New insights into genomic dark regions in human brain affected by Alzheimer's disease
- bessfrost
- Nov 14
- 1 min read
We are excited to share another new study from the lab! This project was led by Dr. Paul Ramirez, Lead Biostatistician for the Brown University Center for Alzheimer’s Disease Research.
Exclusion of genomic “dark regions” from traditional DNA sequencing analysis limits our understanding of human biology and disease. These regions are highly repetitive, structurally complex, and lacking in the standard GRCh38 human reference genome. Dark regions include low-complexity microsatellites, transposable element–rich sequences, and large arrays of ribosomal DNA. Long-read DNA sequencing paired with the new telomere-to-telomere human reference genome helps to overcome these challenges. Nanopore sequencing also preserves native DNA modifications, thus enabling analysis of methylation within repetitive sequences.
Using Oxford Nanopore sequencing of DNA isolated from brains of individuals with early-stage Alzheimer’s disease, late-stage Alzheimer’s disease, and age-matched controls, we find that repetitive areas of the genome are especially prone to genomic changes. For example, we find that putatively somatic retrotransposon insertions are concentrated in centromeric and pericentromeric regions in the aged brain, and that 47S ribosomal DNA arrays have a high frequency of non-allelic homologous recombination compared to other regions. In Alzheimer’s disease, rare somatic retrotransposition events involving the SINE AluY family show a trending increase with advanced disease stage. DNA methylation analyses reveal significant disease stage-specific changes within centromeric and pericentromeric DNA and ribosomal DNA arrays. Taken together, our analyses represent the first long-read analysis of retrotransposons, non-allelic homologous recombination, structural variants, and methylation in genomic dark regions of the aged human brain and identify repetitive regions as key hotspots of variation.
Thank you to the NIH, the Rainwater Foundation, and the BrightFocus Foundation for supporting our work.
