Aneuploidy effects on human gene expression across three cell types.

Area of Science:

• Genetics and Genomics
• Molecular Biology
• Developmental Biology

Background:

• Aneuploidy syndromes affect multiple organ systems, but tissue-specific effects, especially comparing peripheral and brain tissues, are poorly understood.
• Sex chromosome aneuploidies (SCAs) provide a model for analyzing dosage effects due to their diverse karyotypes.

Purpose of the Study:

• To investigate the transcriptomic effects of chromosome X, Y, and 21 aneuploidies across different human cell types.
• To compare the reproducibility of cis- and trans-acting gene expression effects of SCAs in lymphoblastoid cell lines (LCLs), fibroblasts (FCLs), and induced pluripotent stem cell-derived neuronal cells (iNs).

Main Methods:

• Analyzed RNA-sequencing data from 197 individuals with varying sex chromosome dosages (SCDs) in LCLs.
• Validated theoretical models of SCD sensitivity and identified 41 dosage-sensitive genes acting in cis.
• Compared the preservation of cis- and trans-acting SCA effects across LCLs, FCLs, and iNs using complementary analyses and additional datasets.

Main Results:

• Identified 41 genes on the X and Y chromosomes that are obligately dosage-sensitive to SCAs and act in cis.
• Demonstrated that cis-acting SCA effects are largely preserved across LCLs, FCLs, and iNs.
• Showed that trans-acting SCA effects on autosomal gene expression are mostly not preserved across these cell types, a finding also observed in trisomy 21 cell lines.

Conclusions:

• Expanded understanding of how aneuploidies of chromosomes X, Y, and 21 influence human gene expression.
• Suggests that LCLs are a suitable model for studying cis-acting aneuploidy effects in less accessible cell types like brain cells.
• Highlights the differential conservation of cis- versus trans-acting gene expression changes across cell types in response to aneuploidy.