Sequencing of 64 complete human genomes to better understand genetic diversity

64 sequenced human genomes will serve as a new benchmark for genetic variation and predisposition to human disease

Researchers at the University of Maryland School of Medicine (UMSOM) co-authored a study, published today in the journal Science, which details the sequencing of 64 complete human genomes. This benchmark data includes individuals from around the world and better captures the genetic diversity of the human species. Among other applications, the work will enable population-specific studies on genetic predispositions to human diseases as well as the discovery of more complex forms of genetic variation.

Twenty years ago this month, the International Human Genome Sequencing Consortium announced the first draft of the human genome reference sequence. The Human Genome Project, as it was called, took 11 years of work and involved over 1,000 scientists from 40 countries. This reference, however, did not represent a single individual, but rather was a composite of humans who could not accurately capture the complexity of human genetic variation.

Based on this, scientists have carried out several sequencing projects over the past 20 years to identify and catalog the genetic differences between an individual and the reference genome. These differences generally focused on small, single base changes and omitted larger genetic changes. Current technologies are now starting to detect and characterize larger differences – called structural variants – such as insertions of new genetic material. Structural variants are more likely than small genetic differences to interfere with gene function.

The new discovery in Science heralded a new, much more comprehensive reference data set that was obtained using a combination of advanced sequencing and mapping technologies. The new benchmark dataset reflects 64 assembled human genomes, representing 25 different human populations from around the world. Importantly, each of the genomes was assembled without the guidance of the first composite of the human genome. As a result, the new data set better captures the genetic differences of different human populations.

“We have entered a new era of genomics where entire human genomes can be sequenced with exciting new technologies that provide more substantial and precise readings of the DNA basics, ”said study co-author Scott Devine, PhD, associate professor of medicine at UMSOM and faculty member at IGS. “This allows researchers to study areas of the genome that were previously not accessible but that are relevant to human traits and disease.”

The Genome Resource Center (GRC) at the Institute of Genome Science (IGS) was one of three sequencing centers, along with Jackson Labs and the Washington University, which generated the data using new sequencing technology that was recently developed by Pacific Biosciences. The GRC was one of only five early access centers that were asked to test the new platform.

Dr Devine helped lead the sequencing efforts for this study and also led the subgroup of authors who discovered the presence of “moving parts” (i.e. pieces of DNA that can move and fit into other areas of the genome). Other members of the Institute of Genome Sciences (IGS) at the University of Maryland School of Medicine are among the 65 co-authors. Luke Tallon, PhD, Scientific Director of the Genome Resource Center, worked with Dr. Devine to generate one of the first human genome sequences on the Pacific Bioscences platform that contributed to this study. Nelson Chuang, a graduate student from Dr Devine’s lab also contributed to the project.

“The new landmark research demonstrates a giant leap in our understanding of the foundations of genetically motivated health conditions,” said E. Albert Reece, MD, PhD, MBA, executive vice president for medical affairs, UM Baltimore and John Z and Akiko K. Bowers, professor emeritus and dean of medicine at the University of Maryland. “This breakthrough will hopefully fuel future studies aimed at understanding the impact of human genome variation on human disease.”

Reference: “Various human genomes resolved by haplotype and integrated analysis of structural variation” by Peter Ebert, Peter A. Audano, Qihui Zhu, Bernardo Rodriguez-Martin, David Porubsky, Marc Jan Bonder, Arvis Sulovari, Jana Ebler, Weichen Zhou, Rebecca Serra Mari, Feyza Yilmaz, Xuefang Zhao, PingHsun Hsieh, Joyce Lee, Sushant Kumar, Jiadong Lin, Tobias Rausch, Yu Chen, Jingwen Ren, Martin Santamarina, Wolfram Höps, Hufsah Ashraf, Nelson T. Chuang, Xiaofei Yang, Katherine M . Munson, Alexandra P. Lewis, Susan Fairley, Luke J. Tallon, Wayne E. Clarke, Anna O. Basile, Marta Byrska-Bishop, André Corvelo, Uday S. Evani, Tsung-Yu Lu, Mark JP Chaisson, Junjie Chen , Chong Li, Harrison Brand, Aaron M. Wenger, Maryam Ghareghani, William T. Harvey, Benjamin Raeder, Patrick Hasenfeld, Allison A. Regier, Haley J. Abel, Ira M. Hall, Paul Flicek, Oliver Stegle, Mark B. Gerstein, Jose MC Tubio, Zepeng Mu, Yang I. Li, Xinghua Shi, Alex R. Hastie, Kai Ye, Zechen Chong, Ashley D. Sanders, Michae l C. Zo dy, Michael E. Talkowski, Ryan E. Mills, Scott E. Devine, Charles Lee, Jan O. Korbel, Tobias Marschall and Evan E. Eichler, February 25, 2021, Science.
DOI: 10.1126 / science.abf7117