La percée du pangénome : une image limpide de la diversité génomique humaine

Par Université Rockefeller13 mai 2023

Le Consortium de référence du pangénome humain a réalisé des progrès significatifs dans la création d’un génome humain de référence plus inclusif en assemblant les séquences génomiques de 47 individus du monde entier. Le génome humain de référence original était basé sur les données d'un seul individu d'origine afro-européenne, limitant sa représentation de la diversité génétique. Ce nouveau pangénome, qui restitue plus de 99 % de chaque séquence avec une grande précision, révèle près de 120 millions de paires de bases d'ADN inédites. En fournissant une représentation plus précise de la diversité génétique humaine, les chercheurs peuvent affiner leur compréhension du lien entre les gènes et les maladies, accélérer la recherche clinique et, à terme, contribuer à réduire les disparités en matière de santé.

Dans le cadre d'une avancée majeure, les scientifiques ont assemblé des séquences génomiques de 47 personnes d'horizons divers pour créer un pangénome, qui offre une représentation plus précise de la diversité génétique humaine que le génome de référence existant. Ce nouveau pangénome aidera les chercheurs à affiner leur compréhension du lien entre les gènes et les maladies et pourrait, à terme, contribuer à réduire les disparités en matière de santé.

Depuis plus de 20 ans, les scientifiques s’appuient sur le génome humain de référence, une séquence génétique consensuelle, comme référence pour comparer d’autres données génétiques. Utilisé dans d’innombrables études, le génome de référence a permis, entre autres, d’identifier des gènes impliqués dans des maladies spécifiques et de retracer l’évolution de traits humains.

But it has always been a flawed tool. One of its biggest problems is that about 70 percent of its data came from a single man of predominantly African-European background whose DNADNA, or deoxyribonucleic acid, is a molecule composed of two long strands of nucleotides that coil around each other to form a double helix. It is the hereditary material in humans and almost all other organisms that carries genetic instructions for development, functioning, growth, and reproduction. Nearly every cell in a person’s body has the same DNA. Most DNA is located in the cell nucleus (where it is called nuclear DNA), but a small amount of DNA can also be found in the mitochondria (where it is called mitochondrial DNA or mtDNA)." data-gt-translate-attributes="[{"attribute":"data-cmtooltip", "format":"html"}]"> L'ADN a été séquencé dans le cadre du projet Génome humain, le premier effort visant à capturer la totalité de l'ADN d'une personne. En conséquence, cela ne peut pas nous en dire beaucoup sur les 0,2 à 1 pour cent de séquence génétique qui différencient chacune des sept milliards d’habitants de cette planète, créant un biais inhérent aux données biomédicales considérées comme responsables d’une partie des problèmes de santé. disparités qui touchent aujourd’hui les patients. De nombreuses variantes génétiques trouvées dans des populations non européennes, par exemple, ne sont pas du tout représentées dans le génome de référence.

Le nouveau projet de référence sur le pangénome contient 47 génomes au lieu d’un seul, et fournira un bien meilleur point de comparaison que la référence traditionnelle pour trouver et comprendre les différences dans notre ADN. Crédit : Institut national de recherche sur le génome humain

For years, researchers have called for a resource more inclusive of human diversity with which to diagnose diseases and guide medical treatments. Now scientists with the Human Pangenome Reference Consortium have made groundbreaking progress in characterizing the fraction of human DNA that varies between individuals. As they recently published in Nature, they’ve assembled genomic sequences of 47 people from around the world into a so-called pangenome in which more than 99 percent of each sequence is rendered with high accuracyHow close the measured value conforms to the correct value." data-gt-translate-attributes="[{"attribute":"data-cmtooltip", "format":"html"}]">précision.

Superposées les unes aux autres, ces séquences ont révélé près de 120 millions de paires de bases d’ADN inédites.

At the time, Jarvis, one of the consortium’s leaders, was honing advanced sequencing and computational methods through the Vertebrate Genomes Project, which aims to sequence all 70,000 vertebrate speciesA species is a group of living organisms that share a set of common characteristics and are able to breed and produce fertile offspring. The concept of a species is important in biology as it is used to classify and organize the diversity of life. There are different ways to define a species, but the most widely accepted one is the biological species concept, which defines a species as a group of organisms that can interbreed and produce viable offspring in nature. This definition is widely used in evolutionary biology and ecology to identify and classify living organisms." data-gt-translate-attributes="[{"attribute":"data-cmtooltip", "format":"html"}]"species. His and other collaborating labs decided to apply these advances for high-quality diploid genome assemblies to revealing the variation within a single vertebrate: Homo sapiens./p>

With so many genomes represented in a pangenome, that cloudiness threatened to develop into a thunderstorm of confusion. So the HPRC homed in a method developed by Adam Phillippy and Sergey Koren at the National Institutes of HealthThe National Institutes of Health (NIH) is the primary agency of the United States government responsible for biomedical and public health research. Founded in 1887, it is a part of the U.S. Department of Health and Human Services. The NIH conducts its own scientific research through its Intramural Research Program (IRP) and provides major biomedical research funding to non-NIH research facilities through its Extramural Research Program. With 27 different institutes and centers under its umbrella, the NIH covers a broad spectrum of health-related research, including specific diseases, population health, clinical research, and fundamental biological processes. Its mission is to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability." data-gt-translate-attributes="[{"attribute":"data-cmtooltip", "format":"html"}]"National Institutes of Health on parent-child “trios”—a mother, a father, and a child whose genomes had all been sequenced. Using the data from mom and dad, they were able to clear up the lines of inheritance and arrive at a higher-quality sequence for the child, which they then used for pangenome analysis./p>

The pangenome assembly also fills in gaps that were due to repetitive sequences or duplicated genes. One example is the major histocompatibility complex (MHC), a cluster of genes that code proteins on the surface of cells that help the immune system recognize antigens, such as those from the SARS-CoV-2Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the official name of the virus strain that causes coronavirus disease (COVID-19). Previous to this name being adopted, it was commonly referred to as the 2019 novel coronavirus (2019-nCoV), the Wuhan coronavirus, or the Wuhan virus." data-gt-translate-attributes="[{"attribute":"data-cmtooltip", "format":"html"}]">SARS-CoV-2 virusA virus is a tiny infectious agent that is not considered a living organism. It consists of genetic material, either DNA or RNA, that is surrounded by a protein coat called a capsid. Some viruses also have an outer envelope made up of lipids that surrounds the capsid. Viruses can infect a wide range of organisms, including humans, animals, plants, and even bacteria. They rely on host cells to replicate and multiply, hijacking the cell's machinery to make copies of themselves. This process can cause damage to the host cell and lead to various diseases, ranging from mild to severe. Common viral infections include the flu, colds, HIV, and COVID-19. Vaccines and antiviral medications can help prevent and treat viral infections." data-gt-translate-attributes="[{"attribute":"data-cmtooltip", "format":"html"}]"virus./p>