Imagine: all the letters written in this newspaper, and that since 1993. That is roughly the enormous size of the human ‘genome’, the complete structure of a human being written down in chemical language that we carry around in our cells. And now, 21 years after scientists first presented a rough draft of it, the genome of one human being has finally been read into the tiniest, most difficult corners.
Attempts to read the entire human DNA have always got bogged down in the ‘deserts’ of the genome: places where DNA decays in endless repetitions, meaning that existing reading techniques get hopelessly lost. About 8 percent of the building plan of man thus remained illegible.
But by combining a whole series of newer techniques, it is now possible for the first time to explore those unexplored pieces, writes a 100-strong American-European research consortium, in a special edition of the professional journal science† That is ‘impressive’ and ‘incredibly important’, says Bas van Steensel, researcher at the Netherlands Cancer Institute and professor of chromosome biology in Rotterdam. ‘Compare it with the time of the great voyages of discovery. If you want to explore the globe, you also need a good map. The last white spaces of that world map have now been filled in.’
Genetic defect
Bizarrely enough, the person whose hereditary characteristics the consortium plowed down to the last letter was never born. It concerns the DNA of a girl with a very rare genetic defect that caused her mother to miscarry early – but which made her DNA ideal for reading it.
Downside: because girls do not have a Y chromosome, the DNA package that defines male characteristics, the ‘man’ chapter is now completely missing from the complete human body plan. Geneticists think this can be solved with patchwork, by reverting to earlier, incomplete human DNA maps for so long for the Y chromosome.
Scientists are expected to use the new sample to better understand why certain diseases affect one family or population group but not another. The map may also provide insight into new medicines that are better tailored to patients. Know the genome, and you can also look up in detail which genetic cog is broken, and with which molecule you could repair it.
Really everything is grand and overwhelming about the new genetic roadmap. It turns out that we have 63,494 genes – pieces of DNA that ‘do’ something – of which 19,969 contain the building instructions for proteins, the active parts of a cell. No fewer than 79 of these are new to science. ‘Wonderful’, says Van Steensel. ‘You cut away a piece of impenetrable jungle, and suddenly you find open spaces where genes are still hidden.’
New insights
Van Steensel expects that the complete human survey map will generate ‘all kinds of new insights’. After all, many of the illegible pieces of DNA are located in places that biologists know to be important, such as in areas where new genes develop, and in the so-called ‘centromeres’, DNA pieces that play a key role in cell division.
‘There it is bursting with repetitions, completely impenetrable’, Van Steensel outlines. ‘While this is the place where the cables are hooked up to pull chromosomes apart during cell division. An extremely important process, which also often goes wrong, for example with cancer.’
Another who bounces back is professor of biological psychology Dorret Boomsma (VU Amsterdam). In September her group, led by Jenny van Dongen, did a remarkable discovery: single-celled twins have chemical ‘stickers’ on their DNA near the mysterious centromeres, a sign that the DNA is tuned differently there.
‘An insanely clear signature’, says Boomsma, who may be able to shed light on the question of how identical twins are formed. ‘And it is precisely those regions that have now been filled in. This finally complete genome map may have immediate meaning for our work.’
The next step, Van Steensel thinks, is to apply the new techniques to more people. ‘Ten, twenty more of these kinds of genomes, and you get an idea of where the differences are.’ This in turn can provide insight into what is normal and what is ‘deviant’, and in which people differ from each other anyway.
Larger chips
Until now, the human genome was generally read by chopping it into pieces hundreds of letters long, reading the individual pieces and then puzzling them together by looking for where they overlap. As if all episodes of de Volkskrant cut up since 1993, and then put it back together again.
In reality, however, the ‘newspaper’ of life also contains editions with the same sentence, repeated endlessly, with only the occasional subtle change. With the puzzle method it is no longer possible to put this in order: the shreds look too much alike.
With the newer techniques, however, one can also read longer strings of DNA – larger fragments – of even more than a hundred thousand letters in length. Enough to get a handle on the repeating stretches.
In reality, the DNA does not consist of letters, but of chemical groups called ‘nucleobases’, which are chemically glued together in endlessly long, revolving strands: the iconic double helix of DNA. Every person has a copy of that complete building plan in the nucleus of all his cells, folded around chemical bobbins.