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COMPLETION of the human genome project has created an essentially complete sequence of human DNA opening the way for further research into the wider application of genetic knowledge in different areas of medicine, including ophthalmology, said researchers at a symposium on genomics at the annual meeting of the Association for Research in Vision and Ophthalmology (ARVO).
Robert L. Nussbaum MD of the U.S. National Human Genome Research Institute and President- elect of the American Society of Human Genetics reported that the next goal of the human genome project is to develop a haplotype map, which can be used for genome-wide association studies, in order to define particular changes in the human DNA in or around genes that contribute to complex, common diseases.

"We've been doing linkage studies now for some time. But in the more common diseases that have genetic contributions it is very difficult to find what those genes are and what the variants are that are contributing to common diseases by using linkage analysis. Association studies are a more powerful, more sensitive method, but also a very high-resolution method. It requires one to study the genome at a very detailed level in order to find these associations. And the haplotype map is an international effort to generate a tool that will allow those sorts of studies to be done," Dr. Nussbaum said.
In an interview with EuroTimes, Dr. Nussbaum explained that during the last two years, millions of single base differences in the human DNA have been identified in different individuals by using the human genome project sequence.

"These variations constitute our human genetic diversity. And what we start to do is use those variations to find regions of the human DNA that seem to be inherited in a block, without recombination in meiosis. These are blocks of human DNA that seem to be passed on intact through eggs and sperm. What we are finding is that these blocks are perhaps on the order of a few thousand base pairs in length, although some are much longer and a few are shorter. The work that is coming out now from a lot of investigators around the world indicates that these blocks appear to be biologically determined."
Inheritance not always straight forward

There are many human vision diseases that have genetic contributions yet are not, in general, inherited in a straightforward Mendelian manner. Glaucoma and age-related macular degeneration are among them. Dr. Nussbaum and colleagues would like to identify those genes and the changes they bring that contribute to the development of those disorders by identifying segments of human DNA, containing particular DNA variations, that are associated with having a particular disorder.
"Finding those genes will enlighten us as to what pathways, what processes are altered and therefore give us better ideas of how to develop therapies. This is a long-term goal. In the short term, we know there is a genetic contribution, we just don't know how many genes and what the variants are. We want to find those first."

Dr. Nussbaum pointed out that while the human genome project is an extremely exciting and revolutionary change in the way we approach human biology and human genetics, it is extremely important to remember that this is very basic science. People should not feel that this is going to immediately result in major breakthroughs. This is a long-term investment and we have to look at least 10 or 15 years ahead for clinical applications.

Speakers at the ARVO genome symposium touched on the more traditional single gene and biochemical approaches, as well as the broader genomic strategies, emphasising the need to remember that before these are applied in a clinical situation, clinicians have to have a full understanding of what the genes actually mean in a biological context.

Moderator Joann A. Boughman, PhD, Executive Vice President of the American Society of Human Genetics, cautioned that researchers need to be very careful about how they apply findings from genomics research in the clinical situation and think about the impact that it will have.
For example, diagnostic testing to confirm or rule out a known or suspected genetic disorder in a symptomatic individual may help in making a prognosis, in choosing treatment and in planning intervention strategies to determine risk to relatives. But it can also be confusing and traumatic to patients and families

"To be useful in a clinical situation, we need to understand not only how to test for those genes but also how to interpret the results of those tests and make sure that the clinicians, not just the geneticists and genetic counsellors, but all clinicians, understand those complexities as well. If we have not explained and shared these implications with our colleagues in medicine, then we cannot expect our patients to understand the consequences."

Caution advised
Dr. Boughman noted that the proliferation of genetic and genomic topics at this year's ARVO conference emphasised the need to bring this research to the clinical level:
"We need more interaction among disciplines so that we can understand and share with our patients the ultimate meaning of knowing our genetic sequence. One of the things we learned over the years in genetics is, if we test an individual for a specific gene, whether that test comes back positive or negative, the individual now has the piece of information and as a result of having a piece of genetic information, the relationship within the family is automatically changed. It may be better, it may be worse. But whatever the news, it is important information and needs to be managed very carefully."
J. Bronwyn Bateman, MD, of the University of Colorado Health Sciences Centre, spoke about ongoing linkage analysis research. Linkage analysis has been around for a long time and it has been greatly facilitated by the human genome project. The challenge now is to employ the technique in identifying families that have diseases and study those families.

Dr. Bateman also discussed genotype-phenotype correlations, where one cannot necessarily determine just by looking at a gene what is going to happen to that individual. For example, it is impossible to pinpoint an abnormal gene based on the appearance of a patient's cataract.
"As far as the genotype-phenotype correlation is concerned, I think that we are at the stage where the more we know, the more we understand how complicated biological systems are. Just looking at a patient does not necessarily tell us exactly what's going on in the DNA," she noted.

Dr. Bateman emphasised that because the eye is such a sophisticated and complicated structure that is subject to so many genetic diseases, it is an important model for genetic disorders in general.
In another presentation, David Valle, MD, of Johns Hopkins University Institute of Genetic Medicine and President of the American Society of Human Genetics focused on the opportunities that new genomic resources provide for increasing our understanding of how the retina works and how the retina is affected by genetic disease.

Dr. Valle works with mouse models to understand retinal degeneration, specifically gyrate atrophy of the choroid, looking for answers to questions related to the treatment of the disease. His work has provided what he considers unequivocal evidence about the best way to go about the treatment in a mouse, setting the stage for possible human treatments.

"We are using the mouse as a model of human disease. The data that we have available from humans indicates that the expression a particular gene is mimicked in mice. We have been testing treatments in patients for a long time but because of so many variables in the patients and because the disease is so slowly progressive, it is very difficult to tell if you are really having a beneficial effect. The data in the mice show clearly that we are having a beneficial effect," he told EuroTimes.

Robert L. Nussbaum, MD
National Human Genome Research Institute
rlnuss@nhgri.nih.gov

Joann A. Boughman, PhD
American Society of Human Genetics
jboughman@ashg.org

J. Bronwyn Bateman, MD
University of Colorado Health Sciences Centre
Bronwyn.bateman@uchsc.edu

David Valle, MD
Institute of Genetic Medicine
Johns Hopkins University School of Medicine

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