Functional genetics of early human development

Abstract

Understanding the genetic underpinning of early human development is of great interest not only for basic developmental and stem cell biology but also for regenerative medicine, infertility treatments, and better understanding the causes of congenital disease. Our current knowledge has mainly been generated with the use of laboratory animals, especially the mouse. While human and mouse early development present morphological resemblance, we know that the timing of the events as well as the cellular and genetic mechanisms that control fundamental processes are distinct between the species. The rapid technological development of single-cell sequencing and genome editing together with novel stem cell models of the early human embryo has made it feasible and relevant to perform functional genetic studies directly in human cells and embryos. In this review we will discuss these latest advances where combined transcriptional analysis and genome engineering has begun to shed new insights into the key processes of zygotic genome activation, lineage specification, X-chromosome inactivation and postimplantation development including primordial germ cell specification in the human embryo.

Human Embryonic Expression Identifies Novel Essential Gene Candidates

“…Specifically, embryonic expression is a signature of gene essentiality as it correlates to human and murine essentiality, conservation, and constraint. Highly expressed genes in early embryonic stages, particularly those expressed by the zygote, may play key roles in processes occurring early in development, such as lineage specification, implantation or X-chromosome dosage compensation (Ortega et al, 2018). Highly expressed genes in the human seem to turn on early and occupy essential roles throughout the human lifespan, as they are enriched in basic cellular machinery and metabolic processes, congruent with essential genes in other model systems (Hirsh & Fraser, 2001;Kojima, Tam, & Tam, 2014;Pál, Papp, & Hurst, 2001).…”

“…Their disruption may lead to pregnancy loss, early lethality or severe disease. By identifying genes that are essential for early human development, we can provide insights into the molecular basis of fitness and reproductive success (Ortega, Winblad, Plaza Reyes, & Lanner, 2018;T. Wang et al, 2015).…”

“…Wang et al, 2015). Model systems allow for the observation of shared phenotypic traits between species (Mee et al, 2005;Ortega et al, 2018). This approach has successfully identified genes that are critical in early murine development, which appear to translate well to humans (Mee et al, 2005;Muñoz-Fuentes et al, 2018).…”

“…Even though studies of mouse embryo development have provided key insights into early developmental pathways, species-specific differences limit the extrapolation of some findings to humans. Translation is challenging in many instances due to inter-species differences such as those observed in the timing and mechanisms of lineage specification (Ortega et al, 2018;Xie et al, 2010). For instance, humans begin specification of the trophectoderm and inner cell mass in the blastocyst stage while, in contrast, mice begin this differentiation earlier in the morula stage (Niakan & Eggan, 2013;Ortega et al, 2018).…”

“…Translation is challenging in many instances due to inter-species differences such as those observed in the timing and mechanisms of lineage specification (Ortega et al, 2018;Xie et al, 2010). For instance, humans begin specification of the trophectoderm and inner cell mass in the blastocyst stage while, in contrast, mice begin this differentiation earlier in the morula stage (Niakan & Eggan, 2013;Ortega et al, 2018). Such differences in the timing and in the sequence of events between species elucidate the importance of human-specific analyses for the prediction of essential genes.…”