A descoberta do Pangenoma: uma imagem cristalina da diversidade genômica humana

Por Rockefeller University 13 de maio de 2023

O Consórcio de Referência do Pangenoma Humano fez progressos significativos na criação de um genoma de referência humano mais inclusivo, reunindo sequências genómicas de 47 indivíduos de todo o mundo. O genoma humano de referência original baseou-se em dados de um único indivíduo de origem afro-europeia, limitando a sua representação da diversidade genética. Este novo pangenoma, que reproduz mais de 99% de cada sequência com alta precisão, revela quase 120 milhões de pares de bases de DNA nunca antes vistos. Ao fornecer uma representação mais precisa da diversidade genética humana, os investigadores podem refinar a sua compreensão da ligação entre genes e doenças, acelerar a investigação clínica e, em última análise, ajudar a resolver as disparidades na saúde.

Num grande avanço, os cientistas reuniram sequências genómicas de 47 pessoas de diversas origens para criar um pangenoma, que oferece uma representação mais precisa da diversidade genética humana do que o genoma de referência existente. Este novo pangenoma ajudará os investigadores a refinar a sua compreensão da ligação entre genes e doenças e poderá, em última análise, ajudar a resolver as disparidades na saúde.

Durante mais de 20 anos, os cientistas confiaram no genoma humano de referência, uma sequência genética consensual, como padrão para comparar outros dados genéticos. Utilizado em inúmeros estudos, o genoma de referência permitiu identificar genes implicados em doenças específicas e traçar a evolução de características humanas, entre outras coisas.

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"}]"> O DNA foi sequenciado durante o Projeto Genoma Humano, o primeiro esforço para capturar todo o DNA de uma pessoa. Como resultado, pouco nos pode dizer sobre os 0,2 a 1% da sequência genética que torna cada um dos sete mil milhões de pessoas neste planeta diferente umas das outras, criando um preconceito inerente aos dados biomédicos que se acredita serem responsáveis por alguns dos problemas de saúde. disparidades que afetam os pacientes hoje. Muitas variantes genéticas encontradas em populações não europeias, por exemplo, não estão de todo representadas no genoma de referência.

O novo projecto de referência do pangenoma contém 47 genomas em vez de apenas um, e fornecerá um ponto de comparação muito melhor do que a referência tradicional para encontrar e compreender as diferenças no nosso ADN. Crédito: Instituto Nacional de Pesquisa do Genoma Humano

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"}]">precisão.

Sobrepostas umas sobre as outras, essas sequências revelaram quase 120 milhões de pares de bases de DNA que antes não eram vistos.

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>