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

The complete assembly of each human chromosome is essential for understanding human biology and evolution(1,)(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 alpha-satellite array, a 644-kb copy number polymorphism in the beta-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 alpha-satellite array is generally methylated except for a 73-kb hypomethylated region of diverse higher-order alpha-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 alpha-satellite structure evolved in the great ape ancestor with a layered symmetry, in which more ancient higher-order repeats locate peripherally to monomeric alpha-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.

Automated summary

The study completed the linear assembly of human chromosome 8 using long-read sequencing technologies, resolving five long-standing gaps, including regions important for disease risk. The research revealed that the centromeric alpha-satellite sequence is generally methylated, and conducted comparative analysis of centromeres in chimpanzee, orangutan and macaque. The study estimates that the mutation rate of centromeric satellite DNA is accelerated compared to unique portions of the genome.