Complete decryption of the genome: "We have added pages to the book of life"

Nearly 20 years after the announcement of the decryption of most of the human genome, several international teams have announced that they have completed the mapping of the 8% of DNA that still remained unknown. This breakthrough is on the front page of the prestigious American science magazine this week. Science. Jean-François Deleuze, the director of the National Center for Human Genomics Research, explains to L’Express why it took two decades to succeed in “reading” all of our genetic heritage. It also details the hopes raised by this progress.

L’Express: On April 14, 2003, scientists announced that they had deciphered the human genome. But in reality, this first map of our genetic heritage was not complete?

Jean-Francois Deleuze: At the time, the work of dozens of researchers from six countries, with a budget of 3 billion dollars, had made it possible to map more than 90% of our DNA. The geneticists knew that there were “gaps”, that the sequence was not quite complete, but that these gaps were not accessible with the sequencing techniques available at that time.

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This small part of the unknown, whose exact size was difficult to appreciate, was too complicated to read. But the consensus was that these pieces should not be very functional, that is, they should not carry genes associated with diseases, rather they were regulatory elements. And besides, it was clear that we had before us at least two decades of work to begin to understand what had already been deciphered.

What does reading this last part of our genome bring?

If we say that DNA is the book of life, then there were pages missing. These additional pages which have just been added will make it possible to advance scientific knowledge around two main axes. First, a better understanding of the basic biology and functioning of cells. The decrypted regions are found at the ends of the chromosomes (telomeres), and in their center (centromere). They are, for example, very important for the proper distribution of chromosomes in cells as they separate to create new cells. The other major axis, of course, is to seek explanations for diseases for which the genetic mechanisms involved have not yet been discovered.

“A better understanding of the variability of our genome”

What technological developments have enabled these advances?

First, the emergence of what is called “long fragment sequencing”. In the 2000s, to read DNA, we had to “break” it into thousands of small pieces, around a few hundred base pairs (the pairs of ATCG letters that make up genes). Developments in the preparation of DNA and the way it is read in sequencers have made it possible to move to pieces of 100,000 base pairs.

To understand the implications of these technological advances, take the picture of a child’s puzzle with a red balloon that goes to the beach. Some parts are easy to position – the child’s face, the red balloon, etc. But others are so similar, to form the sky, the sea, or the sand, that if you have a lot of small pieces, you don’t know where to put them. But if you have the same scene with 10 or 100 pieces, you will do the puzzle very quickly. By increasing the size of the pieces, you decrease the complexity, it becomes much easier to arrange the pieces in relation to each other.

It’s exactly the same with DNA, because the areas that had not been read at the time were very “repeated” areas (with very similar sequences of letters, which were therefore difficult to store correctly and to read , Editor’s note).

Will this addition of 8% of the genome to our knowledge really make it possible to understand many additional diseases?

It’s too early to tell. We are going to have a more complete reading of the genome, and therefore a better understanding of its variability. It is the analysis of genetic variations between a very large number of individuals that makes it possible to understand diseases: we take 50,000 people suffering from such and such a pathology and 50,000 healthy subjects and we compare their DNA. The variations can be expressed in different ways – by differences at the level of each of the letters (one will have a T instead of a C in one place), but also at the level of groups of letters, by holes ( a set of letters missing in one place), or in the number of copies of the same gene or group of letters. It is these copies, these repeated areas, which were the most difficult to read before the advent of “long fragments” technology. So we have new places to explore to find biological mechanisms or genes that cause disease. But this reading will not be easy, because these new pages have a slightly different script from the rest of the genome.

“France is no longer at the forefront in these areas”

So there is still a lot to do…

First, this new map will have to be clarified little by little. This first truly complete cartography will serve as a reference, like a map with cities. The genomes of other individuals will be sequenced in the same way, and over time they will refine it. The next step will be the so-called multi-omics analysis: we will have to continue to look at what is happening at the level of epigenetics, chromatin, RNA, proteins, as we already do for the rest of the genome. Yes, we still have a lot of work ahead of us to understand the writing of the living.

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What role has France played in reading this last part of our genetic heritage?

In the 1990s, France was very advanced in terms of genetics. The first genome maps were written here. In 2001-2003, we deciphered chromosome 14. But this time, no French team took part in this adventure. It is sad to note that after having been the leader, France is no longer at the forefront in these areas.