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Scientists have mapped an entire unbroken human genome for the first time, a milestone that completes the groundbreaking work started by the Human Genome Project decades ago, according to a motherlode of new studies published in Science and other journals on Thursday.
The final stubborn gaps of the genome, representing about eight percent of this human blueprint, were filled by the Telomere to Telomere (T2T) consortium, an international team consisting of dozens of scientists. The achievement opens the door to a host of new discoveries about the genetic variation between people, the evolution of our species, and the treatment of genetic diseases.
“Hallelujah, we have finally finished one human genome,” said Evan Eichler, a professor and Howard Hughes Medical Institute investigator in the Department of Genome Sciences at the University of Washington School of Medicine, in a press briefing about the breakthrough on Thursday.
“The best is yet to come,” added Eichler, who serves as co-chair of the T2T consortium. “No one should see this as the end. It is the beginning, I think, of transformation, not only for genomic research, but for clinical medicine, although that will take years to achieve.”
Genomes are the language of life, written inside the cells of all living things in four letters (A, C, G, and T) that represent fundamental units of DNA called bases, which in turn combine into two base pairs.
When the Human Genome Project revealed the first draft of a human genome in 2001, it was hailed as one of the biggest advances in modern science. Though the project was undoubtedly a giant leap forward in genomics, it only deciphered the so-called “euchromatin” part of the genome, which makes up about 92 percent of the roughly three billion base pairs (or six billion bases) that make us human.
The remaining eight percent, called heterochromatin, turned out to be a much tougher nut to crack because its DNA sequences are so repetitive, making it difficult to untangle them into the correct order. For this reason, heterochromatic regions have sometimes been dismissed as “junk DNA,” a characterization that the new batch of studies emphatically rejects.
“It turns out that these genes are incredibly important for adaptation,” Eichler said. “They contain immune response genes that help us to adapt and survive infections and plagues and viruses. They contain genes that are important in terms of helping us detoxify agents and they are very important in terms of predicting drug response.”
“But perhaps most interesting to me is they carry genes that make us uniquely human,” he continued. “About half of the genes that are thought to make our bigger brain, compared to the other apes, come specifically from these regions, which were absent in the original Human Genome Project. So for me, it's like a dream come true.”
The comprehensive results fill in the terra incognita of human chromosomes, which are structures inside the cell nucleus that preserve genetic information. Heterochromatic sequences that make up centromeres, a part of the chromosome that serves as a link during cell division, have been exposed for the first time. The T2T consortium has also decoded the short structural “arms” on five of the 23 chromosomes in a human genome (chromosomes 13, 14, 15, 21, and 23).
Even though heterochromatic DNA makes up less than a tenth of the genome, it took researchers almost twice as long to assemble these final painstaking lines, compared to the initial mapping of the euchromatic regions that make up the vast majority of our code. Filling in the missing links of the chain required the development of next-generation laboratory tools, more robust computational methods, and a new generation of genetic research leaders.
“The reason that I'm here today is because I was mystified that parts of our genome are organized in this way,” said Karen Miga, an assistant professor in the Biomolecular Engineering Department at UC Santa Cruz and a co-lead of T2T, in the press briefing. “Why critical functions for our cell are placed over these very uniquely structured regions was very fascinating to me.”
“This is a key genomic feature,” she added. “You can go to plants, insects, and other mammals—the genomic feature is organized in this way.”
This first truly complete genome was not sourced from a living human, but rather a special type of embryo-turned-tumor, called a hydatidiform mole, that was provided by an anonymous woman of European descent about 20 years ago. Whereas living humans inherit two different genomes from their mother and father, a hydatidiform mole rejects its maternal blueprint and duplicates its paternal genome, making it non-viable.
Working with just one version of the genome simplified the process of mapping out the remaining euchromatic genes, though the researchers acknowledged the limitations of working with one specific ancestral heritage. To get a better read on the incredible diversity of humans, the T24 consortium is partnering with the Human Pangenome Reference Consortium to fully map genomes from different lineages that will reveal, in unprecedented detail, how all humans are related to each other.
Eric Green, the director of the National Human Genome Research Institute (NHGRI) at the U.S. The National Institutes of Health (NIH), called the new studies a “remarkable achievement.”
“These publications might be considered the long-awaited closing ceremony, or perhaps the encore, to the incredibly audacious [Human Genome Project], which at the time determined as much of the human genome sequence as was possible with the tools in hand at the time,” he said in the briefing. “Scientists inspired by that initial endeavor have now finished what I, and other members of the Human Genome Project, started. We have come full circle.”