Research Article: A Structural Split in the Human Genome

Date Published: July 11, 2007

Publisher: Public Library of Science

Author(s): Clara S.M. Tang, Richard J. Epstein, Guillaume Bourque.

Abstract: 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.

Partial Text: Evolution of biological complexity involves an environmentally-regulated balance between genetic conservation and variation [1]–[6]. Phylogenetic leaps favoring speciation of higher organisms include the evolution of introns and DNA methylation [7], [8]. A more recent innovation is that of promoter-associated CpG islands (PCIs) [9] which, when methylated, mediate transcriptional repression and/or chromatin condensation [10]. About 60% of human genes contain PCIs [9], most of which are unmethylated [11], [12]. Such PCIs are more common in widely-expressed (housekeeping) genes [13], supporting the view that non-methylated PCIs actively maintain gene transcription [14], [15].

There are three central findings of this study. First, there exists an AT-rich ‘second peak’ of PCI+ genes which, when compared with the GC-rich peak of housekeeping-like PCI+ genes, is characterized by lower transcriptional activity, higher intron number and length, and higher evolutionary rate. We propose that the AT-rich subset has arisen from the GC-rich subset of PCI+ genes via progressive loss of negative selection pressure, accompanied by progressive PCI methylation.