La svolta nel pangenoma: un’immagine cristallina della diversità genomica umana

Di Rockefeller University, 13 maggio 2023

Lo Human Pangenome Reference Consortium ha compiuto progressi significativi nella creazione di un genoma umano di riferimento più inclusivo assemblando sequenze genomiche di 47 individui provenienti da tutto il mondo. Il genoma umano di riferimento originale era basato sui dati di un singolo individuo di origine afro-europea, limitando la sua rappresentazione della diversità genetica. Questo nuovo pangenoma, che riproduce oltre il 99% di ciascuna sequenza con elevata precisione, rivela quasi 120 milioni di coppie di basi del DNA mai viste prima. Fornendo una rappresentazione più accurata della diversità genetica umana, i ricercatori possono affinare la loro comprensione del legame tra geni e malattie, accelerare la ricerca clinica e, in definitiva, contribuire ad affrontare le disparità sanitarie.

Con un importante passo avanti, gli scienziati hanno assemblato sequenze genomiche di 47 persone provenienti da contesti diversi per creare un pangenoma, che offre una rappresentazione più accurata della diversità genetica umana rispetto al genoma di riferimento esistente. Questo nuovo pangenoma aiuterà i ricercatori a perfezionare la loro comprensione del legame tra geni e malattie e potrebbe, in definitiva, contribuire ad affrontare le disparità sanitarie.

Per più di 20 anni, gli scienziati hanno fatto affidamento sul genoma umano di riferimento, una sequenza genetica di consenso, come standard con cui confrontare altri dati genetici. Utilizzato in innumerevoli studi, il genoma di riferimento ha permesso, tra le altre cose, di identificare i geni implicati in malattie specifiche e di tracciare l’evoluzione dei tratti umani.

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"}]"> Il DNA è stato sequenziato durante il Progetto Genoma Umano, il primo tentativo di catturare tutto il DNA di una persona. Di conseguenza, può dirci poco sullo 0,2-1% della sequenza genetica che rende ciascuno dei sette miliardi di persone su questo pianeta diverso gli uni dagli altri, creando una distorsione intrinseca nei dati biomedici ritenuti responsabili di alcuni dei problemi sanitari. disparità che colpiscono i pazienti oggi. Molte varianti genetiche trovate nelle popolazioni non europee, ad esempio, non sono affatto rappresentate nel genoma di riferimento.

La nuova bozza di riferimento sul pangenoma contiene 47 genomi invece di uno solo e fornirà un punto di confronto molto migliore rispetto al riferimento tradizionale per trovare e comprendere le differenze nel nostro DNA. Credito: Istituto nazionale di ricerca sul genoma umano

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"}]">precisione.

Stratificate l’una sull’altra, queste sequenze hanno rivelato quasi 120 milioni di paia di basi di DNA mai viste prima.

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>