Chromosomal mechanics and human pathology

Jérôme Lejeune

Proc. XII Intern. Congr. Genetics. Vol. 3 : 379-387. (1969)


Rapports to Congress are conveniently planned to present an authoritative survey of a particular field of research to specialists of other fields.

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 available data.

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 diploidy.

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 communication).

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 arterial hypotension.

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


a) Malsegregation

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 enormous progress

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 discussed briefly.


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 deleterious.

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 the disease.


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 cells.

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 palate.

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 phenomenon.


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).


a) Chimeras

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 diploid/triploid.

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 1966).

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 malignant cells.

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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