The impact of aneuploidy on early human development

After fertilization, cells in the early embryo rapidly divide to produce the required cell numbers for building embryonic tissues. Such rapid cell divisions can be erroneous, resulting in cells with gains or losses of chromosomes, known as aneuploid cells. If aneuploid cells die off or if they are segregated to non-embryonic lineages (placenta), the embryo development may proceed normally. However, if aneuploid cells persist and proliferate, they may lead to developmental failure and pregnancy loss or, in some instances, the birth of a child with congenital abnormalities. Yet, we currently do not know what determines these different possible outcomes. Consequently, the detection of mosaic aneuploidy during prenatal testing presents a significant challenge for clinicians who have limited options in consulting the patients regarding the prognosis of pregnancy. Resolving this conundrum has been difficult as human embryos are experimentally inaccessible for obvious ethical reasons.
In recent years, human pluripotent stem cells (hPSCs), which encompass cells derived from early human embryos and somatic cells reprogrammed to resemble early embryonic cells, have been used to model different stages of early human development. Through our previous work, we have collated a range of hPSCs with extra or missing chromosomes, resembling aneuploidies found in early embryos and chromosomal mosaicism syndromes, such as the Pallister-Killian syndrome. Utilising such lines, our goal here is to understand the consequences of aneuploidy and chromosomal mosaicism in early human development. To achieve this goal, our work will address the following outstanding questions:
1) How does aneuploidy involving specific chromosomes affect early differentiation and patterning in in vitro models of human embryo development?
2) What is the outcome of interactions of diploid cells with aneuploid cells harbouring specific aneuploidies in models of mosaic embryos?
3) Which signalling pathways are dysregulated by aneuploidy and chromosomal mosaicism and can they be manipulated to promote aneuploid cell elimination?

Aneuploidy, or an abnormal and unbalanced chromosome number, is a pervasive feature of human embryo development. There is a high incidence of aneuploid cells in early human embryos, but their frequency decreases as development progresses. The reduction in the proportion of aneuploid cells has been attributed to the ability of embryos to 'self-correct', for example, by diploid cells outcompeting or eliminating aneuploid cells to establish diploid embryos. However, such self-correction mechanisms are susceptible to errors, as chromosomal mosaicism is associated with pregnancy loss and congenital disorders. Thus, interpretation of the significance of chromosomal mosaicism represents one of the most challenging issues in prenatal diagnosis.
We hypothesise that cell fate and patterning during development are affected by aneuploidy in a chromosome-specific manner and that these defects induce selection mechanisms that eliminate aneuploid cells. In this project, we will combine the use of human pluripotent stem cells (hPSCs) harbouring aneuploidies of specific chromosomes with hPSC-based human embryo models to determine the fate of aneuploid cells during development. To achieve this overarching objective, first, we will determine the consequences of specific chromosome aneuploidies on the ability of hPSCs to differentiate and create appropriate spatial patterns in in vitro models of human gastrulation. Next, to elucidate the fate of aneuploid cells in mosaic embryos, we will perform co-culture experiments using diploid and aneuploid cells, mimicking chromosomal mosaicism of human embryos. Finally, we will determine the pathways dysregulated by aneuploidy and pathways specific to chromosomal mosaicism.
Together, we expect that these results will shed light on how aneuploidy impacts human embryo development and provide future strategies for minimising the impact of aneuploidy on embryogenesis.