Researchers generate the first complete, gapless sequence of a human
genome

Date:
March 31, 2022
Source:
National Institutes of Health
Summary:
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.



FULL STORY ========================================================================== [Genome sequence and DNA | Credit: (c) majcot / stock.adobe.com] Genome sequence and DNA illustration (stock image).

Credit: (c) majcot / stock.adobe.com [Genome sequence and DNA | Credit:
(c) majcot / stock.adobe.com] Genome sequence and DNA illustration
(stock image).

Credit: (c) majcot / stock.adobe.com Close 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, 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.

For more, visit Genome.gov/T2T and follow @Genome_gov.


========================================================================== Story Source: Materials provided by National_Institutes_of_Health. Note: Content may be edited for style and length.


========================================================================== Journal References:
1. Sergey Nurk, Sergey Koren, Arang Rhie, Mikko Rautiainen, Andrey V.

Bzikadze, Alla Mikheenko, Mitchell R. Vollger, Nicolas Altemose,
Lev Uralsky, Ariel Gershman, Sergey Aganezov, Savannah J. Hoyt,
Mark Diekhans, Glennis A. Logsdon, Michael Alonge, Stylianos
E. Antonarakis, Matthew Borchers, Gerard G. Bouffard, Shelise
Y. Brooks, Gina V. Caldas, Nae-Chyun Chen, Haoyu Cheng, Chen-Shan
Chin, William Chow, Leonardo G. de Lima, Philip C. Dishuck,
Richard Durbin, Tatiana Dvorkina, Ian T. Fiddes, Giulio Formenti,
Robert S. Fulton, Arkarachai Fungtammasan, Erik Garrison, Patrick
G. S. Grady, Tina A. Graves-Lindsay, Ira M. Hall, Nancy F. Hansen,
Gabrielle A. Hartley, Marina Haukness, Kerstin Howe, Michael
W. Hunkapiller, Chirag Jain, Miten Jain, Erich D. Jarvis, Peter
Kerpedjiev, Melanie Kirsche, Mikhail Kolmogorov, Jonas Korlach,
Milinn Kremitzki, Heng Li, Valerie V. Maduro, Tobias Marschall,
Ann M.

McCartney, Jennifer McDaniel, Danny E. Miller, James C. Mullikin,
Eugene W. Myers, Nathan D. Olson, Benedict Paten, Paul Peluso,
Pavel A. Pevzner, David Porubsky, Tamara Potapova, Evgeny I. Rogaev,
Jeffrey A. Rosenfeld, Steven L. Salzberg, Valerie A. Schneider,
Fritz J. Sedlazeck, Kishwar Shafin, Colin J. Shew, Alaina Shumate,
Ying Sims, Arian F. A. Smit, Daniela C. Soto, Ivan Sović,
Jessica M. Storer, Aaron Streets, Beth A. Sullivan, Franc,oise
Thibaud-Nissen, James Torrance, Justin Wagner, Brian P. Walenz,
Aaron Wenger, Jonathan M. D. Wood, Chunlin Xiao, Stephanie M. Yan,
Alice C. Young, Samantha Zarate, Urvashi Surti, Rajiv C. McCoy,
Megan Y. Dennis, Ivan A. Alexandrov, Jennifer L. Gerton, Rachel
J. O'Neill, Winston Timp, Justin M. Zook, Michael C. Schatz, Evan E.

Eichler, Karen H. Miga, Adam M. Phillippy. The complete
sequence of a human genome. Science, 2022; 376 (6588): 44 DOI:
10.1126/science.abj6987
2. Ariel Gershman, Michael E. G. Sauria, Xavi Guitart, Mitchell
R. Vollger,
Paul W. Hook, Savannah J. Hoyt, Miten Jain, Alaina Shumate, Roham
Razaghi, Sergey Koren, Nicolas Altemose, Gina V. Caldas, Glennis A.

Logsdon, Arang Rhie, Evan E. Eichler, Michael C. Schatz, Rachel J.

O'Neill, Adam M. Phillippy, Karen H. Miga, Winston Timp. Epigenetic
patterns in a complete human genome. Science, 2022; 376 (6588)
DOI: 10.1126/science.abj5089
3. Mitchell R. Vollger, Xavi Guitart, Philip C. Dishuck, Ludovica
Mercuri,
William T. Harvey, Ariel Gershman, Mark Diekhans, Arvis Sulovari,
Katherine M. Munson, Alexandra P. Lewis, Kendra Hoekzema,
David Porubsky, Ruiyang Li, Sergey Nurk, Sergey Koren, Karen
H. Miga, Adam M. Phillippy, Winston Timp, Mario Ventura, Evan
E. Eichler. Segmental duplications and their variation in a complete
human genome. Science, 2022; 376 (6588) DOI: 10.1126/science.abj6965
4. Savannah J. Hoyt, Jessica M. Storer, Gabrielle A. Hartley, Patrick
G. S.

Grady, Ariel Gershman, Leonardo G. de Lima, Charles Limouse, Reza
Halabian, Luke Wojenski, Matias Rodriguez, Nicolas Altemose, Arang
Rhie, Leighton J. Core, Jennifer L. Gerton, Wojciech Makalowski,
Daniel Olson, Jeb Rosen, Arian F. A. Smit, Aaron F. Straight,
Mitchell R. Vollger, Travis J. Wheeler, Michael C. Schatz,
Evan E. Eichler, Adam M. Phillippy, Winston Timp, Karen H. Miga,
Rachel J. O'Neill. From telomere to telomere: The transcriptional
and epigenetic state of human repeat elements. Science, 2022; 376
(6588) DOI: 10.1126/science.abk3112
5. Sergey Aganezov, Stephanie M. Yan, Daniela C. Soto, Melanie Kirsche,
Samantha Zarate, Pavel Avdeyev, Dylan J. Taylor, Kishwar Shafin,
Alaina Shumate, Chunlin Xiao, Justin Wagner, Jennifer McDaniel,
Nathan D. Olson, Michael E. G. Sauria, Mitchell R. Vollger,
Arang Rhie, Melissa Meredith, Skylar Martin, Joyce Lee, Sergey
Koren, Jeffrey A. Rosenfeld, Benedict Paten, Ryan Layer, Chen-Shan
Chin, Fritz J. Sedlazeck, Nancy F. Hansen, Danny E. Miller, Adam
M. Phillippy, Karen H. Miga, Rajiv C. McCoy, Megan Y. Dennis,
Justin M. Zook, Michael C. Schatz. A complete reference genome
improves analysis of human genetic variation. Science, 2022; 376
(6588) DOI: 10.1126/science.abl3533
6. Nicolas Altemose, Glennis A. Logsdon, Andrey V. Bzikadze, Pragya
Sidhwani, Sasha A. Langley, Gina V. Caldas, Savannah J. Hoyt, Lev
Uralsky, Fedor D. Ryabov, Colin J. Shew, Michael E. G. Sauria,
Matthew Borchers, Ariel Gershman, Alla Mikheenko, Valery
A. Shepelev, Tatiana Dvorkina, Olga Kunyavskaya, Mitchell
R. Vollger, Arang Rhie, Ann M.

McCartney, Mobin Asri, Ryan Lorig-Roach, Kishwar Shafin, Julian
K. Lucas, Sergey Aganezov, Daniel Olson, Leonardo Gomes de Lima,
Tamara Potapova, Gabrielle A. Hartley, Marina Haukness, Peter
Kerpedjiev, Fedor Gusev, Kristof Tigyi, Shelise Brooks, Alice Young,
Sergey Nurk, Sergey Koren, Sofie R. Salama, Benedict Paten, Evgeny
I. Rogaev, Aaron Streets, Gary H.

Karpen, Abby F. Dernburg, Beth A. Sullivan, Aaron F. Straight,
Travis J.

Wheeler, Jennifer L. Gerton, Evan E. Eichler, Adam M. Phillippy,
Winston Timp, Megan Y. Dennis, Rachel J. O'Neill, Justin M. Zook,
Michael C.

Schatz, Pavel A. Pevzner, Mark Diekhans, Charles H. Langley, Ivan A.

Alexandrov, Karen H. Miga. Complete genomic and epigenetic
maps of human centromeres. Science, 2022; 376 (6588) DOI:
10.1126/science.abl4178 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220331151517.htm

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