Elucidating the evolution of fast-evolving homeobox genes and their role in mammalian preimplantation embryonic development

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Summary for a non-specialist audience: Homeobox genes encode transcription factors (TFs) with a characteristic 60 amino acid (aa) DNA-binding homeodomain, which frequently play critical roles in early embryo patterning and cell fate specification. Fast-evolving homeobox genes have in the past been largely overlooked, but are now at the centre of an exciting area of evolutionary developmental biology. I will use the ETCHbox genes, which are a group of homeobox genes unique to the placental mammals, as a model to answer a number of questions about fast-evolving homeobox genes' evolution and function. Intriguingly, these genes are expressed only at the 8- and 16-cell stages of human embryonic development and then never utilised again. I will firstly aim to gain a better understanding of the function of these genes by elucidating where they are expressed in the embryo, and what their transcriptional targets are. I will then look to understand their importance to embryonic development, using CRISPR/Cas9 gene editing to create loss of function mutant bovine embryos. Next, questions regarding their evolution will be tackled. Comparisons between human and bovine genes will test whether they have changed or maintained their function during their rapid evolution, and analysis of RNA-sequencing data will help understand whether they have taken on a pre-existing function, or are performing a novel function that emerged with the genes. Overall, this will provide a better understanding of the role ETCHbox genes play in mammalian embryonic development, and illuminate the processes behind the rapid evolution of fast-evolving homeobox genes.BBSRC priority areas addressed: Animal health - up to 56% cattle embryos are lost before the blastocyst stage, and this infertility is an important issue because it is the largest cause of animal culling. This work aims to give a more complete understanding of the genes involved in pre-blastocyst development, which may identify contributing factors to this early embryo loss. This work is also consistent with the 3Rs, because cattle were selected as a model due to the ability to obtain oocytes from abattoirs without the sacrifice of any animals on top of those used for meat production.