PubMed Highlight: Single-cell genetic variability in neurons

Theoretically any two cells in our body have an high probability to show some genetic diversity, due to somatic mutations and other genetic specific rearrangements activated by cell differentiation. This concept has been proposed as a key factor in neurons. These cells show great plasticity and are divided in several different sub-populations with specific molecular and cellular characteristics and maybe all this diversity should rely on some kind of genetic reorganization particularly active in brain neurons (with retrotransposable elements as best candidates). This hypothesis has been discussed in past years and now this new paper appeared on Cell could shed some light on the real state of genetic diversity in neurons. The authors applied single-cell sequencing on 300 single neurons from cerebral cortex and caudate nucleus of three normal individuals to evaluate specific insertion of LINE-1 elements. Moreover they also evaluate the presence and diffusion of a somatic mutation in AKT3 gene in single cortical cells to characterize the mosaicism in a child with hemimegalencephaly. This study showing that neuronal disorders can arise from mutations that are specific of brain tissue or even neuron sub-populations (somatic mutations appeared in some precursor) and can thus be assessed only by sequencing the neurons themselves.
Further analysis on other neuron populations could lead to definition of a genetic profile specific for each neuron type and/or patients.

Single-Neuron Sequencing Analysis of L1 Retrotransposition and Somatic Mutation in the Human Brain

Gilad D. Evrony, Xuyu Cai, Eunjung Lee, L. Benjamin Hills, Princess C. Elhosary, Hillel S. Lehmann, J.J. Parker, Kutay D. Atabay, Edward C. Gilmore, Annapurna Poduri, Peter J. Parkand Christopher A. Walsh

SUMMARY
A major unanswered question in neuroscience is whether there exists genomic variability between
individual neurons of the brain, contributing to functional diversity or to an unexplained burden of neurological disease. To address this question, we developed a method to amplify genomes of single
neurons from human brains. Because recent reports suggest frequent LINE-1 (L1) retrotransposition in
human brains, we performed genome-wide L1 insertion profiling of 300 single neurons from cerebral cortex and caudate nucleus of three normal individuals, recovering >80% of germline insertions from single neurons. While we find somatic L1 insertions, we estimate <0.6 unique somatic insertions per
neuron, and most neurons lack detectable somatic insertions, suggesting that L1 is not a major generator of neuronal diversity in cortex and caudate. We then genotyped single cortical cells to characterize the mosaicism of a somatic AKT3 mutation identified in a child with hemimegalencephaly. Single-neuron sequencing allows systematic assessment of genomic diversity in the human brain.