Single cell sequencing reveals low levels of aneuploidy across mammalian tissues

Abstract

Significance Aneuploidy refers to the gain or loss of individual chromosomes within a cell. Typically, aneuploidy is associated with detrimental consequences at both the cellular and organismal levels. However, reports of high levels of aneuploidy in the brain and liver suggested that aneuploidy might play a positive role in these organs. Here we use single cell sequencing to determine the prevalence of aneuploidy in somatic tissues. We find that aneuploidy is a rare occurrence in the liver and brain and is no more prevalent in these tissues than in skin. Our results demonstrate high karyotypic stability in somatic tissues, arguing against a role for aneuploidy in organ function and reinforcing its adverse effects at the cellular and organismal levels.

Aneuploidy impairs hematopoietic stem cell fitness and is selected against in regenerating tissues in vivo

“…S7A). This level of aneuploidy is on par with previously reported levels of aneuploidy for the brain (38.1%) and the liver (18.8%) (Knouse et al 2014) as well as for stimulated splenocytes (3%-33%) in adult Bub1b…”

“…The liver and brain are formed during embryogenesis, and hepatocytes and neurons are largely nonproliferative in the adult (Zimmermann 2004;Campisi and d'Adda di Fagagna 2007). Our previous studies showed that aneuploid cells were prevalent in the livers (18.8%) and brains (38.1%) of 8-and 12-wk-old Bub1b H/H animals, respectively (Knouse et al 2014). Sequencing four additional hepatocytes from a 30-wk-old Bub1b H/H mouse and four additional neurons from a 28-wk-old Bub1b H/H mouse estimated the levels of aneuploidy to be 14.3% and 40%, respectively ( Fig.…”

Construction of thousands of single cell genome sequencing libraries using combinatorial indexing

“…Estimates of the frequency of aneuploidy and large-scale copy number variation in the mammalian brain have varied widely, spanning a range of <5% to 33% [1][2][3][4] . This uncertainty largely stems from the inability to profile sufficient numbers of single cells to produce quantitative measurements.…”

“…We posited that the high throughput of SCI-seq and coverage uniformity using the xSDS method of nucleosome depletion may facilitate an in depth analysis of tumor heterogeneity by single cell CNV analysis. We therefore carried out xSDS SCI-seq on a freshly acquired stage III pancreatic ductal adenocarcinoma (PDAC) specimen measuring approximately 250 mm 3 . Our preparation resulted in 1,715 single cell libraries which were sequenced to a median unique read count of 49,272 per cell (M50 of 71,378) with 846 cells having at least 50,000 unique reads at the depth the library was sequenced and carried through CNV calling (Fig.…”

“…The booming field of single cell sequencing continues to shine light on the abundance and breadth of genomic heterogeneity between cells in a variety of contexts, including somatic gains or losses of megabasepair-sized regions of the genome in the mammalian brain [1][2][3][4] , and tumor heterogeneity and clonal evolution [5][6][7] . Single cell genome sequencing studies have taken one of two approaches: high depth of sequencing per cell for purposes of single nucleotide variant detection 2,8 , or low-pass sequencing to identify copy number variants (CNVs) and the presence of aneuploidy 1,9,10 .…”