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.