L'année 1901, trois biologistes, Correns, Tchermak et H. de Vries faisaient, à peu près simultanément, la nouvelle découverte des lois que, trente-cinq ans auparavant, Gregor Mendel avait formulées.

Les soixante ans qui se sont écoulés depuis cette date ont vu se succéder un nombre extraordinaire de découvertes qui ont prodigieusement enrichi l'ensemble de nos connaissances et bouleversé jusqu'à notre conception même de la matière vivante.

Dès le début du siècle, W. Johansenn introduisait la notion de génotype et de phénotype qui précisait l'action respective de l'hérédité et du milieu.

A cette époque, l'aspect particulier que prend le noyau de la cellule au moment de sa division, l'identification des chromosomes, leur forme de bâtonnets, leur colorabilité particulière, tout cela avait été reconnu déjà. Désormais, il était possible de comprendre et d'expliquer les lois mendéliennes de la ségrégation et de la recombinaison. Dès 1903 et 1904, Sutton et Boberi affirmaient que les chromosomes sont les véritables supports de l'hérédité. En 1908, L. Cuénot, expérimentant sur la souris, établissait définitivement que les lois mendéliennes ne s'appliquent pas seulement aux végétaux et aux insectes mais aussi aux mammifères et qu'elles sont des lois générales pour les espèces vivantes.

The purpose of this first “Round-table Conference” could well be to present the historical development of human genetics from the early days of Mendelism to the elaboration of modern genetic research. The refinement of methodological possibilities and the unfolding of problems indicate to us the proper lines for further study. With this introduction I should like to restrict myself to a few remarks concerning the role of the gene analytical system of Gregor Mendel in human genetics. If as a result of corrent research the concept of the gene has undergone important alterations and is no longer the closed unit of the classical formulation, it still remains a useful concept for practical research. Every investigation of a genetically active factor immediately begins with the determination of a segregating unit or a mutating unit. Determining an allele relationship or a series of multiple alleles will remain the principal result. Quite often in human genetics it has not been possible to demonstrate these relationships as pseudoallelal or with other methods to achieve a differentiation of the gene concept into its subunits: the cistron, recon and muton. So far the objectives of human genetics the employment of the gene concept as classically formulated is methodologically necessary.

The ideal goal of the gene analytical method is to determine the function of all genes which take part in the heredity of an organism, the preparation of theoretical chromosome maps for the various linkage groups, the determination of the relationships between the genes and their alleles to visible or measurable characteristics of the organism, and the establishment of relationships between phenotypic expression and dominance or epistasis. Its further area of interest is in the genetic analysis of natural populations, the question of spontaneous mutability, the problem of genetic diversity and the polymorphism caused by it in populations, and the equilibrium between all alleles. These questions lead necessarily to general problems of population dynamics, adaptation and evolution.

La limitazione del tempo messo a mia disposizione, mi impedisce di illustrare le varie tappe della genetica, intesa come scienza morfologico-descrittiva. Dallo studio delle cellule germinali siamo passati via via a quello dei cromosomi, dei geni, dei loci. A sua volta il gene è stato suddiviso in varie unità indipendenti (muton, recon, cistron). Ma un importante passo avanti è stato compiuto soltanto quando lo studio è stato affrontato dai biochimici, i quali hanno dimostrato che le variazioni strutturali della complessa molecola dell'acido desossiribonucleico (D.N.A.) bastano a spiegare l'enorme molteplicità dei geni, e le loro possibili mutazioni.

Grazie alle scoperte della biochimica noi siamo così passati dallo studio dell'eredità cromosomica e genica a quello dell'eredità molecolare.

Bisogna riconoscere che, in questo campo, i clinici hanno precorso i genetisti ed i biochimici. Spetta infatti al medico inglese Archibald Garrod (1902) il grande merito di avere per primo espresso il concetto che una malattia ereditaria può dipendere da una turba metabolica dipendente da un errore nella sintesi di una molecola proteica. Egli partì dall'esempio della alcaptonuria, alla quale malattia altre ne aggiunse, riunendole nel gruppo degli «inborn errors of metabolism». Questo concetto è stato in seguito allargato, ed anzi alcuni genetisti (Pauling) sostengono che tutte le malattie ereditarie sono dovute a formazione di molecole anormali. Altri autori invece restringono il concetto alle sole malattie nelle quali sono state effettivamente dimostrate mutazioni nella struttura molecolare (come per es. le emoglobinopatie). Io ritengo che convenga scartare sia la defmizione troppo allargata che quella troppo ristretta e di ritenerci autorizzati a parlare di «sindromi molecolari» quando noi ci troviamo di fronte ad una malattia in cui si possa dimostrare o per lo meno presumere che l'alterazione caratteristica risieda a livello di una singola o di più molecole.

Ce sont des recherches effectuées sur les bactéries et les bactériophages qui ont apporté la preuve formelle du rôle génétique des acides désoxyribonucléiques (ADN): parmi les nombreux faits qui démontrent ce rôle, il faut surtout citer les transformations bactériennes (Avery) et l'expérience de la «seringue» de Hershey. Dans le premier cas, l'addition à une souche bactériennea d'un ADN spécifique, isolé à partir d'un mutantb, transmet la mutationb, dans un pourcentage élevé des cas, à la descendance; le caractère ainsi acquis se maintient héréditairement. Pour que la transformation s'obtienne, il faut, évidemment, que l'ADN transformant puisse pénétrer dans les bactériesa et s'incorporer dans leur génome. Quant à l'expérience de Hershey, où un double marquage au 35S et au 32P servait à suivre le sort des protéines et celui de l'ADN lors de l'infection de bactéries par des phages, elle a permis de montrer que ces derniers se comportent comme une «seringue» qui injecte la totalité de l'ADN dans la bactérie infectée; en effet, la pénétration des protéines dans ces bactéries est négligeable par rapport à celle de l'ADN. Cette injection d'ADN a pour conséquence la production de particules de phages complètes, présentant les caractéristiques génétiques exactes du phage dont l'ADN provenait.

It is immediately apparent, that the difficulties encountered in studies of the genetics of the mind are formidable, for several reasons. In the first place, the traits concerned are difficult or impossible to classify or to measure with accuracy. In the second place, they may be unstable towards environmental influence; and they vary with age, or exhibit periodic changes.

It is therefore not surprising that our understanding of genetic mechanisms is limited in those conditions where analysis has been carried out merely on the basis of the mental traits.

The situation is strikingly different in the conditions where an association has been found between a mental trait and some clearly recognisable physical or biochemical trait. As we all know, in several such cases an exact genetic analysis in Mendelian terms has been found possible, for instance in the amaurotic idiocies and phenylketonuria.

May I begin by recalling that at the Copenhagen Conference five years ago, Tjio and Levan had just published their almost apologetic announcement that they could only find 46 chromosomes in cultured human somatic cells, and Hamerton and I presented evidence that there were 23 bivalents in spermatocytes, not 24.

Since that time there has been a very marked expansion of work in human cytogenetics. The reason is not hard to seek: the findings have been of significance in so many fields of medicine ranging from endocrinology, through paediatrics, gynaecology and mental diseases to haematology and cancer.

To the biologist, this outpouring of interest may seem at times to have bordered on the hysterical. For him the developments may have done little more than illustrate in our own species the principles that were established in the twenties and thirties with other material. On second throughts he will realize that man offers unique advantages for cytogenetic study in virtue of the enormous numbers of individuals who are subjected to medical scrutiny and thereby become candidates for chromosomal examination. But he will also remember the serious disadvantages, (some shared with human Mendelian genetics) of long generation time, small family size, impossibility of experimental mating and lack of opportunity (except perhaps rarely in males) to study the meiotic pairing which can be so revealing of homology.

If opportunities for direct test of an interpretation are few, reliance on general hypotheses must be the greater. I make it a rule to doubt an observation if it is not in accord with hypothesis. This is not to reject Bateson's exhortation to “treasure your exceptions”; but one must first make quite sure that they are exceptions. Perhaps one does not make so many new discoveries this way, but fewer may later be shown not to be discoveries after all.

The more significant developments in the field of human population genetics during the past decade can for the most part be subsumed under three headings, as follows:

1. The recognition of an increasing number of genetic traits capable of serving as analytic tools in population studies.

2. The recognition that many of these traits attain frequencies, although some only in limited areas, such that they have to be labelled genetic polymorphisms. Table 1 is an attempt to list the presently recognized human polymorphisms for which the genetic basis seems clear.

3. The emergence of at least a few clues as to the factors responsible for the maintenance of some of the plymorphisms, although it must be confessed that for the majority of the traits listed in Table 1, there is as yet no real insight into their role in populations.

As is well known from the contributions of Fisher, Wright, Dobzhansky, Lerner, Crow, Kimura, and others, genetic polymorphisms have the property of acting as stabilizing mechanisms in maintaining certain aspects of the fitness of populations. Consequently, whereas what we may term the “classical model” of the dynamics of a genetic locus in a population looked to mutation pressure as the source of the impairment of population fitness which could be traced to that locus, the “polymorphic model” views that impairment as in part a price a population pays for the maintenance of an optimum level of heterozygosity at that locus. The two models have such profoundly different practical and philosophical consequences that it is small wonder that in recent years the running discussion of their relative merits and roles has generated a degree of heat matched by few other current biological questions.

The intimate connection between natural selection and heredity is indicated by Prof. Dobshansky's definition of evolution as essentially just a change in gene frequencies, for natural selection is the agency that causes gene frequencies to change. Just as mutations are the raw material of evolution, selection is the force that preserves good genes, eliminates bad genes, and produces the changes that lead to the formation of races, and eventually species.

The problem of the action of selection on gene frequencies can be treated, with suitable simplifying assumptions, mathematically, and many years ago Prof. J. B. S. Haldane published a series of papers on this subject (tab. I). The rate at which gene frequencies would change under the action of slow selection is shown in fig. 1. It will be seen that selection acts more slowly, at first, on recessive genes than on dominants, but in the long run the frequencies change from nearly zero to nearly one, or vice versa. Deleterious genes are often never completely eliminated, because they are continually recruited by recurring mutations.

That selection is effective in bringing about considerable changes in organisms is shown by the achievements of domestic plant and animal breeders. The results of selecting for long shanks in chickens are shown in fig. 2, and for a larger number of abdominal chaetae in fruit flies in fig. 3. Though it is not shown here, selection for a lower number of chaetae is also effective.

The concepts of dominance and recessivity as applied to human genetical traits are losing their original connotations. It is better to speak of genes unconditionally deleterious in heterozygote form and those for which such disadvantage is doubtful. The classical dominant traits come into the first category and in the large majority they give rise to grossly pathological conditions and are ipso facto harmful-many in fact are lethal. In the case of these genes it is difficult to conceive that any agency other than recurrent mutation is instrumental in keeping them at their present frequency.

Assuming that such mutation rates are of the same order of magnitude over the entire spectrum, the frequency of these traits will vary inversely with their severity and this is found to be approximately true-from an incidence of 3/million for an almost invariably lethal trait such as acrocephalosyndactyly to 1/1000 for a relatively innocuous trait such as ptosis.

We would not expect genes even at the higher of these frequencies to be often seen and recognised in homozygote form with the low degree of inbreeding prevalent in human populations. This is in fact confirmed in practice and examples of possibly homozygous forms or dominant conditions are very rare. To be recognized as causing a recessive trait, with a few exceptions in inbred communities, a gene must be more common and often cannot therefore be maintained by recurrent mutation alone. Very wide geographical variations in the incidence of such traits also militate against such an interpretation. Phenylketonuria is an excellent example. The abnormal gene reaches a frequency of as much as 1% in some populations and it is unknown in others.

Le problème posé aux généticiens par le mélange de deux populations, d'abord isolées, peut être considéré sous différents angles. On peut avancer, avant tout, qu'estimer l'effet du mélange suppose qu'on connaît bien la composition des populations de départ. Toute grande population est composée de populations partielles.

Wahlund, en 1928, s'est demandé se qui ce passerait si deux populations bien délimitées échangeaient quelques-uns de leurs individus. Le moyen le plus simple, pour répondre à cette question, est d'envisager le cas d'une grande population divisée en plusieurs sous-groupes, d'égale dimension, à l'intérieur desquels les mariages se font au hasard et où les gènes sont distribués suivant la loi de Hardy-Weinberg. La conclusion la plus importante de l'examen des résultats est que, sous l'effet de la subdivision, la proportion des homozygotes pour un gène donné, dans l'ensemble de la population, s'accroît aux dépens des hétérozygotes, d'une quantité égale à la variance moyenne de la fréquence de ce gène.

Cet effet peut se comparer à celui que la consanguinité manifesterait si on envisageait la population dans son esemble. Les résultats sont un peu plus compliqués si les sous-groupes constituant la population sont de dimensions inégales. Mais la formule de Wahlund s'applique encore et donne les mêmes conclusions. A partir de ces constatations, on peut imaginer qu'il soit difficile de déterminer des populations perfaitement homogènes du point de vue génétique, et qu'a fortiori le résultat du mélange de ces mêmes populations ne puisse être que difficilement apprécié.

A century ago, in the midst of a flurry of interest in consanguineous marriages, the Philadelphia Ledger observed, “If one half is true that has been affirmed in regard to the effect of cousins intermarrying, it would seem as if it were the duty of parents and guardians to interfere, and even of all State Legislatures to do what can be done to prevent so injurious a custom”. These sentiments were sufficiently widespread to be echoed in an editorial in the Times of India, dated August 9, 1860, and they might well be justified today if we could establish that, in fact, “one half that is affirmed is true”. Interests in the effect of consanguineous marriage are again high, but they now stem not from a concern for Levitical Law but from the powerful tool consanguinity affords in an appraisal of the relative importance of mutation versus selection in maintaining the genetic burden of a population. Clearly the value of this tool is directly proportional to the quality and quantity of data available.

Recently, numerous studies have been published relating inbreeding to infantile and juvenile mortality. Notable among these are the studies of Sutter and Tabah (summarized in Sutter, 1958) in France, of Böök (1957) in Sweden, of Slatis, Reis, and Hoene (1958) in the United States, of Freire-Maia (1961) in Brazil, of Zerbin-Rüdin (1960) in Germany, and of a number of workers including ourselves in Japan. These studies differ markedly in size, scope, and design. In all, save our own, the mortality data are essentially retrospective in character. Experiences such as those with rubella in pregnancy should make us acutely aware of the possible biased nature of such observations. Be this as it may, it is the purpose of this paper to present the results of a continuing, anterospective investigation of the effects of inbreeding on mortality in Japan.

Gene mutations can be lethal in their effects, they can be mildly disruptive and diminish individual fitness, they can be neutral or even slightly favourable. The same is true for chromosomal aberrations. Consequently, natural selection in populations can be set up by alterations in chromosomal structure just as it is by gene changes which affect the hereditary material of a species. There are, however, important differences in the manner by which selective effects are produced following the various kinds of spontaneous change.

The present paper deals primarily with chromosomal changes but there are two ways in which selection may act on them. First, there is the immediate effect of an aberration upon the fitness of an individual who carries it and which leads to persistence or extinction of that particular aberration. Secondly, there is the less direct effect of an aberration upon the frequency of any gene which may be responsible for inducing it. Study of the immediate effects is comparable to the analysis of the behaviour of mutant genes in populations by classical methods (Fisher 1930, Wright 1931, Haldane 1932). Study of the second, less direct, process is comparable to the analysis of the behaviour of mutagenic genes (mutators).

In der Populationsgenetik gibt es zwei wichtige grundsätzliche Fragestellungen:

1. Zeigt ein bestimmtes genetisch determiniertes Merkmal Häufigkeitsunterschiede bei verschiedenen Populationen?

2. Wie sind diese Häufigkeitsunterschiede zu erklären?

Die Beantwortung der ersten Frage erfordert, dass man von möglichst vielen Populationen in möglichst vielen Stichproben die Merkmalshäufigkeiten untersucht und Verteilungsparameter schätzt, urn etwaige Unterschiede prüfen zu können. Um derartige Untersuchungen an sehr vielen Stichproben und sehr vielen Personen vornehmen zu können, benötigt man ökonomische und zuverlässige Routinemethoden zur Bestimmung des betreffenden Merkmals. Die zweite Frage kann dann bearbeitet werden, wenn genügend Information über die Häufigkeitsunterschiede bei verschiedenen Populationen vorliegt. Wie sich erwiesen hat, ist diese Frage nach den Ursachen von Häufigkeitsunterschieden oft nur sehr schwer zu beantworten.

Für die routinemässige Bestimmung der Haptoglobinserum-Gruppen haben wir die Methode der Stärkegelelektrophorese, wie sie von Smithies angegeben wurde, so weiterentwickelt, dass ohne grosse Mühe sehr viele Bestimmungen durchgeführt werden können. Wir haben diese Technik ausführlich publiziert; mit dieser Technik haben wir schon weit mehr als 30.000 Bestimmungen der Haptoglobinserum-Gruppen durchgeführt.

Zur Zeit bearbeiten wir vor allem die erste Fragestellung: Welche Häufigkeiten zeigen die Phänotypen der Haptoglobinserum-Gruppen und der ihnen zugrunde gelegten Allele Hp1 und Hp2 bei den verschiedenen Populationen?

Untersuchungen wurden von uns hierzu durchgeführt an Blutspendern aus Bayern, Baden-Württemberg, Nordrhein-Westfalen, Berlin, an Patienten aus verschiedenen Kliniken in Westdeutschland; dann haben wir zusammen mit Herrn Dr. Paidoussis Serumproben von Blutspendern aus Athen / Griechenland untersucht; des weiteren Blutspender aus Ljubljana / Jugoslavien (zusammen mit Frau Dr. Sovdat-Banic), aus Prag / Tschechoslowakei (zusammen mit Herrn Dr. Kout) sowie an einer grösseren Zahl von Blutspendern aus Hawaii (zusammen mit den Herren Dr. Pinkerton und Mermod von der Blutbank von Honolulu).

No matter what our everyday activity in the mental health field, we can say with conviction that the function of a new superspecialty such as Psychiatric Genetics, the subject of this late-morning session, is profoundly influenced by contemporary cultural, social and political conditions as well as by the never-ending challenge of scientific conquests. Evidently, therefore, any attempt to formulate a concise and generally acceptable definition of such a modern hybrid discipline is no less difficult than it is to work in it. Actually, since the two parental sciences deal with equally absorbing, intricate and still rather speculative aspects of human existence and health, it would make little difference here if the given definition were developed within the framework of psychiatry or that of human genetics. What is certain only is the empirical observation that there are very few workers in this particular field of superspecialization, who are not prematurely grey or otherwise debilitated.

In order to facilitate a fruitful discussion despite these considerable difficulties, it may be advisable to use a description of psychiatry and its various schools of psychotherapy, which is plain in its formulation and is focused on appropriate medical concepts and techniques from a professional standpoint. This selective procedure is justified, since in many recent conferences on the functions of clinical psychiatry, increasing emphasis has been placed on two general professional requirements. One of them is that psychiatry should never be “a field apart from other areas of scientific discourse”. The other criterion is that a psychiatrist be “a good physician first and always… capable of acting as the trustworthy friend, the wise counsellor, and the discreet and skillful servant” of people in distress.

In musing upon my assignment for this Congress, I became aware of limitations that I must impose upon myself, inherent in the title of the address. First, the words “Psychotic Disorders” point to the fact that the whole province of Psychiatry is not included in its scope, and whilst it is pertinent to include with the psychoses, suicide, which is a not infrequent feature of the psychotic disorders, and the epilepsies, which commonly have a psychotic aspect, the large areas of the psychiatric field characterized as mental defect, psychoneurosis, psychosomatic conditions, psychopathic personalities, and sexual deviations (including homosexuality) are not relevant to to-day's talk. Nor is it my prerogative to treat of recent developments in the realm of chromosome anomalies, such as the trisomy underlying Mongolism, karyotypes and the sexing of cells. In the second place, the term “Classification” suggests to me that my task is to confine myself to the findings of genetic studies in our field of discourse and not stray into the tempting pastures of eugenics, or biochemical genetics with its rich promise of reversibility and cure by modern pharmaceutical means. Even now with our feet firmly on the ground of genetic fact, after this preliminary delimitation, we are not entirely free on the semantic side of things, for, if I mistake not, some appearance of ambiguity would seem to lurk in our title. Is its meaning that within the discipline of Psychiatry we are to attempt a classification of the psychoses from a genetic point of view, or, is it that as an exercise within the realm of Genetics we are seeking to classify the specific and non-specific hereditary mechanisms, which have been postulated as underlying different psychotic disorders? I incline to the view that both of these programmes are significant, and appropriate to the endeavour to which this paper is dedicated.

The first question to be answered is: what is alcoholism? The only realistic answer to this question is that alcoholism is what it is defined to be. The delimitation of the concept is arbitrary. First of all there are in this respect great differences of opinion between different population-groups. What, in one group, may be regarded as just an innocent or even healthy habit would in a second population-group be stamped as a deplorable moral defect with disastrous consequences, and in a third group just as a pure medical problem. It is true, of course, that those members of the medical profession who are especially interested in research on alcoholism will, irrespective of the part of the world from which they come, have a tendency to converge towards a tolerably homogeneous concept of alcoholism. But even if this is the case the selection of alcoholics which come into their scope will to a high degree depend on the attitude of the population and not on the concepts of the doctor. Such selection factors must more or less unconsciously colour the view of the individual research worker. We know that not only do quantitative and qualitative properties of alcoholism differ very much from one population-group to another, but, in addition, the fraction of alcoholics which comes to medical attention is certainly not representative of alcoholism in general in that population-group. Most materials of alcoholics which have been under research must be very heterogenous, and one must necessarily differ from the other. How could it be possible to compare the genetical back-ground of such quite different and heterogenous materials?

The term Pharmacogenetics is defined as the study of genetically determined variations in animal species which are revealed by the effects of drugs.

I am going to deal with examples of these variations which have been found in Man. I must apologise for a certain amount of repetition of some facts which have already been aired in this conference, but it is my intention to give you a bird's eye view of the subject.