March 31, 2022  |  Featured

A new era of genomics: how a truly complete reference will impact human genetic research


What would be possible if every human genetics researcher had a complete reference genome? Today, researchers use a good – but incomplete – reference genome released in 2013. As a result, many analyses miss out on critical genomic regions that may contain the disease-causing variants of interest. Regardless of how many samples are included in studies, this limits discovery. Researchers need a complete reference genome to discover all causative variants. And now, with the first gapless human reference genome from the Telomere-to-Telomere (T2T) Consortium, this is a reality.

The Human Genome Project (HGP) is admired as one of the greatest scientific accomplishments in history. The goal of the project was to discover and map the full blueprint of what makes a human, including the estimated ~25,000 genes, to empower further biological study. The international project formally began in 1990 and ten years later, leaders stood on the White House lawn and announced that the project was complete — the first draft human genome had been sequenced. While it was deemed “complete” at the time, in reality many gaps remained. Improvements in subsequent years closed some gaps, but up until now only 92% of the human genome sequence had been mapped.

What happened?

Even at its end, it was clear that the technology that was available during the HGP had limitations. As a result, scientists soon identified gaps in the draft human genome and launched new projects to truly finish the genome. Despite their efforts, large regions of chromosomes remained unfinished for many years due to limitations of sequencing technologies – such as capillary and short-read sequencing.

That is, until now.

Last year, the Telomere-to-Telomere (T2T) Consortium, a large team of scientists from the National Human Genome Research Institute and dozens of other institutions, released a preprint titled “The complete sequence of a human genome”. The data showed that the consortium had resolved gaps and errors to deliver “the first truly complete human reference genome”, finally mapping the more than 8% missing parts of the genome from two decades before, and “marking a new era of genomics where no region of the genome is beyond reach.”

Now, the complete T2T assembly has been released by Science. This mapping, and the resulting reference genome were made possible with PacBio HiFi sequencing:

“The T2T-CHM13 assembly adds five full chromosome arms and more additional sequence than any genome reference release in the past 20 years. This 8% of the genome has not been overlooked because of a lack of importance but rather because of technological limitations. High accuracy long-read sequencing has finally removed this technological barrier,” the authors highlight.

T2T missing bases

“This feat probably wouldn’t have been possible without new sequencing technology from PacBio,” states Karen Miga, PhD, co-Chair, T2T Consortium.

This work is changing the game in human genetics, “enabling comprehensive studies of genomic variation across the entire human genome, which we expect to drive future discovery in human genomic health and disease.” Now, researchers have access to millions of new, unexplored bases in the human genome to expand studies of disease association and cellular function.

The tools developed to support the T2T Consortium using PacBio HiFi data:

  • Enables all human genetics researchers to generate reference quality genomes from diverse backgrounds to better understand human health
  • Removes barriers of legacy technologies that only provide fractions of the genome
  • Allows researchers to avoid misidentifying disease-linked mutations by expanding the catalog of non-pathogenic person-to-person variation

And by comparing the complete human genome to the genomes of our closest primate relatives, researchers can better understand the differences, i.e. ultimately what makes us ‘human’, even for the previously most challenging regions.

High quality genetic research requires the highest quality and most complete reference genome for a given population. In human genetics, the T2T Consortium has shown that the new gold standard for a reference human genome is here – and to access it, you need to be using HiFi sequencing.

PacBio is pleased that our technology has contributed to this milestone in human genetics. The power and quality of HiFi sequencing is enabling new discoveries and opening regions of the genome that will impact research and discovery for years to come. The success of the T2T Consortium has inspired researchers to team up with the Human Pangenome Reference Consortium which is sequencing over 300 additional reference genomes in the next three years from humans representing diverse ancestries, further increasing our understanding of challenging regions of the genome.

Download the full study and the infographic. Learn more about whole genome sequencing, the benefits of HiFi sequencing, and applications for SMRT sequencing on our site.

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