What is the Human Genome Project? How will it help our understanding of biology?
The Human Genome Project was an international consortium that set out to sequence the whole genome. Everyone's genome varies, but only very slightly. You and I, despite coming from different parts of the world, are mostly alike. Most of our base-pass or code is identical. We probably vary in about 1 per cent of our genome. So, if you sequence just one person, you get 99 per cent of the information about the human genome. A small part of the basic human genome is yet to be decoded. But once done, you have something like the periodic table for chemistry. It is like how it was 100 years ago in the case of chemistry. According to me, biology is 100 years behind the physical sciences in terms of its basic understanding. The genome project is one of the major developments that would help bring rapid progress.
According to reports on the genome project, only mono-gene disorders have been sorted out. How will this help in our understanding of the causes and treatment of disorders arising from a single gene?
You are right. Only simple, mono-gene disorders have been sorted out. But even that is a major development. Such genes act in the family — either you have it or you don't. If you don't, you will not get the disease and if you have the gene, you will get it. Huntington Disease, for instance, comes under this category. It is a dominant disorder coming through the generations. The genome project helps find these diseases very quickly.
From the genome project results, how does one go about finding out the existence of the gene that causes a mono-gene disorder?
You take a family with, say, 20 affected individuals and have markers scattered throughout the genome. You then apply the markers to the family and look for the marker that segregates the disease. Everyone in the family who could get the disease will have one type of marker and those who would not get it, another type of marker. Suppose you apply the markers and those who would not get the disease have the 200th marker and those who could get the disease have the 201st marker, then you know that wherever the 201st marker is must be close to the diseased gene. You then go to the database provided by the genome project, in the computer, and find out what genes are from the region where the 201st marker is. And let us say that you get a list of 20 genes. You then find out which ones of those are expressed in the central nervous system. Say, 10 of them are, and suppose you already know that five of them cause some other disease, then you are left with only five genes, which you then sequence to find out which one of those causes the disease. This is the process by which you identify very rapidly a single gene responsible for a particular disease.
How was this done prior to the genome project?
It was done by a method called `linkage'. Once you know which chromosome the gene causing the disease was on and the marker associated with it, then you had to sequence the DNA [deoxyribonucleic acid] yourself. To do that you had to clone it all and it was a huge task. Now it has been done for you. You just have to find the mutation.
So, do we now have the facility to sort out all single-gene disorders?
In the next five to 10 years almost all disorders caused by a single gene will be sorted out. This is no mean achievement.
What are the dominant mono-gene disorders that are to be sorted out by the genome project?
Huntington, some forms of Alzheimer's, epilepsy and Parkinson's disease and a lot of muscle diseases including muscular dystrophy. There is a long list of rare diseases.
We make up about 30,000 genes; over half of them are expected to be in the central nervous system. Random mutations go on across those genes. So, over half of the diseases that may occur are going to be neurological. It is thus not surprising that the long list of genetic diseases would express itself on the nervous system.
What are poly-gene or complex disorders? Is there a possibility that they will be sorted out in the near future?
For a single-gene disorder, everyone within a family who has a particular genetic disease is likely to have the same genetic abnormality as there is a very strong genetic factor that is causing the disease. This is easy to find out as it stands out.
But take, for example, epilepsy, which is mostly not transmitted through generations. You may just have one or two people in a family with epilepsy and that does not give you enough information. The disease may be a result of a complex interplay of genetic and environmental factors. Thus in the case of complex disorders it is just not the relative abnormality in the genes that causes the disease. By itself the gene does not tell you anything. It is a combination of genes and environmental factors that causes complex disorders such as epilepsy.
To find out the cause of such diseases it is not enough to study one person or a few families, you need to study hundreds of people as you cannot separate them to start with as you do not know what comparisons to make. It is thus best to start the study with a large population and do the mapping. Then go back and say that this type of epilepsy is mostly because of these factors and so on. Even in this case we are only guessing. But, surely, a homogenous approach where one lumps them to start with and splits them later is good. In the past, what was done was to split patients into disease categories and then say you have got this or that type of epilepsy. There is some basis in that but I think one should not get too fixed on that.
Are there genetic differences across ethnic groups? And would that make the identification of genetic disorders easier?
Yes, undoubtedly there are ethnic variations in the genetic make-up. Some common diseases vary in a particular frequency throughout the world. For example, in Singapore, brain haemorrhage, a common cause for stroke, is more common than in the West. The reason for that is not very clear as yet. It may be because of differences in diet, environment and so on. But, as is being increasingly found out, it is to a large extent genetically driven. You will have to take into account what the frequencies of the disease are in different populations. Alzheimer's is a big problem in the United Kingdom. But in some other parts of the world, where the life expectancy at birth is low, people die before they can even get it. Thus, there are diseases such as Alzheimer's, Parkinson's and stroke, as also cancer, that are becoming major problems because people are living longer now.
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