of one chromosome, leading to abnormal zygotes having a
chromosome present in one or in three exemplars, instead of the regular
Examples of such accidents are unfortunately too familiar to human
geneticists for they affect around one child in every hundred live births.
The common features of the diseases resulting from this mechanism are
twofold: one is a general shift of some of the features of the organism toward
a particular syndrome allowing the clinical diagnosis of the disease. The other
is the malfunction of some important embryological steps, leading to congenital
imperfection of the internal organs or impairment of other functions specially
the heart, the kidney and most of all the brain.
Without going in fine details, it must be remarked that the phenotype
follows a simple pattern related to the chromosomal content. In each case in
which the effect of the excess of one particular segment is known, as well as
the elect of deficiency for the same segment, the two resulting phenotypes are
more or less mirror image of each other, realizing the "type and countertype"
opposition (Lejeune 1966b).
This general phenomenon, first observed in Drosophila melanogaster
with haplo-IV and triplo-IV conditions (Bridges 1921) seems to apply also to
simple organism like the plants or even, in some particular instances, the
bacteria. For example Dr. Khush found in tomato (Khush 1967) that the serration
of leaflets is increased in triplo 11 but decreased in haplo 11. The
leaf-margins of triplo 11 are curled downwards, while those of haplo 11 are
curled upwards. Several other characteristics are affected similarly (personal
Two human examples will clarify this opposition.
Trisomy 21 is generally related to the presence of one extra
chromosome 21. The shift in the phenotype is the same in every race, the mask
of the disease being superimposed to the personal feature of the child.
A few cases of partial monosomies of chromosome 21 are known and the
resulting morphological troubles are the contrary (Lejeune 1966b) of the
stigmata of trisomy: hypertonia opposed to hypotonia; prominent nasion versus
fiat nose bridge; hypocanthus v. epicanthus; narrow pelvis v. enlarged iliac
angles; and biochemically, decrease of alkaline phosphatase v. increase; and
increase of H.I.A.A. excretion v. decrease.
The same phenotypic opposition can be demonstrated in trisomy 18
versus syndrome 18q- (with the typical aspect of the ears, the fingers and the
dermatoglyphics) or in cri du chat disease by deletion of part of short arm of
chromosome 5 versus trisomy for the same segment, or between the trisomy 13 and
its partial countertypes resulting either from deleted 13 (Laurent et al, 1967)
or from ring 13 (Lejeune et al. 1968).
The sexual chromosomes seem at first place to escape this symmetry for
the apparently decisive reason that man is obviously not the countertype of the
woman, although their complementarily is a fundamental blessing of nature.
Indeed XX constitution cannot be opposed to XY constitution, because,
they differ not only in their amount of X material but also in the quality of
the genic information; Y-borne genes are, at least for most of them, not
alleles of X-borne ones.
The difficulty could be overcome by comparing XO condition of Turner
syndrome and to triplo X condition which are symmetrical with reference to the
normal XX women. Here another difficulty is raised by the very mechanism of X
chromosome regulation discovered by Lyon (1962), Ohno (1961) and Brauch Russell
(1963). When more than one X is present, the others become heteropycnotic and,
supposedly, genetically inactive, and farm the so-called Barr bodies. Hence XXX
cells containing two Barr bodies have only one X active, like the normal XX
cells having one Barr body. Although this mechanism cannot be perfect, because
if it was, XO Turner should be normal women instead of the frail, sterile
persons they are, this compensation is sufficient enough to prevent the triple
X condition of being an easily recognizable disease.
But, if a four X constitution is realized, the compensating mechanism
is submerged and the phenotypic apposition appear again (Lejeune and Abonyi
1968). Instead of the smallness, large thorax, small pelvis, small vagina, genu
varum, and arterial hypertension of Turner syndrome, tetra X syndrome includes
tallness, narrow thorax, broad pelvis, developed vagina, genu valgum and
As previously quoted the same analysis cannot be applied to Y
chromosome, for XYY man, cannot be opposed to XO Turner, although they could be
considered as symmetrical in relation to the XY normal male.
The only deduction of the available data concerning the effect of an
extra Y is that it increases two male characteristics, the tallness and the
aggressivity (Jacobs et al. 1968). This last point is important because the
likelihood of delinquency among XYY men seems definitely much greater than it
is for the normal XY. This is one of the main points in which human genetics is
touching upon sociological, juridical, and even ethical problems.
All these oppositions between lack and excess of segments of the
genome throw some light in the determination of the individuals. For the
general phenotype as well as far the sexual determination, the harmonious
development is related to an equitable partition of the chromosomes so that
gametes, and later zygotes, receive their right content. This balance of the
karyotype can be disturbed by many different types of accidents. Some of them
are related to the chromosomal mechanics per se, some depends upon abnormal
behavior of the reproductive cells and, finally, some others are related to
these two processes.
II. Chromosomal mechanics
Excess or lack of one chromosome is commonly referred to a meiotic
error or sometimes a mitotic error, leading to the abnormal migration of two
daughter chromosomes in one cell, the other receiving none. This malsegregation
can be primary or related to a previous structural aberration.
Primary cases can be due to abnormal reduction of one gamete and the
oogenesis has been particularly suspected for two statistical reasons: first
the frequency of trisomies, especially trisomy 21, increase exponentially with
the aging of the mother, secondly malsegregations resulting from structural
heterozygosity are much more frequent in the progeny of carrier mothers than in
the progeny of carrier fathers.
If one thinks about that all the eggs which will eventually mature
are present in the newborn girl, and remains in an meiotic phase arrested just
after pachytene (the so-called dictiate stage) for some 15 to 30 years, the
risk of abnormality seems effectively much greater than in the male line in
which a supply of freshly made gametes is constantly available.
Primary malsegregation is the main cause of the segregational load
in man as exemplified by trisomies, and XO or XXY conditions. But more complex
cases do exist.
Structural heterozygosity can produce abnormal segregation if one of
the elements involved in a translocation migrate abnormally. This process
explains the occurrence of some familial aberrations.
The most common of them is a centromeric fusion between two
acrocentric chromosomes like a 21 and a D for example.
From theoretical consideration it was believed that a carrier of a
G-D translocation should produce:
- one quarter of normals
- one quarter of carriers
- one quarter of monosomics G
- one quater of trisomie G
if random segregation was occurring. Indeed, monosomics D and
trisomics D are supposed not to appear either for a mass effect (the D
chromosome being correctly synapted), or for a selective reason (the two
resulting combinations being not compatible with life). For pure monogamy G is
not known, and is also supposed to be lethal, a frequency of 1 trisomic G in
every 3 children was theoretically expected.
Careful statistical treatment of available data (Dutrillaux 1968)
lead to the conclusion that the risk is not 1/3 but merely 1/5.
This discrepancy is most remarkable and is likely to mean that some
ovulations undergo a correct meiosis more often than random segregation would
predict. It could very well be that circumstantial events in the ovary do
increase the risk of malsegregation (Mikamo 1968a and b). For example the data
of Carr (Carr 1967b) indicate that the blockage of ovulation by drugs can
increase the risk of chromosomal malsegregation when fertility is recovered.
This very fact could be of an outmost importance.
If a correlation between the physiology of the ovary and the risk of
chromosomal mistakes could be demonstrated human cytogenetics would make an
When dealing with woman carriers of a translocation, a control of
these phenomena could afford an acceptable answer. Instead of proposing
(Valenti et al. 1968) a puncture of the amniotic sac during pregnancy to
analyze the karyotype of the child and to kill him if he does not fit the
actually required standards of normality, preventive measures could eventually
reduce the risk of malsegregation to a very low level.
The feasibility of such an achievement can be surmised by the fact
that in the progeny of a male carrier, the risk of malsegregation is very low
(Dutrillaux 1968), some 1 in 50.
Such a research is an obvious example of what should be done to
protect cytogenetics from the ever recurring evil and of negative
eugenics-medicine cannot fight genetical misfortune by suppressing the affected
people. If such an apanage was given to geneticists, who is the man who could
be sure that his own constitution would not be voted against someday by
somebody?- and we know that it has happened.
b) Aneusomy by Recombination
In complex rearrangements; i.e. involving three or more breaks of
chromosomes, aneusomy by recombination (Lejeune and Berger 1965) can produce
unbalanced gametes. Normal crossing over inside an inserted fragment for
example or inside a pericentric inversion or in other more complicated figures,
gives rise to duplication/ deficiency in the resulting gametes.
Human cytogenetics is much less advanced than the band pattern
analysis of Dipterian or of Collemboles (Cassagnau 1966) giant chromosomes.
Thus all the rearrangements which do not appreciably change the length of the
chromosomes or the relative position of their centromere are undetectable.
Indeed attempts have been made to analyze meiotic preparation, both
in testicle and in ovary but the difficulties of the prelevements as well as
the imperfection of the actual techniques of analyses restrict greatly the
heuristic potential of this research.
Nevertheless it is surely a field of a great interest. Many familial
syndromes, obviously not related to Mendelian genes, can possibly be due to
some imbalance, and are just awaiting observational recognition.
Among other mechanisms probably at work, two particular ones can be
c) Mitotic Malexchange in Ring Chromosome
From the data of McClintock (1941), it is known that ring chromosome
can produce dicentric ring, which by the classical breakage healing cycle leads
to catastrophic reshuffling of genetic content of the rings.
This fission-fusion cycle, although very different from the
fusion-fission used by the hydrogen bomb firework displayers, is also very
The duplications/deficiencies produced in somatic cells of a carrier
of a ring chromosome appear at random but are regulated by two laws: one is
their production mechanism, which is curiously related to a non-gaussian
(Lejeune 1968b) but pythagorician probability curve (Lejeune 1968a), the other
being the selection pressure inside the organism.
These two components result in a relative convergence of the
phenotype and for example a syndrome related to ring D chromosome can be
observed (Lejeune et al. 1968) . It includes some typical symptoms of the well
known trisomy 13 as well as some deformities which are the countertype of the
stigmata of trisomy. The same mixture is found also in ring-18 syndromes.
Here also theoretical expectation and clinical investigation are
convergent, each of them participating at the understanding of the nature of
d) Selective Endoreduplication
Endoreduplication is produced by two successive duplications of the
whole complement, so that a 2n cell, split finally, in two 4n daughter
Selective endoreduplication (Lejeune et al, 1966) involves only one
element or only a part of it, the rest of the other chromosome having a
perfectly normal behavior. Hence a 2n cell splits in two daughter cells, each
of them being (2n + 1) or (2n + part of a chromosome).
This phenomenon was found to correspond to an inborn lesion of one
chromosome in a very informative family (Lejeune et al, 1968).
A feeble minded woman, who had attempted suicide was found to have a
peculiar gap on the long arm of one of her chromosome 2.
In four cells out of 640, the distal fragment was found
endoreduplicated all the rest of the karyotype being normal.
This person has two daughters-one is normal with normal chromosome;
she has received the normal 2.
The other girl is feeble minded and suffered from a cleft
She also has one abnormal chromosome 2, exhibiting exactly the same
gap as the chromosome of her mother. Identically, selective endoreduplication
of the distal segment was observed.
It is thus quite certain in this case that selective
endoreduplication of the distal fragment of the long arm of chromosome 2 is
related to the preexisting change of structure, the "gap", transmitted from the
mother to the abnormal daughter.
Personal data and enquiries to other laboratories gave us the
conviction that sporadic selective endoreduplicatian can be seen also from time
to time in tissue or in blood cultures. Impression is that 10-4 per
cell is an approximate order of magnitude for the frequency of this
III. Cellular mechanics
Other human conditions with chromosomal aberration are related to
abnormal cleavage of primordial cells.
Two obvious example are known: chimeras and the unidentical monozygous
twins ( so-called heterokaryotic monozygous).
Symbiotic association of two or more populations of cells,
contributing to the realization of one individual can be detected easily if the
two populations differ by their karyotype. Two types are already known on
enough instances to be fairly established: hermaphroditism XX/XY and chimeras
In some cases of true hermaphroditism (Gartler et al. 1962, Grouchy
et al. 1964 and Zuelzer et al. 1964), a double population of cells is detected,
some of them having a normal female karyotype, 46,XX, and the other a normal
male karyotype, 46, XY.
Careful analysis of the blood group systems gives evidence that
erythrocytes are split also in two populations. In some cases it can thus be
proved that the father contributed different alleles to each population; in
other instances it was the mother who furnished the difference.
The primary mechanism of these chimeras is poorly understood.
Broadly speaking they can be considered as the union of two fraternal twin
zygotes who fuse to form one embryo instead of two. Speculation about
simultaneous fecundation of the reduced egg and one of the polar body have been
proposed, but whichever of the steps is the site of the mistake, the chimerical
nature of the individual is beyond any doubt.
An intriguing remark is that if the two "first zygotes" were of the
same chromosomal constitution, i.e. both XY or both XX (and this would happens
in half of the cases) the resulting embryo although a genetic chimera, would be
a phenotypically normal person. The individual would suffer of no obvious
defect, with the reservation of a double population of erythrocytes. Whether
this situation exists or not is uncertain, but the old rule that any human
being is developing from one single egg is possibly not true for every one of
us. Experimentally (Russell and Woodiel 1966) it can be shown that an
individual can have many fathers and many mothers like the compound mice of
Mintz (1965) but this condition is fortunately not to be feared in our species,
as long as the old good days manner of reproduction, will be in usage.
Pure triploidies are not known to be viable in man, as well as in
other mammals (Bomsel-Helmreich 1967), although the frequency of this accident
is fairly high in spontaneous abortions (Carr 1963, 1967a, and Boue and Boue
Nevertheless a few human mosaics including diploid and triploid
cells are known (Böök et al. 1962 and Edwards et al. 1967).
In one case (Lejeune et al. 1967) a double population of
erythrocytes, and the existence of a twin dead in utero, give the proof that
the intersexed infant is a true chimera-the diploid and the triploid cells had
received a different array of blood genes from the father.
The very existence of these chimeras shows that even if most of the
human being are pure clones, some of us represent fully integrated cellular
races. This fruitful and parefull coexistence between elements carrying
different tables of the law of life inside their chromosomes, could be
hopefully a model for societies and nations.
b) Non-Identical Monozygous Twins
Just opposite to the coalescence of two zygotes is the splitting of
one egg in two different embryos. Generally and this is true in the
overwhelming majority of the cases, monozygous twins are identical, that is
looking so much like each other somatically and even psychologically, that
foreigners have difficulties to distinguish one from the other.
If a chromosomal error occurs during the separation of a male
zygote, for example if one of the twins does not receive the Y, the two
children will have very different phenotypes: one being a normal male XY and
the other a sterile woman, an XO Turner (Turpin et al. 1961 and Edwards et al.
1966). Although being genetically of a clonal origin, these twins are different
persons, of different sexes, the imperfect female being a fragment of the male
from which she is issued.
Transposed to the mouse, in which the XO condition is a normal,
fertile female, this accident would give rise to a functional couple, the
equivalent in mammals of the auto-fecundation in plants. A theoretical
application of this phenomenon to the problem of speciation could thus be
envisaged (Lejeune 1968c).
c) Neoplastic Growths
Beside these few examples abnormal replication of chromosomes can be
involved in other conditions, especially in the cancerous process. It would be
much too long to review here how shifts in the karyotype of cells could be
linked with their behavior and how hypothesis on karyotypic clonal evolution
(Lejeune 1966a) can be built to explain the cytological observations made in
For the study of aberrations, it does not matter really whether the
chromosomal mistakes are the cause or the consequence of cancer. The remarkable
fact is that cytogenetics of cancer cells offer us an entire spectrum of all
the possible errors of chromosomal mechanics. From structural rearrangements of
chromosomes, to malsegregation, from selective endoreduplication to abnormal
behavior of rings, from pareful collaboration between cells of different
karyotypes inside the tumor (Hughes 1968), to fight to death against the
carrier organism, all the laws of cytogenetics can be studied in cancer cells,
especially because they happen to be broken in such particular tissues.
The harmfulness of chromosomal errors is fully exemplified in human
cytogenetics but the means by which abnormal phenotypes are constituted are
entirely to be discovered.
After a very promising start some years ago (Jerome 1965), research
of linkage between chromosomal abnormal dosage and specified biochemical
troubles is still in infancy.
If the available data are not summarized in this paper, it is surely
not because of their lack of interest. The recent acquisitions on enzymatic
activities related to chromosomal contents are of an enormous potential
significance, but they are so few and so disparate that any tentative synthesis
is beyond possibility.
This lagging of biochemistry is very much to be deplored and urgent
efforts are needed no matter how great the difficulties can be.
Any success would give the most precious reward to human
geneticists; the first reasonable hope of alleviating the destiny of these
unfortunate, who, having not received an equitable patrimony, are really the
most disinherited of the children of men.
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