According to one genome scan, my DNA makes me 9 per cent more likely than the average European man to develop type 2 diabetes. Should I be concerned? Not really, because in fact I could well be less likely to get diabetes than the typical man with similar ancestry.
The reason is not just that my predicted risk is only slightly higher than normal, and that diet and exercise are more important than genes. It is that so far we have only identified a tiny fraction of the genetic variants that affect our risk of developing common diseases. The 21 variants I had scanned by the Icelandic company , for instance, collectively explain just a shade over 6 per cent of the heritability of type 2 diabetes.
Why is it proving so hard to pin down the genetic variations underlying common disorders, and what does the 鈥渄ark matter鈥� in the genome that accounts for this 鈥渕issing heritability鈥� consist of?
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Based on studies of diseases caused by a mutation in a single gene, such as sickle cell anaemia, some geneticists predicted that more complex conditions would be caused by a larger number of mutations in a series of genes. Each mutation would have a smaller effect, but collectively they would explain most of the heritability of the disease.
Once geneticists knew what a 鈥渘ormal鈥� human genome looked like, the thinking went, they could catalogue the most common variations and look for links with common diseases. That, it was hoped, would lead to ways to treat or prevent these diseases.
Many common genetic variants have now been catalogued, most of them single-letter changes in the genetic code known as SNPs. With the help of 鈥淒NA chips鈥� packed with genetic probes, individuals can now be scanned for about a million common SNPs. In this way, geneticists have been comparing thousands of people affected by common diseases with thousands of healthy controls.
Although such studies have revealed more than 500 disease-associated DNA variants, most only have a tiny effect. In fact, the common variants found so far explain less than 10 per cent of the heritability of most complex traits.
A small part of the reason for this might be that the effect of a variant sometimes depends on the environment in which its owner lives. It can also depend on what other variants an individual has. Conventional studies do not have the power to spot subtleties such as these.
Ironically, though, it seems that the main explanation for the missing heritability is that geneticists underestimated the power of evolution. If a mutation has a seriously bad effect, natural selection prevents it becoming common. The exceptions are variants whose ill effects strike late in life, after people have passed on their genes, or variants that have benefits as well as downsides.
Dark matter
Many biologists now think that the 鈥渄ark matter鈥� responsible for common diseases consists of a host of mutations that are each very rare, but have a powerful effect in individuals unlucky enough to inherit them. That makes the task much harder, because DNA-chip scans cannot reveal rare mutations. Instead, the genomes of many individuals will have to be sequenced.
It will not be easy even then. When genomics pioneer unveiled his entire genome in 2007, it contained 4.1 million variants not seen in the reference human DNA sequence (). Most were rare SNPs, but there were also numerous insertions, deletions and variations in the number of copies of individual genes.
Everyone鈥檚 genome is similarly varied, so the problem is from harmless ones. 鈥淲e might as well admit that we don鈥檛 know how to do it,鈥� says of Duke University in Durham, North Carolina.
Still, geneticists do have some strategies in mind. One is looking for variants shared by people who represent the extreme of a trait 鈥� this might work for high blood pressure, for example. Another is to focus on variants that have cropped up as new mutations within families.
A third approach is to combine conventional studies looking for links between DNA variants and diseases with all kinds of other biological information. With the help of information on gene expression in human tissues and breeding experiments in mice, for instance, geneticists recently pinpointed a gene linked to type 2 diabetes. The link between variants in this gene and diabetes had previously been hidden in the statistical 鈥渘oise鈥� ().
On the face of it, the failure to find many common variants underlying common diseases is bad news for us all 鈥� companies will not develop drugs that work only for a few. However, many rare mutations may act through the same pathways, meaning one drug might still work for large numbers of people even though they do not have precisely the same mutation.
Read more: Unknown genome: What we still don鈥檛 know about our DNA
It鈥檚 not just the sequence, stupid
Making sense of the 6 billion As, Gs, Ts and Cs that make up our genome is hard enough. Making matters even worse are chemical modifications known as 鈥渆pigenetic鈥� marks.
Some of the Cs in our DNA have a small molecule called a methyl group attached. The methylation of lots of Cs in a region blocks gene expression, meaning none of a gene鈥檚 protein will be made. As an embryo develops, methylation is used to shut down different genes in different tissues. Incorrect methylation can lead to disorders such as cancers.
While epigenetic marks can be inherited, the slate is mostly wiped clean with each generation. For this reason, most geneticists think epigenetic effects cannot explain our 鈥渕issing heritability鈥� (see main story, above) 鈥� though .
Indeed, there may be much more to learn about epigenetics. Just last year, we discovered that in many brain cells, some Cs have an hydroxymethyl group attached, rather than a methyl group (). The importance, or not, of this form of methylation in the brain remains unclear.
One of the reasons for this is that detecting epigenetic marks is still difficult. The technology is advancing fast, though: last month, Pacific Biosciences of Menlo Park, California, revealed that its new DNA sequencing method can detect methylation patterns at the same time (). It can even distinguish between a methyl and a hydroxymethyl group.
