Haplotype-resolved diverse human genomes and integrated analysis of structural variation

Area of Science:

• Genomics
• Human Genetics
• Bioinformatics

Background:

• De novo genome assembly is crucial for understanding genetic variation.
• Previous methods often required parent-child trio data for haplotype resolution.
• Short-read sequencing has limitations in resolving complex genomic regions and structural variants.

Purpose of the Study:

• To develop a method for high-quality haplotype-resolved human genome assembly without trio data.
• To create a comprehensive resource of genetic variation, including structural variants (SVs).
• To investigate the mechanisms and impact of SVs in the human genome.

Main Methods:

• Utilized long-read and strand-specific sequencing technologies for de novo genome assembly.
• Assembled 64 haplotypes from 32 diverse human genomes.
• Integrated all forms of genetic variation, including complex loci and mobile elements.

Main Results:

• Achieved highly contiguous haplotype assemblies with an average N50 contig length of 26 million base pairs.
• Identified 107,590 structural variants (SVs), with 68% being novel compared to short-read data.
• Discovered 278 SV hotspots and characterized 130 active mobile element source elements, with 63% of SVs arising from homology-mediated mechanisms.
• Enabled graph-based genotyping for up to 50,340 SVs, identifying 1526 expression quantitative trait loci (eQTLs) and SV candidates for adaptive selection.

Conclusions:

• Long-read sequencing enables high-quality, haplotype-resolved human genome assembly without parental data.
• This study significantly expands the catalog of known human structural variants and their origins.
• The generated resource facilitates advanced genetic analysis, including eQTL studies and the investigation of human adaptation.