Filling the gaps

Featured Journal Content


Volume 376| Issue 6588| 1 Apr 2022
Special issue – Completing the human genome
Introduction to Special Issue
Filling the gaps
BY Laura M. Zahn
31 Mar 2022: 42-43
A fully sequenced human genome was triumphantly announced more than 20 years ago. However, owing to technological limitations, some genomic regions remained unresolved. Here, Science presents research by the Telomere-to-Telomere (T2T) Consortium, reporting on the endeavor to complete a comprehensive human reference genome. Generated primarily by long-read sequencing of a hydatidiform mole, a doubly haploid growth, this effort adds ∼200 megabases of genetic information—a full chromosome’s worth—to the human genome.

Through the resolution of previously unsequenceable and unalignable regions, mostly composed of highly repetitive sequences, this reference genome allows for a detailed characterization of the centromeric satellite repeats, transposable elements, and segmental duplications. Mapping of genomic sequences, including those from previously published studies, resolves aspects of human genetic diversity, including evolutionary comparisons with our primate relatives. Furthermore, it allows for identification of how changes in methylation density differ within and among centromeres and how epigenetics can affect the transcription of repeat sequences.

These investigations have only begun to tease apart how the T2T reference genome influences the detection of biomedically relevant variants and the evolution of genomic regions that determine human traits. Although much remains to be discovered, the T2T reference genome provides another celebratory benchmark to observe as we continue to delve into the genetics that underlie our complete selves.//

The complete sequence of a human genome
BY Sergey Nurk et al [89 authors]
31 Mar 2022: 44-53
Since its initial release in 2000, the human reference genome has covered only the euchromatic fraction of the genome, leaving important heterochromatic regions unfinished. Addressing the remaining 8% of the genome, the Telomere-to-Telomere (T2T) Consortium presents a complete 3.055 billion–base pair sequence of a human genome, T2T-CHM13, that includes gapless assemblies for all chromosomes except Y, corrects errors in the prior references, and introduces nearly 200 million base pairs of sequence containing 1956 gene predictions, 99 of which are predicted to be protein coding. The completed regions include all centromeric satellite arrays, recent segmental duplications, and the short arms of all five acrocentric chromosomes, unlocking these complex regions of the genome to variational and functional studies.



NIH – Researchers generate the first complete, gapless sequence of a human genome
Completion is critical for understanding the full spectrum of human genomic variation and for understanding the genetic contributions to certain diseases.
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 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.”…
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 is external) and follow @Genome_gov(link is external).