Single cell sequencing reveals low levels of aneuploidy across mammalian tissues

Abstract

Whole-chromosome copy number alterations, also known as aneuploidy, are associated with adverse consequences in most cells and organisms. However, high frequencies of aneuploidy have been reported to occur naturally in the mammalian liver and brain, fueling speculation that aneuploidy provides a selective advantage in these organs. To explore this paradox, we used single cell sequencing to obtain a genome-wide, high-resolution assessment of chromosome copy number alterations in mouse and human tissues. We find that aneuploidy occurs much less frequently in the liver and brain than previously reported and is no more prevalent in these tissues than in skin. Our results highlight the rarity of chromosome copy number alterations across mammalian tissues and argue against a positive role for aneuploidy in organ function. Cancer is therefore the only known example, in mammals, of altering karyotype for functional adaptation.

Fig. 1.

Validating detection of aneuploidy by single cell sequencing. (A) Overview of the method used to detect copy number alterations in single cells by whole-genome sequencing. (B) Segmentation plots of a euploid brain cell (Left) and a trisomy 16 brain cell (Right), isolated from male mouse embryos euploid and trisomic for chromosome 16, respectively. Segmentation plots show copy number of single cells relative to a euploid reference on a log₂ scale. Segments above threshold for gain are colored in red, segments below threshold for loss are colored in green. (C) Heat map of chromosome losses and gains in aneuploid brain cells and liver nuclei from BUB1B^H/H mice. (D) Segmentation plots of five aneuploid cells from a BUB1B^H/H mouse brain. (E) Segmentation plots of three aneuploid nuclei from a BUB1B^H/H mouse liver.

Fig. 2.

Prevalence of aneuploidy in brain. (A and B) Prevalence of euploid and aneuploid cells in mouse (A) and human (B) brain. (C) Segmentation plots of euploid human brain cells. (D) Segmentation plot of an aneuploid human brain cell harboring a monosomy for chromosome 22.

Fig. 3.

Prevalence of aneuploidy in liver. (A) Increase in chromosome copy number correlates with an increase in nuclear diameter in mouse and human hepatocytes. Note that only a single octaploid human hepatocyte nucleus was identified. (B) Prevalence of cells of different ploidy for a single chromosome in mouse and human skin (keratinocytes), liver (hepatocytes), and brain (neurons and glia). Polyploid hepatocytes are indicated as being mononucleate (mono) or binucleate (bi). For example, tetraploid (bi) describes a cell with two nuclei, each of which contains two copies of a single chromosome. n = 200 cells per tissue. (C and D) Prevalence of euploid and aneuploid nuclei in mouse (C) and human (D) liver. (E) Segmentation plots of euploid human hepatocyte nuclei. (F) Segmentation plots of a human hepatocyte nucleus for which a karyotype could not be determined (Upper) and a tetraploid human hepatocyte nucleus harboring pentasomy for chromosomes 5 and 7 (Lower).