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A decade of progress and misunderstandings

28 June 2010
By Professor Marcus Pembrey
Chairman of the Progress Educational Trust, Emeritus Professor of Paediatric Genetics at the Institute of Child Health in London and Visiting Professor of Paediatric Genetics at Bristol University
Appeared in BioNews 564

The 10th anniversary of the first draft of the human genome sequence has been characterised by justifiable celebration at the extraordinary progress in DNA sequencing technology, yet disappointment with the impact it has had on medicine to date. Is this disappointment also justified? Not really, for it stems from a misunderstanding of the relationship between genes, health and disease that many commentators, including some scientists, have done little to correct over the last decade.

Advances in DNA sequence analysis continue to bring real benefits to families threatened by serious monogenic diseases and disability. However, this class of disorders is defined by the fact they show a Mendelian pattern of inheritance which, in turn, means there has to be a high-impact gene mutation being transmitted in the family.

With political will and committed clinical genetic services, there is no excuse now for not discovering these gene mutations, even in families with the rarest Mendelian disorders. Systematic DNA analysis is what has improved dramatically in the last 10 years. A systematic analysis of all genes and nearby regulatory DNA sequences will eventually discover the causative mutation in that family.

However, the relationship between common complex disorders, such as asthma and diabetes, and inherited genetic variation is quite a different matter. The relationship is not direct, but conditional on that individual's developmental experience from conception onwards; their prevailing social, physical and nutritional environment; and their physical and psychological responses to the emerging illness, including medication.

The genes and their variations are just one of the numerous players in this dynamic interplay that is somewhat different for every one of us. I say somewhat different, because evolution has placed constraints on how we respond to adversity via protein-coding genes and a plethora of recently-discovered regulatory DNA sequences. These constraints are likely to result in recognisable patterns of response and the development of helpful genome-based biomedical markers of disease vulnerability. These biomarkers are likely to be a combination of DNA changes and epigenetic modification of the genome, such as DNA methylation.

I am not saying we can never understand enough about the determinants of common complex diseases to improve prevention or develop treatments. But a gene-centric approach alone will continue to disappoint. Developmental experience, that other great determinant of our constitution, has to be incorporated more fully into our scientific studies.

We have to remember that not all 'genetic effects' are what they seem in terms of understanding the causes of common complex disease. This last point can be illustrated with an extreme example. If some terrible disaster led to a whole population starving to death, when half had died there would be a clear genetic difference between the dead and those still alive. This tells us nothing about the cause of these deaths. It tells us a little about the differences in the survival response of people in this population to this disaster.

The last decade of genome excitement has naturally brought genes and genetic influences to the fore. In the 1980s common complex disorders were called multi-factorial and correctly so. Now they tend to be called common complex genetic diseases. In the 20 June New York Times supplement in The Observer, Kevin Delaney wrote: 'obesity is often attacked as personal failing, even though science mostly points to genetics'. But it is clear that obesity is multi-factorial and virtually all genetic effects are conditional on the environment. Genetic science will find genetic influences if many thousands of cases and controls are studied and one accepts genetic variants showing tiny effects as potential risk factors, but in reporting such studies a balance must be maintained.

At BioNews, we strive to maintain that balance and put genes in their rightful place. But we need our readers to hold us to the task. And the BioNews website now makes it easier than ever for your opinions to be heard: you can have your say on any article or comment piece by scrolling to the end of it and logging in.

30 August 2011 - by Kyrillos Georgiadis 
A group of Irish scientists has discovered that a supposedly 'dead' pseudogene is, in fact, active. The gene, DHFRL1, was long thought to be inactive, however new research, published in the US Proceedings of the National Academy of Sciences, suggests this is not the case...
21 February 2011 - by Dr Lux Fatimathas 
An article published by a group of international scientists has said an over emphasis on the Human Genome Project (HGP) may risk a 'backlash' in the field of genetics and has called for an evaluation of where the 'real benefits' from genomic medicine will come from....
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