Researchers generate the first complete, gapless sequence of a human genome
From: National Institutes of Health
March 31, 2022 -- Scientists have published the
first complete, gapless sequence of a human genome, two decades after the Human
Genome Project produced the first draft human genome sequence. According
to researchers, having a complete, gap-free sequence of the roughly 3 billion
bases (or “letters”) in our DNA is critical for understanding the full spectrum
of human genomic variation and for understanding the genetic contributions to
certain diseases. The work was done by the Telomere to Telomere (T2T)
consortium, which included leadership from researchers at the National Human
Genome Research Institute (NHGRI), part of the National Institutes of Health;
University of California, Santa Cruz; and University of Washington,
Seattle. NHGRI was the primary funder of the study.
Analyses of the
complete genome sequence will significantly add to our knowledge of
chromosomes, including more accurate maps for five chromosome arms, which opens
new lines of research. This helps answer basic biology questions about how
chromosomes properly segregate and divide. The T2T consortium used the
now-complete genome sequence as a reference to discover more than 2 million
additional variants in the human genome. These studies provide more accurate
information about the genomic variants within 622 medically relevant
genes.
“Generating a truly
complete human genome sequence represents an incredible scientific achievement,
providing the first comprehensive view of our DNA blueprint,” said Eric Green,
M.D., Ph.D., director of NHGRI. “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.”
The now-complete human
genome sequence will be particularly valuable for studies that aim to establish
comprehensive views of human genomic variation, or how people’s DNA differs.
Such insights are vital for understanding the genetic contributions to certain
diseases and for using genome sequence as a routine part of clinical care in
the future. Many research groups have already started using a pre-release
version of the complete human genome sequence for their research.
The full sequencing
builds upon the work of the Human Genome Project, which mapped about 92% of
the genome, and research undertaken since then. Thousands of researchers have
developed better laboratory tools, computational methods and strategic
approaches to decipher the complex sequence. Six papers encompassing the
completed sequence appear in Science(link is
external), along with companion papers in several other journals.
That last 8% includes
numerous genes and repetitive DNA and is comparable in size to an entire
chromosome. Researchers generated the complete genome sequence using a special
cell line that has two identical copies of each chromosome, unlike most human
cells, which carry two slightly different copies. The researchers noted that
most of the newly added DNA sequences were near the repetitive telomeres (long,
trailing ends of each chromosome) and centromeres (dense middle sections of
each chromosome).
“Ever since we had the
first draft human genome sequence, determining the exact sequence of complex
genomic regions has been challenging,” said Evan Eichler, Ph.D., researcher at
the University of Washington School of Medicine and T2T consortium co-chair. “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.”
The cost of sequencing
a human genome using “short-read” technologies, which provide several hundred
bases of DNA sequence at a time, is only a few hundred dollars, having fallen
significantly since the end of the Human Genome Project. However, using these
short-read methods alone still leaves some gaps in assembled genome sequences.
The massive drop in DNA sequencing costs comes hand-in-hand with increased
investments in new DNA sequencing technologies to generate longer DNA sequence
reads without compromising the accuracy.
Over the past decade,
two new DNA sequencing technologies emerged that produced much longer sequence
reads. The Oxford Nanopore DNA sequencing method can read up to 1 million DNA
letters in a single read with modest accuracy, while the PacBio HiFi DNA
sequencing method can read about 20,000 letters with nearly perfect accuracy.
Researchers in the T2T consortium used both DNA sequencing methods to generate
the complete human genome sequence.
"Using long-read
methods, we have made breakthroughs in our understanding of the most difficult,
repeat-rich parts of the human genome," says Karen Miga, Ph.D., a co-chair
of the T2T consortium whose research group at the University of California,
Santa Cruz is funded by NHGRI. “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.”
According to consortium
co-chair Adam Phillippy, Ph.D., whose research group at NHGRI led the finishing
effort, sequencing a person’s entire genome should get less expensive and more
straightforward in the coming years.
"In the future,
when someone has their genome sequenced, we will be able to identify all of the
variants in their DNA and use that information to better guide their
healthcare,” Phillippy said. “Truly finishing the human genome sequence was
like putting on a new pair of glasses. Now that we can clearly see everything,
we are one step closer to understanding what it all means.”
Many early-career
researchers and trainees played pivotal roles, including researchers from Johns
Hopkins University, Baltimore; University of Connecticut, Storrs; University of
California, Davis; Howard Hughes Medical Institute, Chevy Chase, Maryland; and
the National Institute of Standards and Technology, Gaithersburg, Maryland. The
package of six papers reporting this accomplishment appears in today’s issue
of Science, along with companion papers in several other journals.
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