Abstract
A new form of somatic gene recombination (SGR) has been identified in the human brain that affects the Alzheimer's disease gene, amyloid precursor protein (APP). SGR occurs when a gene sequence is cut and recombined within a single cell's genomic DNA, generally independent of DNA replication and the cell cycle. The newly identified brain SGR produces genomic complementary DNAs (gencDNAs) lacking introns, which integrate into locations distinct from germline loci. This brief review will present an overview of likely related recombination mechanisms and genomic cDNA-like sequences that implicate evolutionary origins for brain SGR. Similarities and differences exist between brain SGR and VDJ recombination in the immune system, the first identified SGR form that now has a well-defined enzymatic machinery. Both require gene transcription, but brain SGR uses an RNA intermediate and reverse transcriptase (RT) activity, which are characteristics shared with endogenous retrotransposons. The identified gencDNAs have similarities to other cDNA-like sequences existing throughout phylogeny, including intron-less genes and inactive germline processed pseudogenes, with likely overlapping biosynthetic processes. gencDNAs arise somatically in an individual to produce multiple copies; can be functional; appear most frequently within postmitotic cells; have diverse sequences; change with age; and can change with disease state. Normally occurring brain SGR may represent a mechanism for gene optimization and long-term cellular memory, whereas its dysregulation could underlie multiple brain disorders and, potentially, other diseases like cancer. The involvement of RT activity implicates already Food and Drug Administration-approved RT inhibitors as possible near-term interventions for managing SGR-associated diseases and suggest next-generation therapeutics targeting SGR elements.
Highlights
The human brain is the most complex organ in our body, encompassing astronomical cellular diversity, intricate connectivities, and specialized functions that include cognition and memory
The potential age-related increases in somatic gene recombination (SGR) and genomic complementary DNA (gencDNA) could explain the decades required for neurodegenerative disease to manifest, as well as the common comorbidity of two or more neurodegenerative diseases [106], whereby a threshold of SGR activity operates on distinct sets of pathogenic genes; as pathogenic gene variants accumulate over time, disease initiation results
Brain SGR represents a new mechanism for diversifying gene expression, through the “recording” and “playback” of new gene forms within single somatic-cell genomes of an individual, in long-lived postmitotic neurons
Summary
The newly identified brain SGR produces genomic complementary DNAs (gencDNAs) lacking introns, which integrate into locations distinct from germline loci This brief review will present an overview of likely related recombination mechanisms and genomic cDNA-like sequences that implicate evolutionary origins for brain SGR. Analyses were focused on APP genomic sequences in human neurons: remarkably, the identified APP sequences resembled complementary DNAs (cDNAs): they lacked introns yet were present in genomic DNA and were termed “gencDNAs” (Fig. 1) Their many forms and copies represented novel components of the somatic human genome yet displayed features that were highly reminiscent of known, genetic (for single-celled organisms), or germline evolutionary elements lacking introns: intron-less genes and inactive processed pseudogenes. Other forms of DNA recombination, such as DNA repair mechanisms and meiotic recombination, are beyond the scope of this review
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