国際研究チームは、哺乳類の進化の数百万年にわたって一貫性を保ったヒトゲノムの重要な塩基対を特定した。これらはヒトの病気に重要な役割を果たしており、進化において突然変異が許容されない遺伝子領域を浮き彫りにしており、これは人類の進化につながる可能性がある画期的な成果である。病気の起源を理解し、将来の遺伝子研究に情報を提供します。
人間の病気において重要な役割を果たす DNA の塩基対が、USC の研究者によって特定されました。
南カリフォルニア大学ケック医科大学の人口および公衆衛生科学の助教授であるスティーブン・ガザル博士は、「何百万年もの進化があるにもかかわらず、なぜ人類は依然として病気に苦しむのか?」という難解な質問に答える使命を帯びています。
国際研究チームの一員として、ガザルは画期的な発見をしました。 彼らは、哺乳類の進化の何百万年にもわたって変化せずに残っているヒトゲノム内の特定の塩基対を正確に特定した最初の人物となった。 これらの塩基対は人間の病気において重要な役割を果たします。 彼らの発見は特別号に掲載されました ズーノミア 雑誌の版 化学。
ガザルと彼のチームは、人間を含む 240 匹の哺乳類のゲノムを前例のない解像度で拡大して比較分析しました。[{” attribute=””>DNA. They were able to identify base pairs that were “constrained” – meaning they remained generally consistent – across mammal species over the course of evolution. Individuals born with mutations on these genes may not have been as successful within their species or were otherwise not likely to pass down the genetic variation. “We were able to identify where gene mutations are not tolerated in evolution, and we demonstrated that these mutations are significant when it comes to disease,” explains Gazal.
The team found that 3.3% of bases in the human genome are “significantly constrained,” including 57.6% of the coding bases that determine amino acid position, meaning these bases had unusually few variants across species in the dataset. The most constrained base pairs in mammals were over seven times more likely to be causal for human disease and complex traits, and over 11 times more likely when researchers looked at the most constrained base pairs in primates alone.
The dataset was provided by the Zoonomia consortium, which according to the project website, “is applying advances in DNA sequencing technologies to understand how genomes generate the tremendous wealth of animal diversity.” Gazal gives credit to Zoonomia for making this type of data available to researchers and anticipates it will be widely used by human geneticists. “It’s a cheap resource to generate, as opposed to datasets generated in human genetic studies,” says Gazal.
His team’s findings are a significant step forward, as Gazal notes, “We do not understand 99% of the human genome, so it is fundamental to understand which part has been constrained by evolution and is likely to have an impact on human phenotypes.” Their discoveries and methods could become crucial tools for further research.
The next step for Gazal and his team is to repeat the process with a primate-only dataset. By restricting the subjects, they hope to focus on functions of DNA that appeared more recently in human evolution. “We expect this to be even more useful in determining information on human disease,” says Gazal.
Reference: “Leveraging base-pair mammalian constraint to understand genetic variation and human disease” by Patrick F. Sullivan, Jennifer R. S. Meadows, Steven Gazal, BaDoi N. Phan, Xue Li, Diane P. Genereux, Michael X. Dong, Matteo Bianchi, Gregory Andrews, Sharadha Sakthikumar, Jessika Nordin, Ananya Roy, Matthew J. Christmas, Voichita D. Marinescu, Chao Wang, Ola Wallerman, James Xue, Shuyang Yao, Quan Sun, Jin Szatkiewicz, Jia Wen, Laura M. Huckins, Alyssa Lawler, Kathleen C. Keough, Zhili Zheng, Jian Zeng, Naomi R. Wray, Yun Li, Jessica Johnson, Jiawen Chen, Zoonomia Consortium§. , Benedict Paten, Steven K. Reilly, Graham M. Hughes, Zhiping Weng, Katherine S. Pollard, Andreas R. Pfenning, Karin Forsberg-Nilsson, Elinor K. Karlsson, Kerstin Lindblad-Toh, Gregory Andrews, Joel C. Armstrong, Matteo Bianchi, Bruce W. Birren, Kevin R. Bredemeyer, Ana M. Breit, Matthew J. Christmas, Hiram Clawson, Joana Damas, Federica Di Palma, Mark Diekhans, Michael X. Dong, Eduardo Eizirik, Kaili Fan, Cornelia Fanter, Nicole M. Foley, Karin Forsberg-Nilsson, Carlos J. Garcia, John Gatesy, Steven Gazal, Diane P. Genereux, Linda Goodman, Jenna Grimshaw, Michaela K. Halsey, Andrew J. Harris, Glenn Hickey, Michael Hiller, Allyson G. Hindle, Robert M. Hubley, Graham M. Hughes, Jeremy Johnson, David Juan, Irene M. Kaplow, Elinor K. Karlsson, Kathleen C. Keough, Bogdan Kirilenko, Klaus-Peter Koepfli, Jennifer M. Korstian, Amanda Kowalczyk, Sergey V. Kozyrev, Alyssa J. Lawler, Colleen Lawless, Thomas Lehmann, Danielle L. Levesque, Harris A. Lewin, Xue Li, Abigail Lind, Kerstin Lindblad-Toh, Ava Mackay-Smith, Voichita D. Marinescu, Tomas Marques-Bonet, Victor C. Mason, Jennifer R. S. Meadows, Wynn K. Meyer, Jill E. Moore, Lucas R. Moreira, Diana D. Moreno-Santillan, Kathleen M. Morrill, Gerard Muntané, William J. Murphy, Arcadi Navarro, Martin Nweeia, Sylvia Ortmann, Austin Osmanski, Benedict Paten, Nicole S. Paulat, Andreas R. Pfenning, BaDoi N. Phan, Katherine S. Pollard, Henry E. Pratt, David A. Ray, Steven K. Reilly, Jeb R. Rosen, Irina Ruf, Louise Ryan, Oliver A. Ryder, Pardis C. Sabeti, Daniel E. Schäffer, Aitor Serres, Beth Shapiro, Arian F. A. Smit, Mark Springer, Chaitanya Srinivasan, Cynthia Steiner, Jessica M. Storer, Kevin A. M. Sullivan, Patrick F. Sullivan, Elisabeth Sundström, Megan A. Supple, Ross Swofford, Joy-El Talbot, Emma Teeling, Jason Turner-Maier, Alejandro Valenzuela, Franziska Wagner, Ola Wallerman, Chao Wang, Juehan Wang, Zhiping Weng, Aryn P. Wilder, Morgan E. Wirthlin, James R. Xue and Xiaomeng Zhang, 28 April 2023, Science.
DOI: 10.1126/science.abn2937
The study was funded by the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Swedish Cancer Society, the Swedish Childhood Cancer Fund, the National Institute of Mental Health, the Gladstone Institutes, the National Institute on Drug Abuse, University College Dublin (UCD) Ad Astra Fellowship, and the National Human Genome Research Institute.