Mosaic brain: Neurons in the same brain do not really have the same genome
(by Haohao Wu, 04/12/2013)

You probably learnt in biology class that we everybody hasunique genetic information - DNA, and that allowsthe individuality. Each of the trillions of cells, except germ cells, in our body contains the same DNA despite the structural and functional differences. Quite infrequently, during mitosis or due to mutations, two or more genotypes emerge in one individual, resulting in "somatic mosaicism".

However, along with the technological development, e.g. single-cell sequencing, scientists realized that what we learnt from textbooks was an oversimplification and the genetic diversity is much more common than expected (paper 1, paper 2). The same phenomenon was observed recently in the brain by Michael J. McConnell and collaborators, showing that the genetic makeups of neurons in one brain are considerably diverse.

Mosaic copy number variation (CNV) is detected in human neurons.

Fig. 1: Mosaic copy number variation (CNV) is detected in human neurons.(A and B) Subchromosomal deletions (green down arrow) and duplications(red up arrow) are observed in hiPSC-derived neurons. (C and D) Subchromosomal deletions (green down arrow) and duplications(red up arrow) are observed in FCTX neurons.
(Credit: McConnell, Michael J et al., Science)

Two neurotypes, human induced pluripotent stem cells (hiPSC-derived neurons) and human postmortem frontal cortex (FCTX) neurons, were examined for their DNA copy number variations (CNVs, relatively large regions of genome that have been deleted or duplicated).Using microarray analysis of multiple displacement amplification (MDA) products and single-cellsequencing to map large-scale CNVs in single cells, researchers found that 41% of the FCTX neurons had one or more CNVs and similar ratio was found in culture ofhiPSC-derived neurons.

Using the hiPSC-derived neurons, they further found that each CNV was identified merely in one neuron, suggesting that CNVs are not inherited from parent cells but rather occur in the later stages of differentiation. This was again supported by the results that the hiPSC-derived neurons have significantly larger CNVs than fibroblasts from skin and even neural progenitor cells derived from the same iPSC line.

What are the consequences of genomic diversifications in brain? One positive explanation would be that neurons with different genomes would have different molecular phenotypes, giving another layer of flexibility to survive from viral infections or adapt to ever-changing environment. Some also hypothesize that the mosaicism of brain may have implications of brain disorders, e.g. autism. Michael Snyder added another interesting explanation for this phenomenon, that cells need certain energy to keep everything perfect when replicating DNA, however, the extra energy may not be worth it. In this case, the permission of copying mistakes could be just a economically beneficial way for cells. It’s much easier to have an imperfect life.

You may be interested in:

McConnell, Michael J., Michael R. Lindberg, Kristen J. Brennand, Julia C. Piper, Thierry Voet, Chris Cowing-Zitron, Svetlana Shumilina et al. "Mosaic copy number variation in human neurons." Science 342, no. 6158 (2013): 632-637.