Retrocopy contributions to the evolution of the human genome

Abstract

Background: Evolution via point mutations is a relatively slow process and is unlikely to completely explain the differences between primates and other mammals. By contrast, 45% of the human genome is composed of retroposed elements, many of which were inserted in the primate lineage. A subset of retroposed mRNAs (retrocopies) shows strong evidence of expression in primates, often yielding functional retrogenes.

Results: To identify and analyze the relatively recently evolved retrogenes, we carried out BLASTZ alignments of all human mRNAs against the human genome and scored a set of features indicative of retroposition. Of over 12,000 putative retrocopy-derived genes that arose mainly in the primate lineage, 726 with strong evidence of transcript expression were examined in detail. These mRNA retroposition events fall into three categories: I) 34 retrocopies and antisense retrocopies that added potential protein coding space and UTRs to existing genes; II) 682 complete retrocopy duplications inserted into new loci; and III) an unexpected set of 13 retrocopies that contributed out-of-frame, or antisense sequences in combination with other types of transposed elements (SINEs, LINEs, LTRs), even unannotated sequence to form potentially novel genes with no homologs outside primates. In addition to their presence in human, several of the gene candidates also had potentially viable ORFs in chimpanzee, orangutan, and rhesus macaque, underscoring their potential of function.

Conclusion: mRNA-derived retrocopies provide raw material for the evolution of genes in a wide variety of ways, duplicating and amending the protein coding region of existing genes as well as generating the potential for new protein coding space, or non-protein coding RNAs, by unexpected contributions out of frame, in reverse orientation, or from previously non-protein coding sequence.

Figure 1

Categories of Type I retrocopy events. A. Examples of Type Ia exon acquisitions contributed by "same orientation" of retrocopies (in magenta or dark red) with respect to host gene (light blue); not drawn to scale, splice events are marked by angled lines, open reading frames are depicted as vertically striped thick bars, UTRs by medium size bars, introns in the host gene as light blue lines (for symbols and colors, see also keys below). When parts of retrocopies are described they correspond to what they used to be in the parent gene. The retrocopy's start and stop codons are shown by green and red vertical bars, respectively. Retrogene parts apparently not recruited as functional modules are overlayered with gray. B, Examples of Type Ib exon acquisitions contributed by "reverse orientation" retrocopies. For detailed descriptions, see text.

Figure 2

Novel protein-sequence space generated by parts of retrocopies combined with other transposons or unusual events. For each part of the figure, the spliced parent mRNA is shown first (before retroposition) and the resulting gene(s) are shown below. New sequence space was triggered by a combination of retrogene insertions, recruitment of non-genic regions including retroposons, whereby the contribution of the retrocopy's original in-frame ORF is very small (see text and legend to Fig. 1 including color key for further details). Yellow boxes with grey vertical stripes and yellow medium size bars correspond to retroposed element contributions to ORFs and UTRs, respectively. For detailed descriptions see text.

Figure 3

The retroFinder pipeline for annotating retrocopies. Alignments of all human mRNAs that aligned more than once to the genome were scored for a set of features (see Methods). Number of strict ESTs, mRNAs, and size of ORF were applied to determine evidence of expression. Retrocopies that partially overlapped the protein coding region of annotated multi exon Refseq genes were classified as exon acquisition events. Numbers in parenthesis were reported previously [7] (Additional files 4, 5, 6, 7).