Chromosomal Gains and Losses – the functional consequences of aneuploidy at single cell resolution

MACAULAY_E22DTP1

Aneuploidy, the state in which cells exhibit abnormal chromosomal copy number, is the leading cause of miscarriage and congenital defects in humans and is common in many cancers. Gains or losses of chromosomes occur in individual cells, where they can directly impact gene expression, cell phenotype and function, and ultimately, the health of the organism.

In this project, we seek to understand the impact that gains and losses of chromosomes can impact gene expression in individual cells. We have previously shown that cells harbouring additional chromosomes have changes in gene expression arising from both the “gained” chromosome but also throughout the genome. It is this combination of cis- and trans- effects of aneuploidy we wish to study, at scale, in this project. Furthermore, the student will also explore instances of programmed polyploidy – investigating how the massive gains of chromosome copy number seen in megakaryocytes – large bone marrow cells which make platelets – can influence gene expresssion and terminal differentiation of these cells.

Using a range of technologies, including cell sorting (FACS) and subcloning, single-cell multiomics and next generation seqeuncing and bioinformatics, the student will build a library of aneuploid human cells, confirming their aneuploid status by classical karyotyping and through single-cell genome sequencing. The student will, in parallel, generate transcriptomes for these cells using G&T-seq, thus building a detailed overview of how changes in chromosome copy number can impact gene and isoform expression throughout the genome.

Based in the Macaulay lab at the Earlham Insititute and in collaboration with the Haerty and Nieduszinsky groups at EI the student will receive extensive training in experimental and computational biology, developing a broad and transferrable expertise in cellular genomics.

References

Macaulay, I., Haerty, W., Kumar, P. et al. G&T-seq: parallel sequencing of single-cell genomes and transcriptomes. Nat Methods 12, 519–522 (2015). https://doi.org/10.1038/nmeth.3370

Kojima S, Cimini D. Aneuploidy and gene expression: is there dosage compensation?. Epigenomics. 2019;11(16):1827-1837. doi:10.2217/epi-2019-0135