Segmental duplications and their variation in a complete human genome

Area of Science:

• Genomics
• Human Genetics
• Evolutionary Biology

Background:

• Highly identical segmental duplications (SDs) are challenging to sequence, hindering understanding of their role in disease and evolution.
• The human reference genome (GRCh38) lacked complete sequencing of these complex regions.

Purpose of the Study:

• To provide a comprehensive view of human SD organization using a complete telomere-to-telomere genome assembly (T2T-CHM13).
• To analyze the impact of SDs on genome-wide estimates and human copy number variation.
• To reconstruct the evolution and structural diversity of duplicated genes in primates.

Main Methods:

• Utilized the T2T-CHM13 complete human genome assembly.
• Analyzed 268 human genomes to assess copy number variation within SDs.
• Compared long-read assemblies from human and nonhuman primate genomes (12 human, 5 nonhuman primate).

Main Results:

• SDs constitute nearly one-third of additional sequence, increasing the genome-wide estimate to 7.0% (218 Mbp).
• 91% of previously unresolved T2T-CHM13 SD sequence (68.3 Mbp) better represents human copy number variation.
• Reconstructed evolution and structural haplotype diversity of duplicated genes, revealing primate-specific patterns.

Conclusions:

• The T2T-CHM13 assembly provides unprecedented insight into human SD organization and its contribution to genome complexity.
• SDs are a major source of human copy number variation and have undergone significant evolutionary divergence between humans and other primates.
• This work lays the foundation for understanding the functional and evolutionary impact of SDs in health and disease.