A structural split in the human genome.
BACKGROUND
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.


RESULTS
PCI+ 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.


CONCLUSIONS
Adaptive 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.
Tang
Clara S M
CS
Laboratory of Computational Oncology, Department of Medicine, University of Hong Kong, Pokfulam, Hong Kong, Hong Kong.
Epstein
Richard J
RJ
D000818:Animals; D001482:Base Composition; D018899:CpG Islands / Q000235:genetics; D004251:DNA Transposable Elements / Q000235:genetics; D019143:Evolution, Molecular; D015894:Genome, Human; D006801:Humans; D007438:Introns / Q000235:genetics; D005810:Multigene Family / Q000235:genetics; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011544:Pseudogenes / Q000235:genetics; D013045:Species Specificity; D014158:Transcription, Genetic
D004251:DNA Transposable Elements