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

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.