Origin and significance of autosomal abnormalities

Jérôme Lejeune

Genetics Today; Proceedings of the XI International Congress of Genetics; The Hague, The Netherlands, September, 1963, Pergamon Press, Oxford, London, Edinburgh, New York, Paris, Frankfurt, 1964. 823-831.


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 chromosomal imbalance.

We will try to summarize briefly the available data related to these two features.


1. Predisposing factors


A. Aging

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 21-trisomy syndrome.

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 instability.

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 example.

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 21.

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 below).

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, 1962).


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 fortuitous.

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 (Grell, 1962).

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 himself.

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 21 translocation?).

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 question.

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 abnormality.

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 clone.

The relationship between the evolution of neoplasias and the chromosomal changes in a clone is one of the most important questions of cytogenetics today.

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 deleted chromosome.

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 at work.

This could take account of the simple relationship found between chromosomal number and type of aberration, in the case of leucoblastosis just quoted.

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, e.g.

- 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., 1963).

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 controversy.

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 argument.

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 itself.


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 congress).

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 effects.



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.



ALTER, A. A., LEE, S. L.,, POURFAR, M. and DOBKIN, C. (1962) Leucocyte alkaline phosphatase in mongolism; a possible, chromosome marker. J. Clin, Investig. 41, 1341.

ATKIN, N. B. and TAYLOR, M. C. (1962) 45 chromosomes in chronic myeloid leukaemia. Cytogenetics 1, 97-103.

BEATTLE, K. M., ZUELZER, W. W. and REISMAN, L. (1963) Generalized mosaicism with quantitative disparity of two genetic products attribuable to double fertilisation of two egg nuclei. Proc. Am. Soc. Hum. Genet. July p. 9, Section 15.

BOVERI, T. (1915) Zur Frage des Entstehung maligner Tumoren. Jena Fischer in 8°.

BRODIE, H. R. and DALLAIRE, L. (1962) The E-syndrome (trisomy 17-18) resulting from a maternal chromosomal translocation. Can. Med. Ass. J. 87, 559-561.

COOPER, K. W., ZIMMERING, S. and KRIVSHENKO, J. (1955) Interchromosomal effects and segregation. Proc. Nat. Acad. Sci. Wash. 41, 911-914.

FERGUSON-SMITH, M. A. and HANDMAKER, S. D. (1961) Observations on the satellited human chromosomes. Lancet, i, 638-640.

FORD, C. E., JONES, K, W., MILLER, D. J., MITTWOCH, U., PENROSE, L. S., RIDLER, M. and SHAPIRO, A, (1959). The chromosomes in a patient showing both mongolism and the Klinefelter syndrome. Lancet i, 709-710.

GAGNON, J., KATYK-LONGTIN, N., DE GROOT, J. A. and BARBEAU, A. (1961) Double trisomie autosomique à 48 chromosomes (21 + 18). L'Union Med. Canada 90, 1-7.

GARTLER, S. M., WAXMAN, S. H. and GIBLETT, E. (1962) An XX/XY human hermaphrodite resulting from double fertilization. Proc. Nat. Acad. Sci. Wash, 48, 332-335.

GILBERT, C. W., MULDAL, S., LAJTHA, L. G. and ROWLEY, J. (1962) Time sequence of human chromosome duplication. Nature 195, 869-873.

GRELL, R. F, (1962) A new hypothesis on the nature and the sequence of meiotic events in the female of Drosophila melanogaster. Proc. N. Acad. Sc. Wash. 48, 165-172.

GROUCHY, J. DE, VALLEE, G. and LAMY, M. (1963) Analyse chromosomique directe de deux tumeurs malignes. C. B. Acad. Sci. 256, 2046-2048.

HANNAH, A. (1955) Environmental factors affecting elimination of the ring-X chromosome in Drosophila melanogaster. Z. Indukt. Abstam. Vererb. 86, 600-621.

HANSEMANN, D. VON (1891) Uber pathologische Mitosen. Virch. Arch. 123, 356.

HOLLAND, W. W., DOLL, P.. and CARTER, C. O. (1962) The mortality from leukaemia and other cancers among patients with Down's syndrome (Mongols) and among their parents. Brit. J. Cancer. 16,177.

JACOBS, P., BRUNTON, M., COURT BROWN, W. M., DOLL, R. and GOLDSTEIN, H. (1963) Change of human chromosome count distribution with age : evidence for a sex difference. Nature 197, 1080-1081.

JACOBS, P. A., COURT BROWN, W. M. and DOLL, R, (1961) Distribution of human chromosome counts in relation to age. Nature 191, 1178-1180.

KEMP, N. H., STAFFORD, J. L. and TANNER, R, (1963) Aetiology of leukaemias. Lancet ii, 95.

LEJEUNE, J. (1960) Le mongolisme, trisomie dégressive. Thèse Science-Paris 1960 in: Ann. de Génétique 2, 1-34.

LEJEUNE, J. (1963) Autosomal disorders. Pediatrics, 1963, 32, 326-337.

LEJEUNE, J., BERGER, R., HAINES, M., LAFOURCADE, J., VIALATTE, J., SATGE, P. and TURPIN, R. (1963) Constitution d'un clone à 54 chromosomes au cours d'une leucoblastose chez une enfant mongolienne. C.R. Acad. Sci. 256, 1195-1197.

LEJEUNE, J., LAFOURCADE, J., SCHARER, K., DE WOLFF, E., SALMON, C., HAINES, M. and TURPIN, R. (1962) Monozygotisme hétérocaryote : jumeau normal et jumeau trisomique 21. C. R. Acad. Sci. 254, 4404-4406.

LEJEUNE, J., TURPIN, R. and DECOURT, J. (1960) Aberrations chromosomiques et maladies humaines. Syndrome de Klinefelter XXY à 46 chromosomes par fusion centromérique T-T. C.R. Acad, Sci. 250, 2468-2470.

MOORHEAD, P. S., MELLMAN, W. J. and WENAR, C. (1961) A familial chromosome translocation with speech and mental retardation. Am. J. Human genet. 13, 32-46.

NOWELL, P. C. and HUNGERFORD, D. A. (1960) A minute chromosome in human chronic granulocytic leukaemia. Science 132, 1497.

OHNO, J., TRUJILLO, J. M., KAPLAN, W. D. and KINOSITA, R. (1961) Nucleolus organisers in the causation of chromosomal anomalies in man. Lancet ii, 123.

OIKAWA, K., GROMULTS, J. M. JR., HIRSCHHORN, K. and NOVINS, J. (1962) 13-15 trisomy with translocation. Human Chromosome Newsletter 7, 11.

PATTERSON, J. T., BREWSTER, W. and WINCHESTER, A. M. (1932) Effects produced by aging and X-raying eggs of Drosophila melanogaster. J. Heredity 23, 325-333.

PENROSE, L. S. (1934) A method of separating the relative aetiological effects of birth order and maternal age. With special reference to mongolian imbecility. Ann. Eugenics 6, 108.

RUFFIE, J, and LEJEUNE, J. (1962) Deux cas de leucose aigue myeloblastique avec cellules sanguines normales et cellules haplo (21 ou 22). Rev. Fr. Et. Clin. Biol. 7, 644-647.

RUSSEL, L. B, and SAYLORS, C. L. (1961) Induction of paternel sex chromosome loss by irradiation of mouse spermatogonia. Genetics 47, 7-10.

SASAKI, M. S. (1961) Cytological effect of chemicals on tumors. XII A chromosome study in a human gastric tumor following radioactive colloid gold (Au 198) treatment. J. Fac. Sci. Hokk Zool. 14, 566-575.

SCHADE, H., SCHOELLER, L. and SCHULTZE, K. W. (1962) D-Trisomie (Patau syndrome) mit kongenitaler myeloischer Leukämie. Med. Welt. 2690-2692.

SHEIN, H. M. and ENDERS, J. F. (1962) Transformation induced by simian virus 40 in human renal cell cultures. I Morphology and growth characteristics. Proc. N. Acad. Sci. Wash. 48, 1164-1172.

SHEIN, H. M., ENDERS, J. F. and LEVINTHAL, J. D. (1962) Transformation induced by simian virus 40 in human renal cell cultures. II Cell-virus relationships. Proc. N. Acad. Sci. Wash. 48, 1350-1357.

SHUTTLEWORTH, G. E. (1895) Mentally Deficient Children. H. K. Lewis, Edit. Londres.

STEWART, A. (1961) Aetiology of childhood malignancies and congenitally determined leukaemias. Brit. Med. J. i, 452-460.

STURTEVANT, A. H. (1944) in: T. H. MORGAN and A. H. STURTEVANT, Carnegie, Inst. Wash. Year Book 43, 164-165.

TOUCH, I. M., JACOBS, P. A., COURT BROWN, W. M., BAIKIE, A. G. and WILLIAMSON, E. R. D. (1963) Cytogenetic studies on bone-marrow in chronic myeloid leukaemia. Lancez i, 844-846.

TURPIN, R, and LEJEUNE, J. (1961) Chromosome translocations in man. Lancet i, 616-617.

TURPIN, R., LEJEUNE, J., LAFOURCADE, J., CHICOT, P. L. and SALMON, C. (1961) Présomption de monozygotisme en dépit d'un dimorphisme sexuel: sujet masculin XY et sujet neutre, haplo X. C. R. Acad. Sci. 252, 2945-2946.

UCHIDA, I. A. (1963) The effect of maternal age and radiation on the rate of non-disjonction in Drosophila melanogaster. J. Canad. Genet. Cytol. 4, 402-408.

UCHIDA, I. A. and BOWMAN, J. M. (1961) XXX, 18-Trisomy. Lancet ii, 1094.

VINCENT, P. C., SINHA, S., NEATE, R., DEN DULK, G. and TURNER, B, (1963) Chromosome abnormalities in a mongol with acute myeloid leukemia. Lancet i, 1328-1329.

WINGE, O. (1930) Zytologische Untersuchungen über die Natur maligner Tumoren. II Teerkarzinome bel Mäusen. Z. Zellforsch. 10, 683-735.

YERGANIAN, G., SHEIN, H. M. and ENDERS, J. E. (1962) Chromosomal disturbances observed in human. fetal renal cells transformed in vitro by Simian virus 40 and carried in culture. Cytogenetics 1, 314-324.