The Structure, Function, and Evolution of Human Chromosome 8



The complete assembly of each human chromosome is essential for understanding human biology and evolution. Using complementary long-read sequencing technologies, we complete the first linear assembly of a human autosome, chromosome 8. Our assembly resolves the sequence of five previously long-standing gaps, including a 2.08 Mbp centromeric α-satellite array, a 644 kbp β-defensin copy number polymorphism important for disease risk, and an 863 kbp 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 kbp hypomethylated region of diverse higher-order α-satellite enriched with CENP-A nucleosomes, consistent with the location of the kinetochore. Additionally, 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 chromosome 8 centromeric regions in chimpanzee, orangutan, and macaque for the first time to reconstruct its evolutionary history. Comparative and phylogenetic analyses show that the higher-order α-satellite structure evolved specifically in the great ape ancestor, and the centromeric region evolved with a layered symmetry, with more ancient higher-order repeats located at the periphery adjacent to monomeric α-satellites. Additionally, sequence and assembly of two other primate centromeres confirms the overall organization and evolution of these regions. We estimate that the mutation rate of centromeric satellite DNA is accelerated at least 2.2-fold, and this acceleration extends beyond the higher-order α-satellite into the flanking sequence.

Learning Objectives:

1. Explain why centromeres, segmental duplications, and other repeat-rich regions of the human genome have been historically challenging to resolve

2. Identify recent advances in long-read DNA sequencing technology and assembly algorithms that are now allowing scientists to accurately assemble complex regions of the genome

3. Describe genetic and epigenetic features of newly resolved regions in chromosome 8 and how the chromosome 8 centromere has evolved over the last 25 million years

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