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,