HTML> Bioethics in Asia pp. 201-204 in Bioethics in Asia

Editors: Norio Fujiki and Darryl R. J. Macer, Ph.D.
Eubios Ethics Institute

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6.1. Human Genome Diversity Studies in South America

Genoveva Keyeux.

Universidad Javeriana, Bogota, Colombia


Human genetic studies are not new in South America. Classical genetic markers, like blood groups, serum proteins and major histocompatibility antigens have been studied for over 30 years in different ethnic groups: Mestizos, Amerindians and a little in African Americans. Moreover, important human genetics research centers were created in the fifties: Brazil, Argentina and Chile had national research policies well ahead of other countries in South America, and reasonable funding was given both to form geneticist abroad, and to develop laboratory facilities in the country.

These and the nascent South American groups was established. In the late seventies and eighties some Brazilian, Argentinean, Colombian and Chilean research teams incorporated molecular biology tools to study population genetics, and an important contribution to international human evolutionary studies began at that moment.

International cooperation has always been especially strong at the level of technological support, since dependence of developing countries face to modern technology in almost any scientific domain is not new. Therefore, scientific collaboration between developing and industrialized countriesf research groups has been pursued in the most natural way, observing the ethical rules that characterize high-level scientific work and fair-play relationships between researchers all over the world. This collaboration, either through experimental work, data analysis or materials supply has always had beneficial effects for research itself, and for Third World research groups, since it has created some material infrastructure and the intellectual know-how necessary to ensure growing capacity of developing independent groups in our countries.

Moreover, economic support to science has also been channeled through a series of international agencies, like the former European Economic Community, the North American National Institute of Health, the German Humboldt Stiftung, the Japan Agency for Cooperation, the French National Institute of Health, the WHO (World Health Organization), etc. National agencies, like the National Science Councils of the South American countries (Conicit, Conicet, CNPQ, Colciencias, etc.) have supplied some of the economical support to science development, but unfortunately, even this cooperative economic support has been insufficient to ensure full independence of local scientific activity, especially when cutting edge technology, as in the case of molecular biology, is needed.

Genetics and Medicine

Human genetics and genetic diseases has not been a priority of science funding agencies in South America, since other topics, like tropical diseases, have an undoubtedly higher impact on disease burden and national health programs than genetic diseases. But more recently, even microbial and parasitic diseases are increasingly being recognized as the result of a certain form of interaction between the individualfs genetic constitution and the causal infectious agent. A good example is malaria, a disease responsible for hundreds of thousands deaths per year in South America, where the emphasis and priority interests on developing a vaccine have shown that a genetic approach of the hostfs immune response capacity might be more effectively manipulated to give a high protection against the infectious agent, than does the vaccine itself. Therefore, more and more research funds are driven to support research programs in basic-level genetics research, and for investigation of variant forms of genetic diseases in our patients, given the admixture of South American populations.

In this sense, science is showing more and more that understanding health and disease is a matter of genes and environment. Since all biochemical processes are ruled by a set of genes, either encoded by nuclear or by mitochondrial sequences, health is the expression of a subtle equilibrium that has been established between our genes and the environmental conditions appeals to their function. This equilibrium, which is a reflection of adaptation, was built during mankindfs evolution, and probably even earlier, during vertebrate evolution. Environment has shaped genes in different parts of the world by retaining some of the new mutations that continuously arise in a natural ongoing process. Moreover, environment is so important, that sometimes gharmfulh mutations can confer a benefit to the person bearing this gene, when the mutation co-exists with special environmental conditions, like in the case of sickle-cell hemoglobin S and malaria in Africa, the Mediterranean basin and South America.

History of human groups in South America

Let us briefly summarize South Americafs history, to explain the interest of genetic diversity studies in this part of the world in the context of human peopling and adaptation. The historical context of South America is the shaping and reshaping of populations through at least 30.000 years. In this process, genes that came from the depth of Asia, later from Europe and Africa, mixed together. The first archeologically and anthropologically documented Asian migrations crossed the Bering strait and spread throughout the North-, Central- and South American territories in a lapse of time of at least 15.000 years. These first settlers occupied all ecological strata, from the tropical forests up to the high Andean and Rocky mountains. Other migrants seem also to have left their footprints particularly in South America, like the Melanesians and Polynesians and, according to some newer but controversial theories, Africans.

The native Americans had also probably contacts with Europeans - the Vikings - well before Columbusf arrival in 1492, but the real impact on the indigenous inhabitants came from the process of conquest and later colonization promoted by the Spanish and Portuguese crowns. The importation of slaves from Africa from the XVIIth century on introduced a new human group to this recently and, unfortunately, brutally reshaped human continent.

Today it is clear to us that with time, South America became a real experimental scenario where unique forms of biological and cultural diversity manifested and emerged anew. The resulting present-day populations - Amerindians, African Americans and Mestizos, the mixed European-descent population - evolved in environments quite different from those of their ancestors, thus giving origin to particular genetic constitutions, partly due to admixture, partly to accumulation of new mutations, that have adapted themselves to the plurality of environments, but also that became in some instances fragile due to isolation and endogamy.

South American approach to anthropology and history

Some of the research in the field of human genetics in South America has been oriented to try to understand this shaping of populations, since anthropology, ethnology and archeology have provided sound, but fragmented, pieces of evidence of the process.

Blood group studies are the most widespread research studies in South American human groups, and many publications have been issued. More recently, HLA (human leukocyte antigens), serum proteins and red cell enzymes have been analyzed to document the rooting of the South American Indians and their parents, the Central- and North-American Indians and the Central- and East-Asian populations. In recent years, HLA genes, nuclear genes and anonymous sequences, as well as mitochondrial genes and sequences have been dissected in the hope of getting more informative results from them as from the proteins, which are less polymorphic and therefore less informative in terms of their evolution during humankindfs history.

Despite the great enthusiasm that these studies may have raised, we are more and more confronted to the evidence that this biological history, not only in America, but also in Africa, Asia and Europe, is a sort of puzzle with too many missing pieces, or unintelligible information, that obliges us to go back to cultural history: human population genetics is not as any other speciesf population genetics, as we humans, have a cultural history that pushes genes on the roads, moved by many other pressures than just food, reproduction and survival instincts.

South American approach to genetics and disease

The importance of studying the genetic basis of normal traits as well as of hereditary diseases in particular populations, as opposed to a general model emerging from the study of an archetype human genome, has become apparent from the investigations in the last 20 years in frequent diseases. Let me just give two examples: type I Insulin Dependent Diabetes and Cystic Fibrosis. In these two examples of typical Caucasian diseases, with high incidences in Europe and the USA, and lower ones in the rest of the world, the gene mutations and the manifestation and severity of the disease can be quite different in distinct populations. For instance, IDDM or Insulin Dependent Diabetes Mellitus is linked to different major histocompatibility haplotypes in Orientals, Europeans and African Americans from the USA. Latin American Mestizo patients (Argentineans, Colombians and Mexicans) inherit the susceptibility with roughly the same haplotypes as Europeans, but interestingly, Amerindians from Colombia have also high frequencies of susceptibility alleles from the same genes, especially DQA1 and DQB1, without developing the disease. Probably other genes, interacting with the major susceptibility locus on chromosome 6, as well as environmental factors, might be the explanation for this observation.

In cystic fibrosis, this population-related genetic variability is extreme, since over 700 worldwide distributed mutations of the CFTR gene are known today, and some of them seem to be particular to non-Caucasian populations. The most frequent one, DF508, is present in North Europe in about 70% of the patientsf chromosomes, whereas it is only the second mutation in Ashkenazi Jews in Israel. In South American patients, although they are all Mestizos of European descent, DF508 is present in round 50-60% of Colombian, Mexican, Brazilian and Argentinean chromosomes, whereas it is only present in some 30% Chilean and Cuban chromosomes. Moreover, the Colombian patients from the Atlantic Coast, a mixed population of Spaniards from Andalusia, Africans and Syrian-Lebanese descent, has a quite different distribution of DF508 and other mutations with respect to the rest of the country, which has much more a Basque, Catalonian or Castillean, and Amerindian descent. Furthermore, our studies show that homozygous DF508 patients have less severe symptoms than European patients having the same genotype, thus clearly showing that genetic studies in different populations are important if we want to understand the underlying interactions between genes, and the variable expressions that follow these. We donft know at present, although the hypothesis has been raised, which other genes are interacting with the locus of the disease on chromosome 7, and the explanation of local differences in the manifestations of the disease in patients bearing the same genotypes, might rely on this yet unknown genesf interactions.

One more example is the recent study of a mitochondrial disease, MERRF (myoclonal epilepsy with ragged red fibers), in several Colombian patients. The disease is usually due to a point mutation in the mitochondrial DNA (mtDNA), but our Mestizo patients showed instead a small deletion that was later found to be a population polymorphism. This polymorphism, a 9bp deletion in a non-coding region of the mtDNA molecule, had previously been shown to be present in many Asian and Amerindian groups, as well as in the Colombian Mestizo population, where we found it in 25% of the DNAs analyzed. We therefore concluded that this was not a new disease-related mutation. This example shows that careful study of newly detected variants, put into context of the normal populationfs genetic background, are extremely important, since false diagnosis can easily be made if one ignores this background in the patient under study.

From these few examples, it is clear that investigation of such variants in disease genes, but also in neutral sequences of the genome, has a practical importance. First of all, local parameters, i.e., knowledge of the most frequent mutations and, concomitantly, estimation of the frequency of the carriers of these genes, help to develop regional and national strategies of diagnosis, treatment and family counseling that correspond to the local situation, and not to foreign guidelines. Moreover, if we consider the possibility of using modern molecular tools in medical care, it is important to know the genetic background of the population in order to avoid mistakes in molecular diagnosis and the following therapeutic approach of the disease.

Second, multifactorial diseases, like autoimmune diseases, cancer, coronary diseases and some others, and even tropical diseases, need clear understanding of genetic as well as environmental factors involved in their development. Therefore, comparing populations like Amerindians, who almost donft have these diseases, African Americans and Mestizo, who have them at high frequencies, and some of whom might share to some extent similar environments, but also understanding how different populations manage prevention and health care with own medicines and shaman practices, is an important approach to the understanding of the ethiology of these diseases, but also for the development of locally adapted health care programs that might integrate traditional and western medicines. In the case of South America, this would be a great gain, since our medicine is almost exclusively inspired from European and North American models.

Third, diseases of indigenous populations, almost unknown in Caucasians, are also known. For instance, actinic prurigo in Chimila Indians from Colombia has been found at sea level and to be due to other causes than UV light exposure, which is the usual triggering factor. The possibility of studying the patientsf genetic susceptibility to the disease and particular aspects of this latter, has allowed the development of a better suited therapeutic approach to this highly socially impeding disease, than thalidomide. Although of life-long treatment, patients responded to antibiotics, vitamin E and cyclosporine therapeutics. The importance of bringing relief to such rare diseases, which might not be the canonical western medicinefs concerns, with the help of modern tools of investigation, should not be underestimated.

Human Genome Diversity Project in South America

As previously mentioned, human genetic studies are not new in South America, and even molecular genetics has already made a long way in several research groups. A more recent outcome in our countries was the creation of a South American Human Genome Diversity Project Committee (HGDP) in 1994, three years after proposing the HGDP to the United Statesf Congress for financial support. This committee was joined by several of the most important research groups from the region, but some others, like the Javeriana Universityfs Human Genetics Institute, are still independent research teams.

Although scientific collaboration between South- and North-American research groups has a long-standing tradition of fair-play relationships, the HGDP has been criticized by indigenous organizations, both national as well as international, on the basis of a renewed feeling of North-South domination. In a context of growing international nationalism and chauvinism, which in some parts of South America is quite strong, too, it seems that these reactions are due to the way in which the HGDP has given the impression that genetic research can be a commodity. Its related project, the Human Genome Project, might be liable, in part, of this uneasiness, since research has been, although not exclusively, streamed by profit-making companies in the hope of developing new drugs based on genetic therapy.

On the other hand, late 20th century economy with difficulty can get round patenting, understood as the commercial monopoly over inventions, whereby new elements, to be used in pharmaceutical industry, and resulting from human ingenuity, can be constructed from previous discoveries. Patenting serves to stimulate investments and technological developments necessary to provide these new products and services.

Indigenous and many other people fear that this way of domination, especially through patents granted on biological material, might lead to an exacerbation of the already deep groove separating wealthy and poor societies, since it gives little chance to Third World countries for developing own scientific strategies in the field of diagnosis and therapy. In general, concentration of research within a single group, acting as the organization in charge of scientific and economic ruling of investigation, is also perceived as negative. This opposition has touched not only researchers in the field of genetics, but also of anthropology, ethnobotany, medicine, etc., in many Latin American countries. Other events might also have contributed to this climate of distrust towards research, like political and mass media manipulation.

International cooperation

At the same time, international scientific cooperation was particularly intense at that time: scientists were principally trained in England and North America by outstanding figures of the human genetics, and future collaboration between in this case the HGDP, acting as the organization in charge of scientific and economic regulation of investigation, is perceived negatively. Beside the former considerations, indigenous people have also expressed their fear of genetic misuse of patented genes against them. Although the core of the problem is not that indigenous peoples would likely be a particular source of genes that could be patented by industrialized countries, neither as would be any other human group, and far less, that these patented genes would be used against anyone, this issue is objectively far less critical than the economic impediments for poor societies, and the concerns about accumulative royalties as an obstacle for general access to medical care products in the Third World.

Future outlook

Worldwide disseminated social perceptions, that are not particular to any culture or religion, have also touched researchers in the field of genetics in many Latin American countries. One extreme of these perceptions is, that genetics per se is seen by many as an infringement of the natural order of life. Therefore, no discrimination is made between the ethically acceptable and unacceptable practices, thus leading sometimes to a dangerous diabolification of potential possibilities of genetic manipulation and existential hazards. Moreover, other events might also have contributed to this climate of distrust towards genetics, like political and mass media manipulation.

Social perceptions of cultural goods, natural resources and now, genetic goods, are not the same in every culture and period of history. Difficulty in understanding each otherfs views on ownership, sharing, utilization, etc., and conflicts of interests to raise a consensus view of how to handle them, has opposed the different actors in these last years, touching not only genetics, but also anthropology, ethnobotany, medicine, etc.

Education for understanding and enlightened decision-making, and equitable sharing of welfare are for the moment utopias in most parts of the world, but are reasonable expectancies for our future. A consciousness of species, beyond that of families, clans, groups, nations, would at least guarantee that whatever knowledge emerges from research, in particular of human genetics research, this would come to further the whole of the human species, thus ensuring multilateral participation and benefit at different levels, medical, social, cultural, etc., of humanity as a whole.

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