The structure, function and evolution of a complete human chromosome 8

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 five 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 confirm 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 flanking sequence.

Epigenetic Patterns in a Complete Human Genome

“…Human genomic DNA was extracted from the CHM13 cultured cell line. DNA extraction and sequencing methods are outlined in Miga et al, 2020; Logsdon et al, 2021 and Nurk et al ( 3, 45, 73 ). Data is available at: https://github.com/nanopore-wgs-consortium/CHM13 .…”

Towards complete and error-free genome assemblies of all vertebrate species

“…'Finished' quality (Table 1) is obviously the ideal assembly result, but this level of quality is currently routine only for bacterial and non-vertebrate model organisms with smaller genome sizes that lack large centromeric satellite arrays [65][66][67] and for organelle genomes, as presented here 33 . The possibility of achieving complete, telomere-to-telomere assemblies of vertebrate and other eukaryotic species is foreseeable, given some assembled avian and bat chromosomes with zero gaps in this study, and the recent complete assembly of two human chromosomes 68,69 .…”

Sequence, Chromatin and Evolution of Satellite DNA

“…However, with the improvement of long-read sequencing technology, it has recently become possible to obtain end-to-end maps of the human X chromosome that span centromeric and telomeric regions [317]. Additionally, using the long-read sequencing, the centromeric satellites have been assembled for chromosome 8 and utilized for evolutionary analysis of α-satellite arrays [318]. The rapid improvement in long-read sequencing technology should soon reveal the precise arrangement of satellite blocks, which will provide evidence of the rearrangements that have occurred during their emergence and evolution.…”