Characterization of large-scale genomic differences in the first complete human genome

Area of Science:

• Genomics
• Human Genetics
• Comparative Genomics

Background:

• The telomere-to-telomere (T2T) human genome assembly (T2T-CHM13) represents a significant advancement over the current GRCh38 reference.
• Understanding large-scale genomic differences between these assemblies is crucial for human genomic studies.

Purpose of the Study:

• To characterize the large-scale structural genomic differences between the T2T-CHM13 and GRCh38 human genome assemblies.
• To categorize these discrepant regions and assess their potential impact on human health and evolution.

Main Methods:

• Utilized a newly developed website tool, SynPlotter, to identify and categorize discrepant genomic regions.
• Analyzed structural variations, including deletions and duplications, in approximately 21.6 Mbp of non-telomeric and non-centromeric regions.

Main Results:

• Identified 67 additional large-scale discrepant regions beyond previously reported "non-syntenic" regions.
• These regions exhibit high structural polymorphism, with deletions or duplications potentially linked to immune and neurodevelopmental disorders.
• Analysis of the KLRC gene cluster revealed KLRC2 depletion associated with natural killer cell differentiation in ~20% of humans and rapid KLRC3 amino acid replacements possibly due to natural selection.

Conclusions:

• Provides a foundational understanding of structural genomic differences between T2T-CHM13 and GRCh38.
• Highlights the importance of these differences for future human genomics research, disease association studies, and evolutionary analyses.