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Alzheimer’s Study Reveals First Somatic Gene Recombination Found in Human Neurons

Monday, December 17, 2018

Scientists in California recently released exciting results that could offer an entirely new approach to treating the most common form of Alzheimer’s disease. The project, which was reported in a Nature publication, made extensive use of SMRT Sequencing data using targeted sequencing and some previously released full-length RNA sequencing data.

Somatic APP gene recombination in Alzheimer’s disease and normal neurons” comes from lead author Ming-Hsiang Lee, senior author Jerold Chun, and collaborators at the Sanford Burnham Prebys Medical Discovery Institute and the University of California, San Diego. The team aimed to determine whether somatic gene recombination, which is used throughout the genome to boost molecular diversity but has never been found in the brain, could be linked to Alzheimer’s disease.

Using an impressive array of novel and cutting-edge technologies, the scientists found evidence of significant recombination in the APP gene, which encodes amyloid precursor protein in neurons and has been associated with Alzheimer’s. They focused on APP because it has previously been shown to harbor mosaic copy number variants, with higher numbers in patients with sporadic Alzheimer’s disease (SAD). They found that the APP gene harbored thousands of variant genomic cDNAs (gencDNAs) that occurred mosaically in human neurons. The gencDNAs lacked introns and ranged from full-length cDNA copies of expressed, brain-specific RNA splice variants to myriad smaller forms that contained intra-exonic junctions, insertions, deletions, and/or single nucleotide variations.

But past attempts to find gene recombination in APP had failed. “Interrogation of APP genomic loci (about 0.3 Mb) using low-depth, short-read single-cell sequencing capable of detecting CNVs produced negative results that were complicated by resolution limitations,” the authors report. “We therefore developed an alternative strategy focused on APP in small cell populations, using nine distinct methodologies.”

Among those approaches was the use of SMRT Sequencing of PCR amplicons to assess the diversity of gencDNA sequences. The authors used small neural populations from five individuals with SAD (149 reactions from 96,434 nuclei) and five healthy brain (244 reactions from 162,248 nuclei). The authors generated CCS data and used a cut-off that provided them with ultra-high accuracy reads (99.999999% accuracy), and report that these SMRT Sequencing results were “comparable in fidelity to Sanger sequencing.”

They identified 6,299 unique sequences — including 45 different intra-exonic junctions — in neural nuclei from the brains of individuals with SAD, and 1,084 unique sequences — including 20 intra-exonic junctions — in neuronal nuclei from the non-diseased brains. “Critically, both qualitative and quantitative differences in the sequences of gencDNA variants distinguished the brains of individuals with SAD from healthy brains,” the authors note. “Distinctions included gencDNAs with novel intra-exonic junctions and SNVs, which were far more prevalent in the brains of individuals with SAD.”

Because of the need for reverse transcriptase in genomic cDNAs, the scientists also speculate that existing anti-retroviral therapies used for patients with HIV might inhibit the progression of SAD. They note that HIV patients who take such therapies and are older than 65 appear less likely to develop Alzheimer’s disease. “If confirmed, this observation would suggest the immediate use of FDA-approved [combined anti-retroviral therapy]” for patients with this form of Alzheimer’s, they write.

The team concludes with the idea that the recombination findings are unlikely to be specific to the one gene they chose to study. Additional investigation should be considered for other genes active in the brain using the types of technologies that made such a difference in this project.

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