Deciphering Haplotype-level Chromosome Conformation Alteration in Down Syndrome by Haplotype-resolved Multi-omics...

Area of Science:

• Genomics
• Molecular Biology
• Genetics

Background:

• The impact of genomic variations on chromosome conformation and gene transcription in chromosome abnormalities (CA), like Down syndrome (DS), is not fully understood.
• Investigating the link between genetic alterations and their functional consequences is crucial for understanding disease pathogenesis.

Purpose of the Study:

• To delineate a comprehensive atlas of parental-specific genomic and transcriptomic profiles in a Down syndrome patient.
• To investigate the correlation between one-dimensional genomic variations (SNPs, CNVs) and alterations in 3D genome structure and gene expression.
• To understand the role of 3D genome alterations in the mis-regulation of DS-related genes.

Main Methods:

• Whole-genome sequencing of parents of a Down syndrome patient.
• Systematic delineation of haploid single nucleotide polymorphism (SNP) and copy number variation (CNV) profiles.
• Analysis of three-dimensional (3D) genome conformation and RNA expression in the diencephalon.
• Integrated haploid multi-omics analysis.

Main Results:

• One-dimensional genomic variations (SNPs, CNVs) are highly correlated with 3D genome alterations and subsequent gene transcription changes in Down syndrome.
• This correlation is maintained at the haploid level.
• 3D genome alterations are associated with the mis-regulation of Down syndrome-related genes.

Conclusions:

• The study deciphers the relationship between one-dimensional genomic variations, 3D genome architecture, and gene transcription in healthy individuals and disease states.
• Findings provide insights into the pathogenesis of chromosome abnormalities by linking genomic variations to functional genomic changes.
• This work establishes a framework for understanding how genetic variations translate to altered gene expression through 3D genome organization.