Illustration by Claudio Munoz


It didn't quite work out like that. Knowing the protein-coding genes has been useful. It has provided a lexicon of proteins, including many previously unknown ones. What is needed, though, is a proper dictionary—an explanation of what the proteins mean as well as what they are. For that, you need to know how the genes' activities are regulated in the 220 or so different types of cell a human body is made from. And that is the purpose of the American government's Roadmap Epigenome Programme, results from which are published this week in Nature by Ryan Lister and Mattia Pelizzola of the Salk Institute in California, and their colleagues.

Epigenomics studies the distribution over the genome's DNA of control molecules called methyl groups. These can attach themselves to cytosine, one of the four chemical bases that form the “letters” of the genetic code. In so doing, they help control a process called transcription, in which a copy of a gene is made in the form of a molecule called RNA, the first stage in the translation of a gene into a protein. The presumption is that the pattern of methylation, by controlling which proteins are manufactured, helps determine what type of cell is produced. A cell with its haemoglobin genes switched on to overdrive, for example, will become a red blood cell. One that churns out actin and myosin, which link up to form units that can expand and contract, will become a muscle cell. And so on. Dr Lister and Dr Pelizzola have tested this idea by describing the first two reasonably complete human epigenomes.

Waving or drowning?

The cells they chose to look at were embryonic stem cells, which retain the potential to turn into a variety of other cell types, and fetal lung fibroblasts, which are the end of one line of cell specialisation. They read the methylation patterns of these cells using a chemical trick that turns methylated cytosine (letter C) into another base, called uracil. In nature, this base is found in RNA, rather than DNA, but it is just as susceptible to being recorded by one of Dr Watson's mechanical monkeys as the others are. Altogether, the researchers were able to read and compare about 90% of the genomes of their two types of cell.

Their first discovery was that the stem cells were more methylated than the lung cells—5.8% of cytosines, compared with 4.3%. Moreover, the difference was largely accounted for by something strange. Previous studies have shown that methylated cytosines are usually next to a letter called guanine (G). It is a common characteristic of the so-called promoter regions of genes, where transcription begins, that they contain long, repetitive sequences of alternating Cs and Gs. If these areas become methylated, it tends to suppress transcription of the gene in question. A quarter of the methylated cytosines in stem cells, however, were not followed by guanines. Nor were they found in the promoter regions of genes, but rather in the transcribed parts of the genes themselves. They also had the opposite effect from methylated cytosines found in promoter regions. The genes they occurred in tended to be transcribed more than usual, not less. In particular, a lot of genes involved in processing RNA were activated in the stem cells in this way.

One unexpected discovery made during the decade since the genome project was finished is that there are thousands of small genes whose RNA copies are not translated into proteins. Instead, the RNA acts in its own right. In plants, for example, it is one of the things that switches other genes on and off at their promoter sites. Whether it does so in mammals has yet to be established. But it might. In any case, unusual patterns of RNA processing in stem cells are something that will require further examination.

The complexities of methylation, then, are myriad—as are the complexities introduced by all these unexpected small genes. Reading the human genome in the first place may, indeed, have been work for mechanical monkeys. Interpreting the result will require the finest minds that humanity can muster.