New tool to generate mosaic aneuploidies and analyse their impact on development

Aneuploidy, an unbalanced number of chromosomes and the leading cause of miscarriages in humans, has recently been recognized as highly prevalent in early human embryos due to chromosome segregation errors during the initial cell divisions. To ensure healthy development, aneuploid cells are effectively eliminated from the fetus at later stages. Later in life, aneuploidy is associated with several pathological conditions such as cancer. Unfortunately, the mechanisms underlying the detection and removal of these cells remain poorly understood. The team led by Marco Milán at IRB Barcelona has utilized a specialized “molecular scissors” tool in Drosophila to generate cells containing molecularly defined segmental aneuploidies of various sizes and types in a developing organ. This new study indicates that cells carrying segmental monosomies affecting only a few hundred genes impede clonal growth and manifest indications of out-competition by the surrounding wild type cells. The observed cellular behaviors are caused by dose-dependent effects of either single genes or the cumulative effects of a discrete number of genes. By simultaneously inducing cells carrying segmental monosomies and trisomies of the same genomic location, this study shows that segmental trisomies potentiate or alleviate the negative effects of the monosomy on growth, thus revealing a key role of cell interactions in defining the in vivo elimination of aneuploid cells. These results are relevant for both human development and disease where two daughter cells bearing complementary aneuploidies (gains and losses of the same chromosome or chromosome region) are produced as a consequence of segregation mistakes in the mother. The elimination of aneuploid cells thus depends on both the internal gene deficit and the cellular environment. This cellular duel helps explain embryo selection criteria in IVF (In vitro fertilization) and paves the way for potential therapies to clear pathological clones, such as aneuploid cancer cells, by modifying the surrounding healthy tissue.