De Novo Origins of Human Genes

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Where do new genes come from? For a long time the answer to that question has simply been “from other genes”. The most prolific source of new loci in eukaryotic genomes is gene duplication in all its guises: exon shuffling, tandem duplication, retrocopying, segmental duplication, and genome duplication. However, in recent years there has been a growing appreciation of the oft-dismissed possibility of evolution of new genes from scratch (i.e., de novo) as a rare but consistent feature of eukaryotic genomes [1], [2]. Pioneering work identified several de novo genes in Drosophila [3]–[5], and since then, additional Drosophila cases have been identified [6], as well as cases in yeast [7], [8], Plasmodium [9], rice [10], mouse [11], primates [12], and human [13], [14]. It would appear that whenever anyone makes the effort to search, candidate novel genes are found. In this issue of PLoS Genetics, Wu et al. [15] report 60 putative de novo human-specific genes. This is a lot higher than a previous, admittedly conservative, estimate of 18 such genes [13], [16]. The genes identified share broad characteristics with other reported de novo genes [13]: they are short, and all but one consist of a single exon. In other words, the genes are simple, and their evolution de novo seems plausible. The potential evolution of complex features such as intron splicing and protein domains within de novo genes remains somewhat puzzling. However, features such as proto-splice sites may pre-date novel genes [9], [17], and the appearance of protein domains by convergent evolution may be more likely than previously thought [2]. The operational definition of a de novo gene used by Wu et al. [15] means that there may be an ORF (and thus potentially a protein-coding gene) in the chimpanzee genome that is up to 80% of the length of the human gene (for about a third of the genes the chimpanzee ORF is at least 50% of the length of the human gene). This is a more lenient criterion than employed by other studies, and this may partly explain the comparatively high number of de novo genes identified. Some of these cases may be human-specific extensions of pre-existing genes, rather than entirely de novo genes—an interesting, but distinct, phenomenon.