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Over the last few years, there has been an increasing amount of evidence for the  de novo  emergence of protein-coding genes, i.e. out of non-coding DNA. Here, we review the current literature and summarize the state of the field. We focus specifically on open questions and challenges in the study of  de novo  protein-coding genes such as the identification and verification of  de novo -emerged genes. The greatest obstacle to date is the lack of high-quality genomic data with very short divergence times which could help precisely pin down the location of origin of a  de novo  gene. We conclude that, while there is plenty of evidence from a genetics perspective, there is a lack of functional studies of bona fide  de novo  genes and almost no knowledge about protein structures and how they come about during the emergence of  de novo  protein-coding genes. We suggest that future studies should concentrate on the functional and structural characterization of  de novo  protein-coding genes as well as the detailed study of the emergence of functional  de novo  protein-coding genes.

Fact or fiction: updates on how protein-coding genes might emerge de novo from previously non-coding DNA