Somatic Genomic Mosaicism
Somatic genomic mosaicism (GM) in the brain is a surprising phenomenon whereby cells from the same brain actually have different genomes. We continue to define forms of GM, involved cell types, and GM’s impact on normal brain function and disease, including neurodegenerative diseases (Alzheimer’s, Down syndrome, Parkinson’s), neuropsychiatric disorders, and substance abuse.
Understanding the brain remains one of the great challenges of science and medicine. Composed of hundreds of billions of enormously diverse cells, the brain is organized in ways that provide both functional stability, such as memories and skills that can last a lifetime, yet also maintain enormous plasticity, allowing us to continue learning. During the last quarter century, it has become increasingly clear that brain cells – particularly post-mitotic neurons – have distinct genomes that vary at the level of their DNA sequence (in addition to epigenetic changes that do not affect sequence). This arises somatically, without affecting the germline, to produce somatic genomic mosaicism. Sequence changes vary (in decreasing size) from the very large that include multiple chromosomes – aneuploidies – and other large DNA content changes, to smaller structural and copy number variations (CNVs), to repeat elements like LINE-1, to single nucleotide variations (SNVs), which all combined produce the genomically mosaic brain. Most of these changes involve non-coding sequences. However, more recently, reverse transcriptase (RT)-mediated somatic gene recombination (RT-SGR) (SGR) has been identified within neurons, producing “genomic cDNAs” or “gencDNAs,” which affect cellular genes to produce CNVs, structural variants, and mutations. RT-SGR diversifies neurons at both the genomic (ie. DNA) and transcriptomic (ie. RNA) levels. In Alzheimer’s disease and likely other neurodegenerative conditions, new gencDNAs and endogenous active RT offer potential drug targets for intervention, while real-world data related to inhibition of endogenous RTs support this approach towards accessing near-term benefits for patients suffering from Alzheimer’s disease, Down syndrome (DS), Parkinson’s disease (PD), traumatic brain injury (TBI), and other neurodegenerative diseases.
Our studies on genomic mosaicism utilize a wide range of methodologies, predominantly short- and long-read sequencing technologies on bulk populations, small populations, and single nuclei from the human and mouse brain, that are supported by traditional cell and molecular biology techniques.
Somatic Gene Recombination
We first speculated that somatic gene recombination (SGR) might operate in the brain (Chun et al. 1991), which could vastly expand the repertoire of gene forms beyond the relatively limited number of annotated genes, by comparison to the universe of immunological diversity produced by V(D)J recombination. New techniques in recent years enabled the discovery of brain SGR that becomes dysregulated in the Alzheimer’s disease (AD) brain, affecting the pathogenic gene, amyloid precursor protein (APP). Unlike V(D)J recombination, SGR requires an RNA intermediate, reverse transcription and retroinsertion of cDNA-like sequences. Studies on involved genes, mechanisms and functional consequences of SGR in healthy and diseased human brains of donors, as well as cellular and animal models, are ongoing.
Alzheimer’s Disease and Other Related Dementias
Understanding and treating Alzheimer’s disease (AD) and its related dementias (ADRDs) is a major unmet medical need. Somatic gene recombination (SGR) of APP and other genes has the potential to bridge multiple areas of AD research, potentially linking ADRDs towards explaining disease comorbidities, and providing a novel mechanism for AD therapeutics.
Other Forms of Somatic Genomic Mosaicism
We first identified somatically generated genomic mosaicism in the human brain in 2001 appearing as chromosomal aneuploidies and aneusomies in brain cells that could be functionally integrated into the brain’s circuitry and survive into adulthood. We continue to investigate other forms of somatic genomic mosaicism including aneuploidies, large CNVs, and total DNA content variation. Aneuploidies and large CNVs are often assessed in the context of brain developmental effects caused by exposure to lipids, alcohol, or other noxious insults to mimic neurodevelopmental diseases such as hydrocephalus and fetal alcohol syndrome.