The life history of retrocopies illuminates the evolution of new mammalian genes

Abstract

New genes contribute substantially to adaptive evolutionary innovation, but the functional evolution of new mammalian genes has been little explored at a broad scale. Previous work established mRNA-derived gene duplicates, known as retrocopies, as models for the study of new gene origination. Here we combine mammalian transcriptomic and epigenomic data to unveil the processes underlying the evolution of stripped-down retrocopies into complex new genes. We show that although some robustly expressed retrocopies are transcribed from preexisting promoters, most evolved new promoters from scratch or recruited proto-promoters in their genomic vicinity. In particular, many retrocopy promoters emerged from ancestral enhancers (or bivalent regulatory elements) or are located in CpG islands not associated with other genes. We detected 88–280 selectively preserved retrocopies per mammalian species, illustrating that these mechanisms facilitated the birth of many functional retrogenes during mammalian evolution. The regulatory evolution of originally monoexonic retrocopies was frequently accompanied by exon gain, which facilitated co-option of distant promoters and allowed expression of alternative isoforms. While young retrogenes are often initially expressed in the testis, increased regulatory and structural complexities allowed retrogenes to functionally diversify and evolve somatic organ functions, sometimes as complex as those of their parents. Thus, some retrogenes evolved the capacity to temporarily substitute for their parents during the process of male meiotic X inactivation, while others rendered parental functions superfluous, allowing for parental gene loss. Overall, our reconstruction of the “life history” of mammalian retrogenes highlights retroposition as a general model for understanding new gene birth and functional evolution.

LTR-mediated retroposition as a mechanism of RNA-based duplication in metazoans

“…A recent work identified approximately 5000 retrocopies across various placental mammals and found that only 4% were robustly expressed (FPKM ≥ 1) (Carelli et al 2016). The expressed retrocopies were found to have evolved their promoters de novo or to have recruited proto-promoters from nearby regions (Carelli et al 2016). In our study, the two recently evolved non-LTR-mediated retrocopies in Drosophila also demonstrate that the fate of these retrocopies depends on whether a promoter is fortuitously gained.…”

“…In mammals, L1 retrotransposons are known to be a major driver of retroposition (Esnault et al 2000;Kaessmann et al 2009;Abyzov et al 2013) and have generated thousands of retrocopies (Carelli et al 2016). We implemented multiple filters (Methods) to identify the possibly small number of retrocopies created by LTR retrotransposons.…”

“…Because it has been shown that FPKM values from 0.1 to 0.4 could reflect active transcription (Hart et al 2013), we took the high cutoff of 1 to define robust expression as done in Carelli et al (2016) and the low cutoff of 0.1 to define modest expression. For read counts, a cutoff of 0.1 (FPKM) corresponds to at least nine reads in Figure 3.…”

“…Herein, the retrotransposon machinery reverse transcribes messenger RNAs (mRNAs) into complementary DNAs (cDNAs) and inserts them back into the genome as retrocopies (Kaessmann et al 2009). Unlike DNA-based duplicates, functional retrocopies or retrogenes inherently lack the ancestral regulatory sequences, having to recruit new ones from the vicinity and/or by evolving them de novo (Kaessmann et al 2009;Carelli et al 2016). The contribution of retrogenes to phenotypic evolution is well recognized ranging from the avoidance of male-male courtship in fruit fly to the short-legged phenotype in domestic dogs (Parker et al 2009;Chen et al 2013).…”

Characteristic Features of Male Germline Development in Primates

“…Therefore, it is likely that some aspects of male primate germ cell development as well as some cases of human infertility cannot be modeled in mice due to the absence of the relevant genes. In general, the aspect of the evolution of novel genes, particularly in the testis, has probably been underestimated until recently [92] , except for the sex chromosomes [93][94][95] .…”