Evolutionary and functional dynamics of chimeric pseudogenes ({varphi}genes)

Genome-associated changes during evolution followed by selection, facilitate development of new genes, gene families and even species. Pseudogenes ({varphi}genes) generated during such genome rearrangements are often considered "dead on arrival" due to compromised expression arising from disruptive mutations or loss of regulatory elements. In an earlier study, we traced the expression of several {varphi}genes, which challenges this notion. Here, we report segmental duplications at proximal genomic locations occasionally generate chimerism as a continuum of sequences from two or more genes, some of which involve intron fusions. These specific introns and flanking exons are likely to have co-evolved from ancestral parent genes. Notably, co-opting upstream regulatory sequences of 5' parent gene may enable activation of chimeric {varphi}genes, while modifications in 3' sequences impart transcript stability. Few chimeric {varphi}genes also harbor strong coding ORFs to be potentially translated into novel or truncated proteins retaining parental domains. Interestingly, chimeric {varphi}genes are expressed only in human tissues, and display signatures of purifying selection. Examining potential functions associates ANAPC1P2 with genotoxic stress responses, while HYDIN2 may play a putative role in regulating cell cycle progression and neuronal differentiation. Taken together, our results suggest chimeric {varphi}genes and their de novo functions may be relevant to speciation. Significance statementThis study challenges the conventional paradigm that designates pseudogenes ({varphi}genes) as "Dead-On-Arrival" sequences in the genome. Identification of chimeric {varphi}genes formed by segmental duplications involving novel intron fusions highlights their role in evolutionary innovation. Notably, a subset of these chimeric {varphi}genes demonstrates signatures of purifying selective pressure and exhibits exclusive, human-specific expression. More importantly, these {varphi}genes may co-opt regulatory sequences, and contribute to novel gene functions such as genotoxic stress responses, and neuronal differentiation revealing putative mechanisms by which {varphi}genes may foster evolutionary novelty. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=129 SRC="FIGDIR/small/679709v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@4e30b6org.highwire.dtl.DTLVardef@1601166org.highwire.dtl.DTLVardef@1652b5org.highwire.dtl.DTLVardef@1900d05_HPS_FORMAT_FIGEXP M_FIG C_FIG