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Since the beginning of the Human Genome Project in 1990, there have been many efforts to obtain the sequence of our DNA. In June 2000, US President Bill Clinton and British Prime Minister Tony Blair announced the first draft of this ordered series of organic compounds that make up our genetic material. In 2003, two years earlier than expected, the complete genome was completed.

The sequence consists of 6,000 million chained letters. It is not an alphabet. It only has 4 characters (A, C, T, G), which stands for Adenine, Guanine, Cytosine and Thymine, the chemical bases that make up the double helix of DNA in which these letters face each other in pairs. Getting it was complicated, since they are repeated many times. For this reason, and despite the fact that 17 years have passed, 8% of what we know can still be improved. The project also included a map of the 23 pairs of human chromosomes, the last one completed in 2006.

Now, a study published Wednesday in the journal Nature has unveiled, for the first time, the highest quality, unbroken, unbroken sequence of a human chromosome, the X chromosome. The work is led by Karen Miga, a researcher at the Institute of Genomics from the University of California Santa Cruz (USA), Adam Phillippy, expert scientist in computational genomics at the National Institute for Human Genome Research (USA) and 21 other scientific institutions in the United States and the United Kingdom.

In DNA sequencing, the genetic material is cut into millions of fragments to be read by parts. You could say that with ACTG letters, scientists reconstruct words and, with words, phrases. The problem comes when one or more words repeated thousands of times appear in the series. How to know your correct order?

This team of geneticists and bioinformatics has developed a methodology that solves how to place DNA repeats , revealing very long gaps of uncertainty that finally come to light. These are sequences obtained in a way that can be applied to other parts of the DNA. "The effort focused on the X chromosome has laid the foundation for completing all the chromosomes in the human genome," Karen Miga told EL MUNDO. This type of sequencing is called telomere to telomere (T2T), for traversing entire chromosomes from one end (telomere) to the other. It is investigated from the international T2T consortium, co-chaired by Miga and Phillippy.

Understanding of diseases

On the X chromosome, the most inaccessible piece of this blind puzzle has been the centromere. If a chromosome is x-shaped, with two arms up (left and right) and two arms down, the centromere is the center of the x, where they meet. On the X chromosome, the centromere is a very broad region spanning 3.1 million highly repetitive base pairs. The repeated sequences are the ones that present the greatest variability between populations, so these results will allow us to study our evolution and many human diseases. "This first complete human chromosome will lead to new discoveries to understand how millions of bases, previously missing from our map, contribute to our understanding of the disease," Miga said.

The study has been carried out using human CHM13 cells. In them, the pair of X chromosomes is identical, something that does not happen in ordinary human cells. To date, the differences in the sequence of the X chromosome pair are the great unknown, since there was no complete model with which to compare. "We could synthetically mix our CHM13 X chromosome sequencing readings with readings from a different male sample to make a synthetic diploid X chromosome and test the accuracy of future methods," Miga explained.

Its methodology may be used on other chromosomes. Chromosomes 1 and 9 have higher repeats than those on the X chromosome, which is a new challenge for science. "This work has accelerated our progress and we hope that the next advances will be faster. From the Telomero to Telómero Consortium we have continued to improve our maps of the CHM13 chromosomes and we hope to issue our next release this summer," Miga told this newspaper.

Multiple clinical applications

The centromere is a region of great medical interest. As the cell divides, the chromosomes are split in two in the middle (one right half and one left) to divide equally between the daughter cells. The centromere plays an important role in the correct distribution of chromosomes in this division. A mistake in this process leads to faulty divisions that lead to very serious and even lethal developmental ailments. They are the so-called aneuploidies, which cause a number of chromosomes other than 46 (23 pairs), the general number of chromosomes that the human species has.

The X chromosome is one of the so-called sex chromosomes. We all have at least one copy and this determines our genetic sex: females when we have two (genotype XX) or males due to the presence of the Y sex chromosome, accompanied by a copy of X (genotype XY). This number may vary due to factors for which more information will now be available. This is the case of Klinefelter syndrome (XXY men), trisomy of the X chromosome (XXX women) or Turner syndrome (X0 women who have lost an X chromosome), which involve alterations of the sexual organs and sterility. In the human species, the lack of any chromosome is lethal. Turner syndrome is the only viable case of this type, since the affection of one of the X chromosomes is compensated by the other copy.

About 1,400 genes are known from the X chromosome, many involved in various diseases. Hemophilia, color blindness, congenital night blindness, adrenoleukodystrophy, Duchenne and Becker muscular dystrophy, or Martin-Bell syndrome are some examples related to mutations on the X chromosome. These mutations have greater consequences in men than in women. , since the females still have an unaltered X chromosome.

The study by Miga and her collaborators has also provided epigenetic data. For the sequencing of the X chromosome they have used the nanopore technique, very useful to decipher repeated sequences but also to detect methylated bases. That is, parts of DNA attached to one carbon and three oxygens (one methyl group CH3). This is important because the presence of methyl groups modifies the behavior of DNA. It causes some genes not to act as expected, not because of the genome sequence itself, but because of what surrounds it. This is called epigenetics and it is also responsible for certain diseases, as is the case with certain types of cancer, where some genes are blocked by the presence of methyl groups.

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