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First complete sequence of a human genome

Researchers completed the first gap-free sequence of the entire human genome.vitstudio / Shutterstock

The , completed in 2003, covered about 92% of the total human genome sequence. The technologies to decipher the gaps that remained didn’t exist at the time. But scientists knew that the last 8% likely contained information important for fundamental biological processes.

Since then, researchers have developed better laboratory tools, computational methods, and strategic approaches. The final, complete human genome sequence was described in a set of six papers in the April 1, 2022, issue of Science. Companion papers were also published in several other journals.

The work was done by the Telomere to Telomere (T2T) consortium. T2T is led by researchers at NIH’s National Human Genome Research Institute (NHGRI), the University of California, Santa Cruz, and the University of Washington, Seattle. NHGRI was the primary funder.

“Short-read” technologies were originally used to sequence the human genome. These provide several hundred bases of DNA sequence at a time, which are then stitched together by computers. Such methods still leave some gaps in genome sequences. 

Over the past decade, two new DNA sequencing technologies emerged that can read longer sequences without compromising accuracy. The PacBio HiFi DNA sequencing method can read about 20,000 letters with nearly perfect accuracy. The Oxford Nanopore DNA sequencing method can read even more—up to 1 million DNA letters at a time—with modest accuracy. Both were used to generate the complete human genome sequence.

In total, the new project added nearly 200 million letters of the genetic code. This last 8% of the genome includes numerous genes as well as repetitive DNA sequences, which may influence how cells function. Most of the newly added sequences were in the centromeres, the dense middle sections of chromosomes, and near the repetitive ends of each chromosome.

The complete genome sequence will be particularly valuable for studies that aim to understand how DNA differs from person to person. For example, T2T researchers used the sequence as a reference to discover more than 2 million previously unknown sequence variants in the human genome. These included variants within many medically relevant genes. 

“This complete human genome sequence has already provided new insight into genome biology, and I look forward to the next decade of discoveries about these newly revealed regions,” says Dr. Karen Miga, a co-chair of the T2T consortium at the University of California, Santa Cruz.

“Truly finishing the human genome sequence was like putting on a new pair of glasses,” says consortium co-chair Dr. Adam Phillippy, whose group at NHGRI led the effort. “Now that we can clearly see everything, we are one step closer to understanding what it all means.” 

This accomplishment can now serve as a model for sequencing genomes from globally diverse people—a goal researchers are pursuing. Further work is also needed to finish the complete sequence of the Y chromosome, which was not contained in the cells used for this study.

“This foundational information will strengthen the many ongoing efforts to understand all the functional nuances of the human genome, which in turn will empower genetic studies of human disease,” says Dr. Eric Green, director of NHGRI.