Abstract
Nested protein-coding genes accumulated throughout metazoan evolution, with early analyses of human and Drosophila microarray data indicating that this phenomenon was simply due to the presence of large introns. However, a recent study employing RNA-seq data uncovered evidence of transcriptional interference driving rapid expression divergence between Drosophila nested genes, illustrating that accurate expression estimation of overlapping genes can enhance detection of their relationships. Hence, here I apply an analogous approach to strand-specific RNA-seq data from human and mouse to revisit the role of transcriptional interference in the evolution of mammalian nested genes. A genomic survey reveals that whereas mammalian nested genes indeed accrued over evolutionary time, they are retained at lower frequencies than in Drosophila. Though several properties of mammalian nested genes align with observations in Drosophila and with expectations under transcriptional interference, contrary to both, their expression divergence is not statistically different from that between unnested genes, and also does not increase after nesting. Together, these results support the hypothesis that lower selection efficiencies limit rates of gene expression evolution in mammals, leading to their reliance on immediate eradication of deleterious nested genes to avoid transcriptional interference.
Highlights
Surveys of eukaryotic genome architecture have uncovered high frequencies of nested protein-coding genes, in which one “internal” gene is located in an intron of a second “external” gene [1,2,3,4,5,6]
A comprehensive analysis across three metazoan lineages illustrated that internal genes often arise via gene duplication, and that nested genes are formed when the resulting young duplicate genes are inserted into introns of existing genes [3]
This study revealed that nested genes accumulated over evolutionary time, as evidenced by the predominance of nesting relative to unnesting events in all three metazoan lineages [3]
Summary
Surveys of eukaryotic genome architecture have uncovered high frequencies of nested protein-coding genes, in which one “internal” gene is located in an intron of a second “external” gene [1,2,3,4,5,6]. The usage of correlation coefficients to assess expression divergence is biased when measurement error is large [11] With these limitations in mind, a recent study used RNA-seq data [12,13] and Euclidian distance estimates of gene expression divergence [11] to reexamine the hypothesis that transcriptional interference impacts nested gene evolution in Drosophila [6]. This analysis uncovered widespread expression divergence between nested genes that was greater than that between either intraor inter-chromosomal genes, providing strong support for transcriptional interference between nested genes in Drosophila [6]. Joint consideration of these findings allows me to assess whether and how transcriptional interference influences the evolution of nested genes in the mammalian lineage
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