De Novo Gene Emergence: Summary, Classification, and Challenges of Current Methods

A novel mechanism of de novo gene origination from nongenic sequences was first proposed in the early 2000s. Subsequent studies have since provided evidence of de novo gene emergence across all domains of life, revealing its occurrence to be more frequent than initially anticipated. While studies mainly agree on the general concept of de novo emergence from nongenic DNA, the exact methods and definitions for detecting de novo genes differ significantly. Here, we provide a comprehensive step-by-step description of the most commonly used methods for de novo gene detection. In addition, we address the limitations of nomenclature and detection methods and clarify some complex concepts that are sometimes misused. This review is accompanied by the publication of a de novo gene annotation format to standardize the reporting of methodology, enable reproducibility and improve the comparability of datasets.