The Structure, Function and Evolution of a Complete Human Chromosome 8

Nature, April 9, 2021

Project 8p Foundation is proud to be working with the Eichler Lab and Glennis Logsden on our patient cell lines to investigate the underpinnings of this disorder.

Abstract

The complete assembly of each human chromosome is essential for understanding human biology and evolution1,2 . Here we use complementary long-read sequencing technologies to complete the linear assembly of human chromosome 8. Our assembly resolves the sequence of fve previously long-standing gaps, including a 2.08-Mb centromeric α-satellite array, a 644-kb copy number polymorphism in the β-defensin gene cluster that is important for disease risk, and an 863-kb variable number tandem repeat at chromosome 8q21.2 that can function as a neocentromere. We show that the centromeric α-satellite array is generally methylated except for a 73-kb hypomethylated region of diverse higher-order α-satellites enriched with CENP-A nucleosomes, consistent with the location of the kinetochore. In addition, we confrm the overall organization and methylation pattern of the centromere in a diploid human genome. Using a dual long-read sequencing approach, we complete high-quality draft assemblies of the orthologous centromere from chromosome 8 in chimpanzee, orangutan and macaque to reconstruct its evolutionary history. Comparative and phylogenetic analyses show that the higher-order α-satellite structure evolved in the great ape ancestor with a layered symmetry, in which more ancient higher-order repeats locate peripherally to monomeric α-satellites. We estimate that the mutation rate of centromeric satellite DNA is accelerated by more than 2.2-fold compared to the unique portions of the genome, and this acceleration extends into the fanking sequence.

Author

Glennis A. Logsdon , Mitchell R. Vollger , PingHsun Hsieh , Yafei Mao , Mikhail A. Liskovykh , Sergey Koren , Sergey Nurk , Ludovica Mercuri , Philip C. Dishuck , Arang Rhie , Leonardo G. de Lima , Tatiana Dvorkina , David Porubsky , William T. Harvey , Alla Mikheenko , Andrey V. Bzikadze , Milinn Kremitzki , Tina A. Graves-Lindsay , Chirag Jain , Kendra Hoekzema , Shwetha C. Murali, Katherine M. Munson , Carl Baker , Melanie Sorensen , Alexandra M. Lewis , Urvashi Surti, Jennifer L. Gerton , Vladimir Larionov , Mario Ventura , Karen H. Miga11, Adam M. Phillippy & Evan E. Eichler,

The Project 8p Foundation (Project 8p) was created in 2018 to:

  • Accelerate future treatments, not only for 8p, but potentially for other chromosome-wide diseases as well.
  • Lead with knowledge from patients. Currently, there is no cure for 8p disorders, nor is there a standard course of treatment.

The Project 8p Foundation (Project 8p) was created in 2018 to:

  • Raise transformative funding for pioneering scientific research into treatments for a complex, rare disease involving 250+ affected genes on the short arm of the 8 th chromosome (8p). Rearrangements of these genes causes significant abnormalities to the entire neurological system, thus all organs and functions of the body– with variance in cognitive functions, gross motor skills, social development and other challenges during infancy, and throughout life;
  • Empower a unified community of 8p patients and their families so they can have meaningful lives today; and
  • Accelerate future treatments, not only for 8p, but potentially for other chromosome-wide diseases as well.