Peptides Encoded by Short ORFs Control Development and Define a New Eukaryotic Gene Family

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Abstract
Despite recent advances in developmental biology, and the sequencing and annotation of genomes, key questions regarding the organisation of cells into embryos remain. One possibility is that uncharacterised genes having nonstandard coding arrangements and functions could provide some of the answers. Here we present the characterisation of tarsal-less (tal), a new type of noncanonical gene that had been previously classified as a putative noncoding RNA. We show that tal controls gene expression and tissue folding in Drosophila, thus acting as a link between patterning and morphogenesis. tal function is mediated by several 33-nucleotide–long open reading frames (ORFs), which are translated into 11-amino-acid–long peptides. These are the shortest functional ORFs described to date, and therefore tal defines two novel paradigms in eukaryotic coding genes: the existence of short, unprocessed peptides with key biological functions, and their arrangement in polycistronic messengers. Our discovery of tal-related short ORFs in other species defines an ancient and noncanonical gene family in metazoans that represents a new class of eukaryotic genes. Our results open a new avenue for the annotation and functional analysis of genes and sequenced genomes, in which thousands of short ORFs are still uncharacterised. How cells organize into embryos remains a fundamental question in developmental biology. It is likely that significant insights into embryo development will emerge from the characterisation of novel types of genes. Yet most current genome annotation methods rely heavily on comparisons with already-known gene sequences, so genes with previously uncharacterised structures and functions can be missed. Here we present the characterisation of one of these novel genes, tarsal-less. tarsal-less has two unusual features: it contains more than one coding unit, a structure more similar to some bacterial genes; and it codes for small peptides rather than proteins. In fact, these peptides represent the smallest gene products known to date. Functional analysis of this gene in the fruit fly Drosophila shows that it has important functions throughout development, including tissue morphogenesis and pattern formation. We identify genes similar to tarsal-less in other species, and thus define a tarsal-less–related gene family. We expect that a combination of bioinformatic and functional methods, such as those presented in this study, will identify and characterise more genes of this type. These results suggest that hundreds of novel genes may await discovery.