Abstract
Microproteins (<100 amino acids) are receiving increasing recognition as important participants in numerous biological processes, but their evolutionary dynamics are poorly understood. SPAAR is a recently discovered microprotein that regulates muscle regeneration and angiogenesis through interactions with conserved signaling pathways. Interestingly, SPAAR does not belong to any known protein family and has known homologs exclusively among placental mammals. This lack of distant homology could be caused by challenges in homology detection of short sequences, or it could indicate a recent de novo emergence from a noncoding sequence. By integrating syntenic alignments and homology searches, we identify SPAAR orthologs in marsupials and monotremes, establishing that SPAAR has existed at least since the emergence of mammals. SPAAR shows substantial primary sequence divergence but retains a conserved protein structure. In primates, we infer two independent evolutionary events leading to the de novo origination of 5′ elongated isoforms of SPAAR from a noncoding sequence and find evidence of adaptive evolution in this extended region. Thus, SPAAR may be of ancient origin, but it appears to be experiencing continual evolutionary innovation in mammals.
Highlights
The human genome, as annotated in reference genome databases like RefSeq [1] and Ensembl [2], contains around 20,000 protein-coding genes
The SPAAR orthologs we identified throughout all three mammalian lineages divergence on the SPAAR protein, we examined SPAAR conservation at the amino acid (Figures 1–3) had been missed by automatic genome annotation pipelines because of and structural level
Summary
The human genome, as annotated in reference genome databases like RefSeq [1] and Ensembl [2], contains around 20,000 protein-coding genes. The lack of evident distant homology could indicate a recent de novo origin from a noncoding sequence [7,20,21,22], or may reflect homology detection failure due to the short length or rapid evolutionary divergence [23]. It is currently unclear whether recently discovered microproteins constitute a pool of previously unappreciated evolutionary molecular in-
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