Inference for the Initial Stage of Domain Shuffling: Tracing the Evolutionary Fate of the PIPSL Retrogene in Hominoids

Abstract

Domain shuffling has provided extraordinarily diverse functions to proteins. Nevertheless, how newly combined domains are coordinated to create novel functions remains a fundamental question of genetic and phenotypic evolution. Previously, we reported a unique mechanism of gene creation, whereby new combinations of functional domains are assembled from distinct genes at the RNA level, reverse transcribed, and integrated into the genome by the L1 retrotransposon. The novel gene PIPSL, created by the fusion of phosphatidylinositol-4-phosphate 5-kinase (PIP5K1A) and 26S proteasome subunit (S5a/PSMD4) genes, is specifically transcribed in human and chimpanzee testes. We present the first evidence for the translation of PIPSL in humans. The human PIPSL locus showed a low nucleotide diversity within 11 populations (125 individuals) compared with other genomic regions such as introns and overall chromosomes. It was equivalent to the average for coding sequences or exons from other genes, suggesting that human PIPSL has some function and is conserved among modern populations. Two linked amino acid-altering single-nucleotide polymorphisms were found in the PIPSL kinase domain of non-African populations. They are positioned in the vicinity of the substrate-binding cavity of the parental PIP5K1A protein and change the charge of both residues. The relatively rapid expansion of this haplotype might indicate a selective advantage for it in modern humans. We determined the evolutionary fate of PIPSL domains created by domain shuffling. During hominoid diversification, the S5a-derived domain was retained in all lineages, whereas the ubiquitin-interacting motif (UIM) 1 in the domain experienced critical amino acid replacements at an early stage, being conserved under subsequent high levels of nonsynonymous substitutions to UIM2 and other domains, suggesting that adaptive evolution diversified these functional compartments. Conversely, the PIP5K1A-derived domain is degenerated in gibbons and gorillas. These observations provide a possible scheme of domain shuffling in which the combined parental domains are not tightly linked in the novel chimeric protein, allowing for changes in their functional roles, leading to their fine-tuning. Selective pressure toward a novel function initially acted on one domain, whereas the other experienced a nearly neutral state. Over time, the latter also gained a new function or was degenerated.

Landscape of Standing Variation for Tandem Duplications in Drosophila yakuba and Drosophila simulans

“…Chimeric genes have been known to produce peptides with novel functions in Drosophila (Long and Langley 1993; Ranz et al 2003; Zhang et al 2004) and in humans (Zhang et al 2009; Ohshima and Igarashi 2010) and many are associated with adaptive bursts of amino acid substitutions (Jones and Begun 2005; Jones et al 2005). We observe large numbers of recently derived chimeric constructs within populations, with 222 chimeric genes or genes that recruit noncoding sequence in D. yakuba and 134 in D. simulans , even in a limited sample of 20 strains per species.…”

LINE-1 Elements in Structural Variation and Disease

“…For example, retrotransposition of a cyclophilin A cDNA into the TRIM5-α locus of New World monkeys led to the creation of a chimeric protein that confers HIV resistance to owl monkeys (206). Similarly, a novel testes-specific hominoid gene, PIPSL , is a chimeric ubiquitin-binding protein derived from a fusion of the PIP5K1A and 26S proteasome subunit RNAs that underwent retrotransposition (7, 184). The PIPSL gene appears to have been subject to positive selection and is conserved among humans, suggesting a functional role in modern genomes.…”

The Genomic Impact of Gene Retrocopies: What Have We Learned from Comparative Genomics, Population Genomics, and Transcriptomic Analyses?

“…Following the discovery of several chimeric retrogenes in D. melanogaster (Long and Langley 1993; Wang et al 2002; Zhang, Dean, et al 2004; Nozawa et al 2005; Dai et al 2008), dozens of new cases have been described in primates (Nisole et al 2004; Vinckenbosch et al 2006; Baertsch et al 2008; Ohshima and Igarashi 2010), zebrafish (Fu et al 2010) and plants (Zhang et al 2005; Wang et al 2006; Zhu et al 2009; Elrouby and Bureau 2010; see also Kaessmann et al 2009). Additionally, many retrogenes have recruited exons that originated de novo from non-genic regions.…”