a structural split in the human genome结构在人类基因组中.pdfVIP

A Structural Split in the Human Genome Clara S. M. Tang, Richard J. Epstein* Laboratory of Computational Oncology, Department of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, Hong Kong 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 CpGRTpA 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. Citation: Tang CSM, Epstein RJ (2007) A Structural Split in the Human Genome. PLoS ONE 2(7): e603. doi:10.1371/journal.pone.0000603 INTRODUCTION characterized not only by higher CpG island frequency and Evolution of biological complexity involves an environmentally- greater