Human trisomy 21, responsible for Down syndrome, is the most prevalent genetic cause of cognitive impairment and remains a key focus for prenatal and preimplantation diagnosis. However, research directed toward eliminating supernumerary chromosomes from trisomic cells is limited. The present study demonstrates that allele-specific multiple chromosome cleavage by clustered regularly interspaced palindromic repeats Cas9 can achieve trisomy rescue by eliminating the target chromosome from human trisomy 21 induced pluripotent stem cells and fibroblasts. Unlike previously reported allele-nonspecific strategies, we have developed a comprehensive allele-specific (AS) Cas9 target sequence extraction method that efficiently removes the target chromosome. The temporary knockdown of DNA damage response genes increases the chromosome loss rate, while chromosomal rescue reversibly restores gene signatures and ameliorates cellular phenotypes. Additionally, this strategy proves effective in differentiated, nondividing cells. We anticipate that an AS approach will lay the groundwork for more sophisticated medical interventions targeting trisomy 21.

Keywords: CRISPR/Cas; Down syndrome; allele specificity; chromosome cut; chromosome loss; human trisomy 21.

© The Author(s) 2025. Published by Oxford University Press on behalf of National Academy of Sciences.

Studies of genetics conducted in yeast cells, human neurons, mice or other model systems often reveal networks of genes that could contribute to complex diseases, such as breast cancer, type 2 diabetes and Parkinson’s disease. But those findings don’t always translate to human biology. Human genetics offers a path to determining which genes among those networks are most relevant to human disease.

Researchers at Harvard Medical School have developed a new statistical framework to link networks identified in models with human genetic data. This could make it faster and easier for researchers to identify which groups of genes are most likely to contribute to a particular human disease, uncover rare disease-causing mutations and zero in on promising therapeutic targets.

The work was published in Cell Genomics.

A compelling longitudinal study of over 350 older adults with early beta-amyloid accumulation reveals that the genetic risk for Alzheimer’s disease is not strictly deterministic, but is profoundly modulated by sleep quality through the AQP4 gene—a critical regulator of the brain’s glymphatic waste-clearance system. By cross-referencing specific AQP4 variants with multi-year MRI and PET imaging alongside cognitive assessments, researchers demonstrated that poor sleep parameters, such as shorter duration and delayed onset, significantly accelerate neurodegenerative markers like gray matter loss and ventricle expansion in carriers of specific risk alleles. Paradoxically, however, carriers of certain rare variants exhibited slower cognitive decline even in the presence of sleep disturbances. Ultimately, these findings illuminate a complex gene-environment interplay, proving that identical genetic predispositions can either expedite or buffer against brain atrophy depending on sleep architecture, thereby highlighting the critical necessity of personalized, sleep-targeted lifestyle interventions as a highly actionable strategy for Alzheimer’s prevention.

Scientists have discovered an important link between sleep, genetics, and Alzheimer’s disease. New findings suggest that getting poor sleep can accelerate brain shrinkage and memory loss in older adults carrying specific genetic variants.