Found: the gene that causes short sight: now experts say condition could be halted by eye drops

The above was a headline (13^th September, 2010) from the UK tabloid The Daily Mail a well known arbiter of rationalism and restraint. To be fair to the Mail, the story was picked up by most of the UK media and tagged with similarly lurid headlines. E.g. “Short-sightedness gene discovery could consign glasses to history” from the Telegraph. And it was not just the UK press. The story had gone global: “Rogue gene causes short-sightedness” (Times of India), “Gene for nearsightedness found; treatment could eliminate need for eyeglasses, contact lenses” (New York Daily News). “Australian discovery of myopia gene link” (Sydney Morning Herald).

The headlines, I am afraid, are rather far from the truth as usual. Indeed, if one reads further into these articles you eventually get to the quotes from the poor scientists involved, caught between a desire to publicise their research while at the same time issuing a plaintive bleat for the facts.

The story originates with two papers published in Nature Genetics Hysi PG, Young TL, Mackey DA et al. A genome-wide association study for myopia and refractive error identifies a susceptibility locus at 15q25. Nature Genetics, 12 September 2010

Solouki AM, Verhoeven VJM, van Duijn CM et al. A genome-wide association study identifies a susceptibility locus for refractive errors and myopia at 15q14. Nature Genetics, 12 September 2010

Both studies used DNA microarray technology to identify variations in DNA sequences amongst thousands of individuals. The idea is simple. Each cohort consists of individuals who are short sighted, those who are long sighted and those who have no sight defects. Thousands of positions of known DNA sequence variability known as single nucleotide polymorphisms – that is a change at a single letter of the DNA sequence - across the whole genome of each individual were analysed. Statistics was then used to identify DNA variants that are strongly associated with defective eyesight. The two studies identified different DNA variants, but in both cases the variations were close to genes that are known to be expressed strongly in eye tissues and in one case have been shown to be necessary for normal lens formation in mice eyes. Hence the headlines compelling us to believe that ‘the gene’ for short-sightedness has been discovered.

Even the most cursory reading of the above paragraph should reveal the fallacy of these headlines. The two studies identified different variants. So already, we know that there is more than one DNA variant involved in eyesight defects. In fact, variations near three different genes were identified. The second more fundamental issue is that variations in these genes do not cause sight defect in all individuals. In fact the effect is surprisingly small.  For example, individuals with the variant rs8027411 were only 1.16 times more likely to have myopia than no eye problems. So even if gene therapy was routine and it was possible to administer a magic eye drop that would fix the ‘bad’ DNA variant (conservative estimates reckon it will be at least ten years before such a treatment is possible) then the patients’ risk of developing eye problems would decrease by only 16%.

The problem is that the genetic component of vision defects seems to be swamped by environmental effects. In modern society short-sightedness is on the rise. In some parts of Asia, the incidence of myopia has reached extraordinary levels. Nowhere is this more so than in Singapore where 80% of 18-year old army recruits are now short sighted (up from 25% just 30 years ago). And before you Westerners get complacent, this is not some sort of genetic pre-disposition in the Asian population. For example, Ian Morgan and Kathryn Rose of the Australian National University show in their paper “How genetic is school myopia?” published in Progress in Retinal and Eye Research, 24 (2005) 1-38, that 70% of men of Indian origin living in Singapore are short sighted, even though the incidence of short sightedness in India itself is only 10%.

There is little doubt as to the cause. Too much time spent focused on close objects, the computer screen probably being the biggest evil. Light reaching the eye from a near source has to be bent more to bring it into focus on the retina. The eye compensates by growing longer so that the muscles of the lens have to work less hard. The problem then comes when you look up across the room and try to bring something from further away into focus. These more parallel waves of light fall into focus in front of the retina in the long eye. You are now short sighted. In countries like Singapore, a particularly reading-intensive school programme is thought to be behind the high incidence of short sightedness, the still developing eye the most likely to grow longer.

The solution appears to be simple. As Terri Young of Duke University Medical Center (a lead author of one of the Nature Genetics papers) said in a Duke University press release: “People need to go outside and look at the horizon”. Rather makes you wonder why they spent thousands of dollars doing all that genome analysis, doesn’t it?

Will the wheat genome really feed the world?

On the 27^th of August, a team of British scientists led by Professor Neil Hall at the University of Liverpool announced that they had ‘decoded’ the wheat genome and the story was picked up by the media accompanied by predictably rabid headlines: “Decoding of wheat genome will help address global food shortage”, “Wheat genome boost to food supply”, “Scientists crack wheat genome and offer yield potential”. You could be forgiven for thinking that the looming food crisis we keep hearing about is more or less solved. Now that the genome has been sequenced, it is only a matter of time before those clever plant scientists start churning out new varieties of wheat that are higher yielding, that can better tolerate drought and pests, that can grow on marginal soils. In short, all the challenges facing the agricultural industry as a result of the twin pressures of population growth and climate change will be successfully met thanks to modern plant genetics. The truth, alas, is rather different.

The first problem is that sequencing an organism’s genome does not automatically lead to an understanding as to how that organism works, a fact that pharmaceutical companies attempting to exploit the human genome have become only too aware. A genome is merely a set of instructions, a parts list. The challenge is to understand how that parts list fits together. Imagine a car engine disassembled, all the parts neatly laid out on the floor. Would knowledge of all those parts naturally lead one to understand how an engine works? Not at all. It is only by seeing how all of those parts fit together and work as a system that the magic of internal combustion is revealed. And the internal combustion engine is ridiculously simple compared to biological organisms whose parts list number in the tens of thousands.

Moreover, all this rather assumes that the function of each part is known, which remains far from the case. Take the model plant species Arabidopsis thaliana. This is the plant scientists’ equivalent of the laboratory mouse. Its genome was sequenced some ten years ago and this unassuming weed has been the subject of intense research ever since. And yet, despite a huge international research effort costing billions of pounds, the function of around 30% of the genes in the Arabidopsis genome remains unknown (incidentally, this is more or less the same figure as when the genome was initially sequenced, but that is another story). The clues to high yield, drought resistance, pest resistance and so on, could lie in those mysterious genes whose purpose remains completely obscure.

The wheat breeders are right to be excited about the prospect of a sequenced genome because it will be a significant tool for breeding. The process of breeding is essentially unchanged since the dawn of agriculture. Two different species of a related plant cross fertilise and if the resultant hybrid has an improvement in some desirable trait it is selected for future use. The only difference now is that rather than selecting for visible traits such as grain size, modern breeders can select for the transfer of specific pieces of DNA. These pieces of DNA are identified by the presence of marker sequences, small differences in DNA sequence between the two parent species that can be easily identified in the lab, telling the breeder which of the two parents the DNA between the markers must be derived from. The breeders are excited because the complete genome sequence will allow them to identify many more of these markers allowing them to breed across specific pieces of DNA with much greater precision.

But the headlines are regrettably premature. 

First of all, the wheat sequence released by Professor Hall and his colleagues is unordered. To sequence the genome, you chop it up into small bits and read each small fragment. Assembling all those fragments into the correct order is a mammoth task, without which the sequence data is essentially meaningless. It is a bit like taking the scissors to War and Peace and trying to work out the story from fragments of sentences and paragraphs. Already, there are moves afoot to calm the hyperbole with the International Wheat Genome Consortium (www.wheatgenome.org) issuing a press release disagreeing with the claims made in relation to the British scientists’ first draft sequence.

In addition, those DNA markers that the breeders so desperately crave cannot be identified from a single genome sequence. The markers are differences in sequence meaning that you would need the sequence of more than one species of wheat to identify them. This is perhaps a minor quibble. Sequencing DNA is now quick and relatively cheap (and becoming quicker and cheaper all the time), so sequences of other wheat species are surely round the corner. But the final and biggest problem is to know which bits of DNA to breed across. Which genes are responsible for controlling a complex trait such as drought tolerance? How does one track the many hundreds of genes that might collectively impart greater resistance to pathogens? Which genes are linked to increased yield? Geneticists have been hunting for the answer to these questions for decades. There is no doubt that genome sequence information will be an incredibly useful tool in their search for answers. But it could still be decades more before the wheat genome is truly ‘decoded’ and those answers are found.