Two decades after the Human Genome Project delivered the first draft human genome sequence, scientists have published the first full, gapless sequence of a human genome. Researchers believe that possessing a complete, gap-free sequencing of our DNA’s around 3 billion bases (or “letters”) is crucial for comprehending the whole spectrum of human genomic variation and the genetic connections to particular disorders. The Telomere to Telomere (T2T) team led by experts from the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health; the University of California, Santa Cruz; and the University of Washington, Seattle, carried out the research. The NHGRI was the study’s principal funder.
Analyses of the entire genome sequence will considerably improve our understanding of chromosomes, including more accurate maps of five chromosomal arms, opening up new avenues of inquiry. This contributes to answering basic biology concerns concerning how chromosomes segregate and divide properly. The T2T consortium utilized the now-complete genome sequence as a reference to find nearly 2 million new variations in the human genome. These studies provide more precise information on the genetic variants found in 622 medically important genes.
“Generating a fully complete human genome sequence is a remarkable scientific achievement, delivering the first comprehensive picture of our DNA blueprint,” stated NHGRI director Eric Green, M.D., Ph.D. This foundational information will boost the many continuing efforts to grasp all the functional subtleties of the human genome, empowering genetic investigations of human disease.
“Ever since we had the first draft human genome sequence, determining the exact sequence of complex genomic regions has been challenging. I am thrilled that we got the job done. The complete blueprint is going to revolutionize the way we think about human genomic variation, disease and evolution.”
said Evan Eichler, Ph.D., researcher at the University of Washington School of Medicine and T2T consortium co-chair.
The now-complete human genome sequencing will be especially useful for studies aimed at establishing comprehensive views of human genomic diversity, or how people’s DNA differs. Such discoveries are critical for understanding the genetic contributions to particular disorders and for the future use of genome sequencing as a standard aspect of clinical care. Many research groups have already begun to use a pre-release version of the entire human genome sequence in their studies.
The entire sequencing process builds on the work of the Human Genome Project, which mapped approximately 92 percent of the genome, and subsequent studies.To comprehend the intricate sequence, thousands of researchers have developed improved laboratory tools, computer methodologies, and strategic approaches. Six publications covering the entire sequence are published in Science, along with companion papers in numerous additional journals.
That remaining 8% contains multiple genes and repetitive DNA and is the size of a complete chromosome. The whole genome sequencing was created using a rare cell line that has two identical copies of each chromosome, as opposed to typical human cells, which have two slightly different copies. The majority of the newly inserted DNA sequences were found near repeated telomeres and centromeres (the long, trailing ends of each chromosome) and the dense middle sections of each chromosome.
“Determining the exact sequence of complicated genomic areas has been difficult ever since we received the first draft human genome sequence,” said Evan Eichler, Ph.D., a researcher at the University of Washington School of Medicine and T2T collaboration co-chair. “I am happy that we completed the task. The entire blueprint will change the way we think about human genomic variation, disease, and evolution.
The cost of sequencing a human genome utilizing “short-read” technology, which delivers several hundred bases of DNA sequence at a time, is only a few hundred dollars and has dropped dramatically since the Human Genome Project’s conclusion. However, utilizing only these short-read approaches results in some gaps in completed genome sequences. The substantial decrease in DNA sequencing prices coincides with growing expenditures on new DNA sequencing technology to create longer DNA sequence reads without sacrificing accuracy.
Two novel DNA sequencing technologies that yield substantially longer sequence reads have emerged over the last decade. The Oxford Nanopore DNA sequencing method can read up to 1 million DNA letters in a single read with reasonable precision, but the PacBio HiFi DNA sequencing method can read roughly 20,000 letters with near-perfect accuracy. To obtain the full human genome sequence, researchers in the T2T consortium used both DNA sequencing methods.
“We have made advancements in our understanding of the most difficult, repeat-rich portions of the human genome using long-read approaches,” says Karen Miga, Ph.D., a co-chair of the T2T consortium whose research group at the University of California, Santa Cruz is sponsored by NHGRI. “This full human genome sequence has already yielded new insights into genome biology, and I eagerly await the next decade of findings regarding these newly revealed regions.”
According to consortium co-chair Adam Phillippy, Ph.D., whose NHGRI research group spearheaded the final effort, sequencing a person’s full genome should become less expensive and easier in the future.
“In the future, when someone’s genome is sequenced, we’ll be able to detect all of the variants in their DNA and utilize that information to better direct their healthcare,” Phillippy explained. Completing the human genome sequence was akin to putting on a new pair of glasses. We’re one step closer to comprehending what it all means now that we can see everything clearly. “
Many early-career researchers and trainees, including those from Johns Hopkins University in Baltimore, the University of Connecticut in Storrs, the University of California in Davis, the Howard Hughes Medical Institute in Chevy Chase, Maryland, and the National Institute of Standards and Technology in Gaithersburg, Maryland, played critical roles. This achievement is reported in a bundle of six publications in today’s edition of Science, as well as companion papers in numerous other journals.
