Aneuploidy and Confined Chromosomal Mosaicism in the Developing Human Brain

Abstract

BackgroundUnderstanding the mechanisms underlying generation of neuronal variability and complexity remains the central challenge for neuroscience. Structural variation in the neuronal genome is likely to be one important mechanism for neuronal diversity and brain diseases. Large-scale genomic variations due to loss or gain of whole chromosomes (aneuploidy) have been described in cells of the normal and diseased human brain, which are generated from neural stem cells during intrauterine period of life. However, the incidence of aneuploidy in the developing human brain and its impact on the brain development and function are obscure.Methodology/Principal FindingsTo address genomic variation during development we surveyed aneuploidy/polyploidy in the human fetal tissues by advanced molecular-cytogenetic techniques at the single-cell level. Here we show that the human developing brain has mosaic nature, being composed of euploid and aneuploid neural cells. Studying over 600,000 neural cells, we have determined the average aneuploidy frequency as 1.25–1.45% per chromosome, with the overall percentage of aneuploidy tending to approach 30–35%. Furthermore, we found that mosaic aneuploidy can be exclusively confined to the brain.Conclusions/SignificanceOur data indicates aneuploidization to be an additional pathological mechanism for neuronal genome diversification. These findings highlight the involvement of aneuploidy in the human brain development and suggest an unexpected link between developmental chromosomal instability, intercellural/intertissular genome diversity and human brain diseases.

Single cell sequencing reveals low levels of aneuploidy across mammalian tissues

“…This observation is in agreement with a recent single-neuron sequencing study that, despite identifying a high frequency of subchromosome copy number variants, did not observe high levels of whole-chromosome aneuploidy in neurons (30). Prior reports used SKY and FISH to assess the prevalence of aneuploidy and found it to exceed 50% and 20% in the liver and brain, respectively (13,14,(16)(17)(18)(19)(20). We attribute this difference to drawbacks associated with using FISH to detect somatic aneuploidy.…”

“…We conclude that the prevalence of aneuploidy in the adult human brain is 2.2% (95% CI 0.3%-7.9%; Fig. 2B and Table S1), significantly less than the more than 20% aneuploidy reported by prior studies (16)(17)(18)(19)(20).…”

“…Using spectral karyotyping (SKY), they reported that 33% of embryonic mouse neural progenitor cells harbored loss or gain of one or more chromosomes. Subsequent studies using FISH indicated that approximately 20% of adult mouse and human brain cells were aneuploid (16)(17)(18)(19)(20). These aneuploid cells were believed to arise from chromosome mis-segregation events in neural progenitor cells and were shown to integrate into brain circuitry (21,22).…”

Copy number detection in discordant monozygotic twins of Congenital Diaphragmatic Hernia (CDH) and Esophageal Atresia (EA) cohorts

“…Application of nextgeneration sequencing methods will allow for an easier and more sensitive calling of the smallest mosaic aberrations in the near future and will add up to the (scarce) data generated recently on this topic by some other groups. [30][31][32][33] Various causes could account for the discrepancy in CNV findings between our congenital anomaly twin cohort and the Parkinson's cohort. First of all, an age factor: the rather high prevalence of mosaic CNVs in PD twins could have been generated during lifetime.…”

Le cancer et ses gènes insaisissables

“…La distinction entre ces deux types de mutations est ainsi fondée sur des inférences non véri-fiables, étant donné qu'il s'agissait là de cancers déjà développés. Il est alors pertinent de signaler ici que des mutations somatiques (silencieuses) ont été identifiées dans les cellules des tissus normaux [17,18]. Les données les plus frappantes, qui réfutent probablement définitivement la théorie des mutations somatiques, viennent de la publication d'une étude récente qui n'a identifié aucune mutation somatique dans un certain type de tumeurs humaines, les épendymomes [19].…”