Genetic disease and the development of Human Genetics*

Bernardo Beiguelman
* English condensed version of the lecture given in Portuguese in the Symposium on" Genetic factors in the etiology of frequent diseases" during the 43rd National Congress of Genetics promoted by the Brazilian Society of Genetics in Goiânia, GO, Brazil (13-16 August, 1997).
Departamento de Parasitologia, Laboratório de Epidemiologia Genética, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP. E.mail:

Since the "rediscovery" of Mendel’s work in 1900, most investigations on the genetic nature of human traits have been devoted to those classified as qualitative. Of course, this preference was due to the fact that when the familial distribution of a qualitative trait paralleled with mitotic and meiotic phenomena, then the hypothesis of the existence of a gene locus responsible for the trait could be accepted. On the other hand, simple methods for testing a monogenic hypothesis for qualitative traits in nuclear families or in pedigrees were available since the first decades of this century. Among the pioneers who created such methods it is mandatory to mention the names of Wilhelm Weinberg, Laurence Hasbrouck Snyder, Ronald Alymer Fisher, John Burdon Sanderson Haldane, Gunnar Dahlberg, Lancelot Hogben and Felix Bernstein.

One of the most important consequences of these methodological facilities has been that the concept of qualitative traits has been extended to the rare constitutional and degenerative diseases with undetected exogenous causes. Such initiative for testing a monogenic hypothesis for rare endogenous diseases, made in the beginning of this century, was indeed methodologically too audacious, since for investigating their pathogenesis, geneticists oversimplified all signs and symptoms displayed by the patients, which were summarized under the name trait.

To most clinicians this sounded as an excessive abstraction and to some of them as a heresy, since the genetic methodology seemingly disrespected the variations of the patients’ clinical pictures. This may have been perhaps one of the most important reasons of the great delay of the physicians in accepting the use of the word trait with its plasticity and the different levels of abstraction associated to its use. This resistance persisted for a long time, even when it became clear that in Genetics, as in the exact sciences, the artificial concepts employed for working out hypotheses are a consequence of the need of applying statistic analysis for obtaining laws that represent natural phenomena with great accuracy, which are used to interpret the real world.

Other advances in the medical field in the beginning of Human Genetics have been the introduction of the concepts of phenocopy and genocopy. The former term was introduced to be used when it was observed that some inherited diseases could be mimicked by environmental factors, while genocopy was introduced to be used when it was seen that some diseases, apparently unique, exhibited more than one pattern of hereditary transmission. Thus, by detecting genetic heterogeneity in clinical entities, apparently homogeneous, geneticists denied the supposed uniquity of these diseases and have foreseen different pathogeneses for the different genetic entities they recognized.

However, more impressive has been the detection, in the first half of this century, of genetic heterogeneity of recessive autosomal monogenic diseases only on the basis of population data (incidence of the disease, proportion of patients born to consanguineous parents, mean coefficient of inbreeding, and rate of consanguineous marriages). Thus, whenever the proportion of patients with a recessive disease born to consanguineous parents was higher than the expected proportion, based on the estimate of the gene frequency of this disease, one might suppose genetic heterogeneity. Of course, such methods, derived from the fundamental papers of Sewall Wright and Gunnar Dahlberg, were only able to detect genetic heterogeneity determined by non-alleles.

The concept of expressivity, to indicate the variability of phenotypic manifestation of some genotype, and the concept of penetrance (incomplete or complete), to designate the probability of manifestation of a genotype on the dependence of external factors, were both created in the first half of this century too. In spite of being well known that there are no genes with a constant manifestation, the denomination variable expressivity is, until now, very convenient for medical purposes. Thus, when one says that a disease is determined by a genotype with variable expressivity, it is easy to understand that this disease is manifested through different clinical forms and/or that it shows a variable distribution according to age groups and/or a different picture according to sex. Otherwise, the terms variable expressivity according to age, variable expressivity according to sex, sex-controlled expressivity and expressivity limited to sex derived from this knowledge.

Biochemical Genetics was a field that Archibald Edward Garrod started precociously in 1908, but, unfortunately, this important branch of Genetics remained unexplored until the late forties. Nevertheless, when the investigations in this area were retaken, and it was demonstrated that the primary product of the genes are polypeptide chains that make up the structural proteins and the enzymes, a remarkable advance in the study of inherited diseases has been observed, since this demonstration contributed to render clear several important points.

Thus, it became clear that if monogenic inheritance is attributed to some disease, it is allowed to suppose that the primary product of the allele responsible for this disease is a protein (structural or enzyme) with an important role for life or in some phase of the development. It also became clear that the terms variable expression and/or incomplete penetrance attributed to a disease served to attest our ignorance on its etiopathogeny, since the phenotypic variability of a monogenic trait increases according to the distance from the primary effect of the involved gene. Even the attribution of genocopies to a disease became considered as derived from the lack of clinic and pathologic information, since the characterization of the primary effect of the involved genes annulled the previous genetic heterogeneity.

Due to this knowledge, a monogenic pattern attributed to a disease prompted the analysis of its physiopathology at a biochemical level, in order to find the primary product of the gene responsible for the morbidity under study. Otherwise stated, starting simply from a clue of monogenic inheritance of a disease, on statistical grounds, one could uncover the inborn error of metabolism responsible for its manifestation and, therefore, the definition of its pathognomonic sign. This also rendered clear that the excessive abstraction inherent to Human Genetics methodology, which summarizes all signs and symptoms of a disease under the name trait, afforded one of the most important methods for investigating the etiology of endogenous diseases.

In spite of the human karyotype having been correctly described in 1956 by Joe-Hin Tjio and Johan Albert Levan, it may be said that Human Cytogenetics has began, in fact, after 1959, when Jérôme Jean Louis Marie Lejeune, Marthe Gautier and Raymond Alexandre Turpin discovered an extra small acrocentric chromosome, later classified as number 21, in metaphases of fibroblasts of Down syndrome patients. On the other hand, this specialty gained a fantastic development since 1960, when Paul Moorehead and co-workers described a technique for short-term culture of lymphocytes that brought facilities beyond accounts for the implantation of Human Cytogenetics laboratories all over the world. The impact provoked in medicine by the possibility of investigating the etiology of a large number of endogenous diseases by means of the search of numerical or structural chromosomal aberrations is not easy to be described to our younger colleagues. However, the evaluation of such impact may perhaps be easier when it is remembered that Lejeune, Gautier and Turpin’s discovery of the etiology of Down syndrome knocked down, at once, 39 wrong theories for explaining the origin of this disorder.

The karyotype analysis became then a noteworthy instrument for the investigation of the etiology of a large number of sporadic diseases and even of familial disorders with no Mendelian pattern. This test gained exceptional strength in the beginning of the seventies, when the possibilities of detecting structural chromosomal abnormalities have been amplified by the introduction of the techniques of chromosomal banding. Here it is important to stress that geneticists, besides introducing the karyotype research into the medical armamentarium, created a specific semiology for diseases with abnormal karyotypes, derived from their studies on the phenotypekaryotype correlations.

For the immediate acceptance of Human Cytogenetics as a medical practice in the sixties, it seems to have highly contributed the fact that chromosomal aberrations embodied the changes of genetic material at a microscopic level, when Genetics still was dominated by abstract notions. At that time, we were far from the use of DNA technology that allows the investigation of the structure and function of human genes and the diagnosis of inherited diseases by the examination of the gene itself.

In the first half of this century, when the familial distribution of individuals affected with some end genous disease did not allow to accept a monogenic hypothesis, the incidence of this disease was investigated in twins. If the twin studies pointed out that the proportion of monozygotic pairs concordant for the disorder was significantly higher than that observed among dizygotic pairs, it was concluded that an important polygenic component should be responsible for the manifestation of the disease. It was Sewall Wright that in 1934 firstly created a threshold model for explaining how a polygenic system could be responsible for the manifestation of qualitative traits, like diseases. This model was improved in 1951 by Hans Grüneberg, who introduced the concept of quasi-continuous variation.

The quasi-continuous variation model lead Douglas Scott Falconer to create another one, in 1967, that allowed to estimate the heritability of a disease based on the knowledge of its frequency in population and among the consanguineous relatives of the patients. Nevertheless, the extraordinary advance concerning the study of diseases that may deviate from Mendelian proportions only began with the spectacular development of methods of complex segregation analysis that culminated in 1983 with the unified model of Jean-Marc Lalouel, Dabeeru C. Rao, Newton Ennis Morton and Robert C. Elston. Complex segregation analysis enabled geneticists not only to detect a major gene responsible for a rare disease with an irregular familial distribution, but even to investigate the role of genetic factors in determining frequent diseases (prevalence higher than 1:1,000). Moreover, when dealing with chronic infectious diseases that show family aggregation, complex segregation analysis allows to investigate if the predisposition to such diseases depends upon a major gene, its dominant or additive effect, and to evaluate the contribution of multifactorial and environmental factors to the manifestation of such disorders.

All these beautiful contributions to the study of genetic diseases are in the imminence of being obscured by the consequences of the applications of DNA technology to Human Genetics, that enable mapping and sequencing human genome and to identify the DNA changes responsible for diseases. The main alarming consequence of this technology is the rapid increase of the number of persons that, in spite of being clinically healthy, will be considered as potentially sick, since the concept of disease will not be restricted to a collection of clinical signs and symptoms, but be extended to genetic predisposition for future symptomatic manifestations. We are not far from the moment when the denomination circumstantial diseases will be introduced in medical terminology to indicate DNA changes, detected in healthy children, which have some probability of being expressed as genetic illnesses by adult people. It is easy to imagine how this can affect the possibilities of work, insurance, acceptance in associations and school registration.

At the end of this century we are entering the biotechnological era, and we are witnessing how the technological principles used industrially have been extended to human reproduction (control of quality, projects, and foreseeability of the product) and introduced a deep change in the relations between relatives and children. The prejudice and intolerance towards disabled people are stimulating the acceptance of the idea that those who have genetic diseases should never exist, since their births should have been avoided. We are pushed towards an eugenic civilization that disdain the effect of the environment and is worried with the technology necessary to the manipulation of our genome, as we were no more than our genotype. It urges to begin public discussions of these questions for analyzing the ethical, legal and social consequences of mapping and sequencing human genome. We cannot allow that, like in nazi Germany, a small group of scientists will provide organized ideas to be prepared by legislators and announced in the media, before such ideas are critically analyzed and approved by society as a whole.