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

## TL;DR

This study explores how genetic variations in Down syndrome affect 3D genome structure and gene activity using detailed multi-omics analysis.

## Contribution

The study introduces a haplotype-resolved multi-omics approach to link 1D genomic variations with 3D genome architecture and gene transcription in Down syndrome.

## Key findings

- 1D genomic variations like SNPs and CNVs correlate with 3D genome organization changes in Down syndrome.
- Haplotype-level analysis reveals how 3D genome alterations affect DS-related gene dysregulation.
- The findings provide insights into how genomic variations contribute to the pathogenesis of chromosome abnormalities.

## Abstract

For chromosome abnormalities (CAs), such as Down syndrome (DS), the influence of genomic variations on chromosome conformation and gene transcription remains elusive. Based on the complete genomic sequences from the parents of a DS trisomy patient, we systematically delineated an atlas of parental-specific, haplotype-resolved single nucleotide polymorphisms (SNPs), copy number variations (CNVs), three-dimensional (3D) genome architecture, and RNA expression profiles in the diencephalon of the DS patient. The integrated haplotype-resolved multi-omics analysis demonstrated that one-dimensional (1D) genomic variations including SNPs and CNVs in the DS patient are highly correlated with the alterations in the 3D genome organization and the subsequent changes in gene transcription. This correlation remains valid at the haplotype level. Moreover, we revealed the 3D genome alteration-associated dysregulation of DS-related genes, which facilitates understanding the pathogenesis of CAs. Together, our study contributes to deciphering the coding from 1D genomic variations to 3D genome architecture and the subsequent gene transcription outcomes in both health and disease.

Graphical abstract