The thirteenth Human Genome Meeting, held in Hyderabad, India, in late September presented an opportunity for invited speaker Professor Hans-Hilger Ropers to express his concern with the genomic research priorities some developing countries are adopting. These priorities follow Western epidemiological prerogatives instead of reflecting the unique genetic landscape many developing countries face: specifically, the rare, often severe, monogenic disorders that have a higher prevalence in certain developing countries. Western genomic research programmes prioritise complex multi-gene disorders (such as diabetes and heart disease) that have a high prevalence in rich, largely sedentary countries and which also dangle the carrot of potential lucrative blockbuster treatments. Many developing nations, however, especially those that allow consanguineous marital and parenting arrangements, have a significantly higher frequency of miscarriages, developmental defects and particularly intellectual deficit, which Professor Ropers qualifies as the "biggest unmet challenge in clinical genetics".
His presentation in Hyderabad echoed an article which Professor Ropers was invited to write for the American Journal of Human Genetics and which was published in August 2007. OrphaNews Europe asked Professor Ropers, a human geneticist at the Max Planck Institute for Molecular Genetics in Berlin, Germany, to elaborate on his ideas, and particularly the recommendations he would propose to developing countries defining their genomic research priorities and policies:
OrphaNews Europe: Why do single gene disorders deserve more attention?
Professor Ropers: First, it is likely that monogenic disorders are more common than previously thought, but often they are not recognised as such, because in industrialized societies like ours, single gene disorders are rarely familial. This holds for severe autosomal dominant disorders, where carriers of the gene defect are clinically affected and will rarely reproduce, but also for autosomal recessive defects: in the German population, where on average, each couple has 1.4 children, most affected children are isolated cases; in this situation, the possibility of a genetic causation will often not be considered. Secondly, it is becoming increasingly clear that the complexity of common disorders is often due to genetic heterogeneity, with many different gene defects giving rise to the same phenotype. This is true for mental retardation, where the number of underlying gene defects could run into the thousands, but also for autism and probably for many other disorders which are considered as primarily multifactorial. So far, no more than 10 percent of the human genes have been linked to disease; clearly, this is just the proverbial ’tip of the iceberg’.
OrphaNews Europe: What could a developing country gain by switching its genomic research priority to rarer monogenic conditions?
Professor Ropers: Developing countries have other health problems than rich, developed ones, such as malnutrition and infectious diseases due to scarcity of food and clean water, or a high perinatal mortality due to low hygienic standards and lack of education. Undoubtedly, these factors can also influence the physical and mental development of a child. But contrary to what most health care policy makers believe, these factors are not the only explanation, and probably not even the most important one, for the higher early childhood mortality, the high rate of developmental defects and the frequent intellectual disability (ID) observed in many developing countries. Given the high rate of parental consanguinity in Arab countries, Turkey, Egypt, Iran, Pakistan and parts of India, it is likely that recessive defects are a major reason for these health problems, and this is supported by numerous observations, e.g. the fact that such conditions are also common in families living abroad, e.g. Pakistanis living in the UK or Turkish families living in Germany.
Contrary to many complex disorders such as type 2 diabetes and obesity, which are lifestyle related, become manifest only later in life or are relatively mild, single-gene disorders are mostly severe, early onset conditions, necessitating life-long care and support. Single gene disorders are also costly: e.g., lifetime costs for the fragile X mental retardation syndrome (FXS) amount to 1 to 2 million euros in developed countries. As an MD and a clinical geneticist, I think that it is our obligation to first focus on the severe genetic disorders before turning to the milder, late-onset conditions. In populations with large consanguineous families, carrier detection and prenatal diagnosis is remarkably efficient in preventing recessive disorders, and thus, their molecular elucidation will significantly reduce health care costs in developing countries. Moreover, identification of the molecular defect is the basis for understanding the relevant pathogenetic mechanisms, which in turn is the key to the development of (patentable) therapeutic drugs.
OrphaNews Europe: Why have governments and industry worldwide to date invested so much in the search for DNA variants in patients with more common complex disorders?
Professor Ropers: In the early 1990s, several important monogenic disorders including Duchenne muscular dystrophy, cystic fibrosis and FXS had already been elucidated, and for the leading laboratories, using positional cloning strategies to identify gene defects underlying Mendelian disorders was becoming routine. This was also the time when the second 5 year plan for the Human Genome Project was written, which requested more money than any previous research project in biology. In this context, presenting common disorders as the future target of genome research was a clever move to ensure continued public support for this endeavour.
This plan was based on the ’common disorder – common variant’ (CDCV) hypothesis – the assumption that for most or all common disorders, there are common genetic risk factors – and it was fuelled by the expectation that within a decade or so, it would be possible to prevent or treat many of these disorders. However, this hypothesis was wrong. Today, 15 years later, after spending billions of dollars for genome wide association studies (GWAS), it is clear that the CDCV hypothesis only holds for a small minority of complex disorders (see also News Feature, Nature 456:18-21, 2008). Strictly speaking, this does not rule out the possibility that specific gene defects play an important role in the pathogenesis of some of the common disorders, as GWAS are only able to ’see’ changes that are evolutionarily old and shared by many of the patients. Fortunately enough, whole genome sequencing is becoming cheaper every month, and sooner rather than later it will replace GWAS as the strategy of choice for finding sequence variants that predispose to disease.
OrphaNews Europe: What is needed to help a developing country define and implement research policies that would better reflect and serve its particular health needs?
This is an extremely delicate matter. For many years, genome research in industrialized countries was entirely focused on common diseases. For developing countries setting up their own genome programs and trying to catch up, it was therefore natural to think along the same lines, particularly after having been told for half a generation that identifying risk factors for common diseases is a lucrative business that will pave the way for the development of blockbuster drugs. One also has to understand that in most of these countries, genome research has to make money to survive, because compared to the USA, the UK and several European countries, public support is quite limited. For this reason, the Indian Genome Variation initiative is devised as a hub for early stage clinical trials on behalf of foreign pharmaceutical companies.
To some extent, the orientation of this program may also be influenced by its organization. When setting up genome research in a country as large and multi-faceted as India, there is probably no alternative to a top-down approach involving the big institutes for Life Sciences, and this is exactly how this endeavour is presently organized. This is the right setting for GWAS involving large cohorts of patients and controls, but less so for the elucidation of hundreds or thousands of different recessive gene defects underlying early onset disorders, which depends in the first place on the recruitment and thorough clinical characterization of large consanguineous families. Thus, the most important prerequisite for this kind of research is the same as required for genetic health care: a country-wide network of clinical geneticists and genetic centres. Where this infrastructure does not yet exist or is insufficient, all possible efforts should be made to strengthen genetic services and to train clinical geneticists for this task. Moreover, with the Personal Genome around the corner, it is absolutely certain that experienced clinical geneticists will soon be short in supply, not only in developing countries, but worldwide.
OrphaNews Europe: If developing countries were to heed your recommendations, how could developing and developed countries then collaborate in a way that would exploit each entity’s contribution to understanding genetic diseases?
Professor Ropers: After a series of incidents where (mostly) US-based companies successfully tried to obtain patents on Indian plants or plant-derived products, India, China and other countries have adopted legislation banning or severely restricting the exchange of biological material, even in the context of formalized collaborations involving Western countries. Fortunately, other countries where parental consanguinity is common have not followed suit, including Pakistan, India’s nearest neighbour, and Iran, where our own group has found an excellent partner for fruitful collaborative research into recessive forms of cognitive impairment.
As mentioned above, recessive disorders can only be studied efficiently in populations where parental consanguinity and large families are common, e.g. in all countries of the so-called ’consanguinity belt’ which extends from Morocco to India. Therefore, recessive disorders are a particularly plausible target for genome research in these countries, also because such research will address one of their most important health care problems. (In my personal opinion, they even have a certain moral obligation to focus on recessive disorders, because these diseases cannot be studied elsewhere – as it should be the moral obligation of industrial countries to do what they can to defeat malaria and bilharziosis, because the countries where these disorders are common do not have the know-how or the means to fight against them effectively.)
In the past, there have been various attempts of Western genetic laboratories to recruit families with recessive disorders in the respective countries; in our case, we were fortunate that it was our Iranian colleague who identified us as his potential partner. After more than five years of collaborative research into autosomal recessive cognitive impairment, my conclusion is that these collaborations will only work if (i) there is strong support for these activities within the developing country, (ii) the collaboration is based on the principle of equality, meaning that all results will be the shared property of both partners, and (iii) if they have complementary resources and means – good intentions and trust are necessary, but not sufficient for the success of such trans-national collaborations.
OrphaNews Europe: Could you comment on the advances in technology that are lowering costs and accelerating research and the impact these could have for developing countries (and organisations) inhibited by budget constraints?
Professor Ropers: Systematic research into recessive disorders became possible only a few years ago with the availability of high resolution oligonucleotide arrays, which can be used to type several hundred thousand DNA markers in the genome in one single experiment. This has been a breakthrough for homozygosity mapping in consanguineous families and has paved the way for the chromosomal localization of many recessive gene defects. The next step, however, i.e. the identification of the specific disease-causing mutations, is still a bottleneck for this approach.
Linkage intervals determined by homozygosity mapping tend to be wide and may contain hundreds of genes; screening them for mutations one by one is extremely tedious and costly. A recent alternative entails the enrichment of relevant genomic intervals or the respective coding sequences, followed by high-throughput sequencing using novel (e.g., Illumina, ABI or Roche) ’next generation’ sequencing platforms. At present, however, this combination of techniques is only available in a few laboratories worldwide. This is one of the reasons why international collaborations are often indispensable for this kind of research, even for laboratories in developing countries where the clinical expertise and the necessary molecular know-how are available.
However, there is hope that this situation will soon change: it is widely believed that in two years from now, (i.e. in the autumn of2010) novel sequencing platforms will be commercially available that will reduce the costs of sequencing the entire (non-repetitive portion of the) human genome to less than 1000 US$, and this development will not stop there. Thus, screening entire genomes for disease-causing mutations will no longer be the privilege of well-equipped and well-financed US-American or European groups, nor will it have to be confined to large genome centres. This will also have far-reaching implications for genetic health care and the organization of genetic services. For developing countries, this development will create a plethora of novel opportunities for making original contributions in the field of genome research – reasons enough to carefully reconsider present ideas and plans, and for avoiding the trodden path of GWAS.
