Abstract
BackgroundPromoter-associated CpG islands (PCIs) mediate methylation-dependent gene silencing, yet tend to co-locate to transcriptionally active genes. To address this paradox, we used data mining to assess the behavior of PCI-positive (PCI+) genes in the human genome.ResultsPCI+ genes exhibit a bimodal distribution: (1) a ‘housekeeping-like’ subset characterized by higher GC content and lower intron length/number, and (2) a ‘pseudogene paralog’ subset characterized by lower GC content and higher intron length/number (p<0.001). These subsets are functionally distinguishable, with the former gene group characterized by higher expression levels and lower evolutionary rate (p<0.001). PCI-negative (PCI-) genes exhibit higher evolutionary rate and narrower expression breadth than PCI+ genes (p<0.001), consistent with more frequent tissue-specific inactivation.ConclusionsAdaptive evolution of the human genome appears driven in part by declining transcription of a subset of PCI+ genes, predisposing to both CpG→TpA mutation and intron insertion. We propose a model of evolving biological complexity in which environmentally-selected gains or losses of PCI methylation respectively favor positive or negative selection, thus polarizing PCI+ gene structures around a genomic core of ancestral PCI- genes.
Highlights
Evolution of biological complexity involves an environmentallyregulated balance between genetic conservation and variation [1,2,3,4,5,6]
We propose that the AT-rich subset has arisen from the GC-rich subset of promoter-associated CpG islands (PCIs)+ genes via progressive loss of negative selection pressure, accompanied by progressive PCI methylation
PCI- genes have a higher evolutionary rate and lower expression breadth than PCI+ genes. This suggests either that (i) only widely-transcribed genes are under selection pressure to acquire or retain PCIs, and/or (ii) PCI loss represents a separate pathway towards pseudogenization for less-transcribed tissue-specific genes
Summary
Evolution of biological complexity involves an environmentallyregulated balance between genetic conservation and variation [1,2,3,4,5,6]. In addition to the functional effects of PCI methylation on transcription, methylcytosine residues in coding regions may undergo oxidative deamination to thymine, with such events being quantifiable as an excess of CGRTA transitional mutations[16]. This interaction between methylation-dependent transrepression and mutation drives adaptive evolution [17]. Promoter-associated CpG islands (PCIs) mediate methylation-dependent gene silencing, yet tend to co-locate to transcriptionally active genes. To address this paradox, we used data mining to assess the behavior of PCI-positive (PCI+) genes in the human genome. We propose a model of evolving biological complexity in which environmentally-selected gains or losses of PCI methylation respectively favor positive or negative selection, polarizing PCI+ gene structures around a genomic core of ancestral PCI- genes
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