Presidential Address 2001
Genome, Genomics and Human Genetics:
The Indian Perspective
P.S. Chauhan
Presidential address delivered on February 20, 2001, at the Centre for Cellular and Molecular Biology, Hyderabad, during the XXVII Annual Conference of the Indian Society of Human Genetics, "ISHG 2001".
The sequencing of the human genome is destined to revolutionize biological research and medical practice in the 21st century and beyond. It is not too far that all human genes will eventually be found, and perhaps accurate diagnostics developed for most of the inherited diseases. There is increasing evidence implicating genetic susceptibilities in several polygenic and major fatal and disabling diseases including cardiovascular, neurological, diabetes and several kinds of cancer. The identification of these genes and their proteins is likely to pave the way to more effective therapies and preventive measures. The better emerging understanding of the underlying biology of genome organization and gene regulation will begin to understand how humans develop from single cells to adults, why this process sometimes falters, and what changes take place among people with advancing age. This will also facilitate developing animal models for human diseases, for research to understand gene function in health and disease. It has been recognized that single gene can be associated with a number of diseases, such as cystic fibrosis, duschene muscular dystrophy, neurofibromatosis, etc. It will be possible to uncover the mechanisms for diseases caused by several genes or by a gene interacting with environmental factors. The phenomenon of incomplete penetrance, variable expressivity, phenotype/genotype heterogeneity, non-traditional inheritance, so frequently being encountered in human genetics and baffling Mendelian genetics will also be approached with greater insights and precision. Gene therapy will commence and transgenetics will be employed to address critical basic and applied issues. The availability of the human genome sequence has silenced the debate on the feasibility and the technological aspects of the programme that had arisen since the very beginning. But, serious debate on ethical legal and social issues have emerged and will remain in focus in the new century.
Development of new technology and genetic manipulations had never progressed at a pace as during the time of human genome project. New technologies such as the chip and nanotechnology, microarrays, throughput sequencing, high speed computation with super computers will address various issues in population genetics, genetic epidemiology as well as map and ultimately improve the genomes of economically important animals and agriculture crops. Infact, studies on human diversity, population genetics, forensic medicine could have never been approached with such an unprecedented precision as revolutionized by the post human genome era. New terms are being coined by prefixing or sufixing with `genomics' so much is being spoken about and of course being done too in computational genomics, pharmacogenomics and so on. Obviously, the functional genomics and rightly so, would be the new challenge during the post human genome era. I see it as the resurgence of biochemistry, enzymology, even physiology, and the veteran molecules `the proteins'.
Very recently, surprises have been expressed about the smaller number of genes, which make a human being. According to new estimates there are perhaps 30,000 to 40,000 genes in the human genome as compared to the estimated number in the range of 60,000 to 1,00,000 genes believed so far. Such debates will occupy several intelligent minds. But, how do we overlook that earlier estimates were made when much less of biology was known compared to what is known today. New genetics is blessed with the discovery of the new phenomena of cellular economy in the discovery of wonder molecules; gene products having multidimensional properties, regulating diverse physiological phenomena. The gene for Attractin, the RBI and TP53 gene families have been known to regulate several regulatory pathways and checkpoints with multiple roles in regulations. It is amazing that three genes with alternate promoters and splicing can generate thousand of `neuroxins'. Which contribute to the neural network involving about a trillion of neurons present in the human brain. Humans by evolution have acquired certain important characteristics, which make them so different from the rest of the species. They have the best brain, intelligence, and memory, thinking power, logistics and reasoning. Emotions are well known to be associated with the mammalian kingdom, but the human life and personality thrives on emotions to a much greater extent. If genes for emotions can ever be found, their number may perhaps be different between mouse and man. Have humans also learnt much more to conserve their body resources, to preserve the genomic or the cellular integrity, developed an efficient cell renewal system that they can live much longer than the other species? Perhaps, the genomic damage per unit time, although substantial, still is much less or repaired more efficiently and accurately or the damaged cells are targeted and eliminated faster compared to other species. Disregarding the number, it may be the differential expression of genes that makes the difference between men and say mice. As said earlier, of course, there is the role of gene expression, and the physiological genomics. Thus, it is no surprise that functional genomics attains so much attention after the genome sequence is in hand.
The new technology has already led to generation of abundance of genetic data, fortunately with a concomitant revolution in information technology; entirely new possibilities have emerged in genetics, rather in biology as a whole. Large data banks and libraries are available free of cost from several international agencies; the Welcome Foundation has promised to bring in the SNP database free to all. The concerted and enormouse efforts in terms of technology, funding, manpower, skill that have been employed amounts to entirely a new phase in biology. It is certainly beyond majority of the nations worldwide single handedly, but for a country with vast resources like US, who could perceive and institute such a programme. Even then, HGP has emerged through collaboration between nations and infused with competitive spirit brought in by the corporate sector, in addition to the enormous DOE and NIH Govt. funding.
At the national scenario, in this regard, are we prepared, rather how well are we prepared even to retrieve, store this vast information, use and make it available among those who may be the interested groups in this country. There are individualized efforts but much larger, and well-organized efforts are required to harvest the fruits of this new revolution, available at no cost. We have neither means nor it would be wise to consider to generate this information again. At the national scenario, I am apologetic to say that genetics as a whole like many other disciplines of science has been rather an individual effort. Only few, not even half a dozen, universities provide a Masters degree in human genetics. Not only the university system, but even the Medical Council of India has ignored to bring medical genetics in the curriculum of medical education. Is this not surprising? We have yet to make a national registry of major congenital malformations in the country, although we may have the largest number of deformed individuals. It is hard to believe that one has to search for trained manpower, capable of identifying major malformations at birth. Under a DAE sponsored programme titled "Study of Malformations and Down syndrome in India" about 90,000 newborns have been monitored at Delhi, Baroda and Mumbai. As an extension of this programme to Chennai, other 70,000 newborns have been added. With over 60,000 newborn from South West Kerala, this is the first prospective study instituted to establish malformation rates in the Indian population. A wealth of information will emerge from the analysis of the combined data, but even preliminary results show very interesting correlation and trends. Consanguinity posing distinctly greater risk of malformations emerges from all the studies. This is only a very small effort, there is a need to establish a registry of malformations, twinning, Down's and other chromosomal syndromes, dominant and recessive diseases. Like wise a central facility for DNA samples, cells and tissues to function as a material resource for future, is required.
Fortunately, there is a new hope, Govt. agencies such as DBT, DST, CSIR have come forward to institute programmes in human genetics. The Indian Council of Medical Research in recent years has launched a programme in medical genetics. A postgraduate degree programme in medical genetic at Sanjay Gandhi Post Graduate Institute of Medical Sciences has been introduced. There are several scientists taking up projects in molecular human genetics at various institutions and the university systems. Indeed, it is very enlightening and creditable effort on their part. But, this is not enough for a country which has such a large scientific force, including biologists, clinicians, medical faculty, and perhaps the largest, most diverse, and interesting human population. As said earlier is this not the time to think of making efforts to introduce human resource development in the area of human genetics, at university and medical education level as soon as possible? It is an appeal to all concerned through all of you, who are here today to do your best in this effort. To repeat it again, there is a strong need of establishing a centralized facility for Research, Training and Human Resource Development in the area of human genetics in the country, which may have regional centers or affiliations. Such an institution should create infrastructure, be equipped with new technology and provide facilities for the interested and generate programmes for the country. With strong facility in bioinformatics, one of the objective should be to retrieve information, store, and make available to all those interested at the level of university system, medical education, national laboratories and even the college and school levels.
We do share the ethical, legal and social implications in genetic research with the rest of the world. But, there are our own ethical, legal, social implications due to our exclusive social structure, poverty, economic diversity, population heterogeneity etc. The cytogenetic analysis expected to ascertain whether the child has a normal or abnormal karyotype to provide prenatal diagnosis and counselling is often misused for gender bias against the unborn. Enforcement of appropriate regulations and quality surveillance should be helpful to quite an extent and need to be instituted. I would also like to stress on other aspects, which may appear trivial, but in my view are not so in human genetics research. This country has a unique distinction of having perhaps the largest human diversity due to its geographical dimensions, invasions, origins, migrations, and more importantly due to social practices and orchestrated breeding almost amounting to inbreeding. Would it not be interesting to find out how this orchestrated breeding has influenced the gene pool, the recessive diseases and even polygenic traits in the population? The gegraphical and linguistic features are important, but the states within the Republic of India were constituted only within the last 50 years, i.e. since independence. During the colonial rule, the country was administered through different regions e.g. states like Bombay and Madras and so on. That, this classification or categorization has a limited scope in genetical interpretations should be considered. It is also requested that the political or the social categorization should be avoided, as far as possible for genetic interpretations. Why not to address them as different ethnic groups, without qualifying their economic or social status. Historically, the westren historians believe that, in addition to the original inhabitants, hordes of several tribes from Central Asia entered in waves into India and adopted the local way of life. The Kusans, the Huns, the Gurjara Partiharas with a confederation of the Parmaras, Chalukyas, Chamhanas etc. were among the latest tribes. Would you believe that even after 1500 to 2000 years of history clusters of villages of people who call themselves Huns exist in the this country even today, so also the large belts of Kusanas across several states in the so called Madhya Bharatha to north Punjab and Himalayan foot hill regions. Like wise, the other clans are well spread all over from Western to Eastern part of India. The story is not different in Southern part of country. Would it be interesting to look at these people to know whether the orchestrated breeding prevalent for centuries has influenced the gene pool or has some other genomic implications. At least the gene pool should be preserved before it is lost with time in this modern world. There are other issues in the social order; the country has been for centuries largely and agriculture economy, with land holding in certain hands. If one knows the realities, why should one be surprised to find the gene flow of the Y-chromosome in one direction of the so called social structure and of mitochondrial genes in the reverse? It would be nice to do this research, but the question remains, what does one want to answer out of these studies.
Lastly, in my opinion, the Indian genome initiative (programme) launched
in recent years should concentrate more on genes or markers of some
relevance to disease, susceptibility to a disease or a toxin (chemical,
physical or a biological agent) rather than taking random markers. For
this, the genes responsible for genomic repair and maintenance of the
integrity of immune defence and those responsible for detoxifying
xenobiotics or those responsible for scavenging reactive oxygen species
should be more relevant. This would almost amount to launching an
environmental human genome programme. It is my fervent hope that not
only geneticists but the large group of individuals interested in
biology, medicine, anthropology and ethical and social sciences, will
continue their efforts to provide a better world fully devoted to
`science for humanity'. Each member of the Indian Society of Human
Genetics must come forward and play his/her role in the endeavor, the
endeavor of bringing human genetics, in totality, in the education
system and to public life as a basic and applied science. I conclude
with an appeal to all, that in the new millennium and in this fast
changing world, let the goal of human genetics be only a solitary one
i.e. the `Human Welfare'.
