Identifying cis-regulatory elements by statistical analysis and phylogenetic footprinting and analyzing their coexistence and related gene ontology

Discovery of cis-regulatory elements in gene promoters is a highly challenging research issue in computational molecular biology. This paper presents a novel approach to searching putative cis-regulatory elements in human promoters by first finding 8-mer sequences of high statistical significance from gene promoters of humans, mice, and Drosophila melanogaster, respectively, and then identifying the most conserved ones across the three species (phylogenetic footprinting). In this study, a conservation analysis on both closely related species (humans and mice) and distantly related species (humans/mice and Drosophila) is conducted not only to examine more candidates but also to improve the prediction accuracy. We have found 124 putative cis-regulatory elements and grouped these into 20 clusters. The investigation on the coexistence of these clusters in human gene promoters reveals that SP1, EGR, and NRF-1 are the dominant clusters appearing in the combinatorial combination of up to five clusters. Gene Ontology (GO) analysis also shows that many GO categories of transcription factors binding to these cis-regulatory elements match the GO categories of genes whose promoters contain these elements. Compared with previous research, the contribution of this study lies not only in the finding of new cis-regulatory elements, but also in its pioneering exploration on the coexistence of discovered elements and the GO relationship between transcription factors and regulated genes. This exploration verifies the putative cis-regulatory elements that have been found from this study and also gives new insight on the regulation mechanisms of gene expression.

Copy number variation and transposable elements feature in recent, ongoing adaptation at the Cyp6g1 locus

The increased transcription of the Cyp6g1 gene of Drosophila melanogaster, and consequent resistance to insecticides such as DDT, is a widely cited example of adaptation mediated by cis-regulatory change. A fragment of an Accord transposable element inserted upstream of the Cyp6g1 gene is causally associated with resistance and has spread to high frequencies in populations around the world since the 1940s. Here we report the existence of a natural allelic series at this locus of D. melanogaster, involving copy number variation of Cyp6g1, and two additional transposable element insertions (a P and an HMS-Beagle). We provide evidence that this genetic variation underpins phenotypic variation, as the more derived the allele, the greater the level of DDT resistance. Tracking the spatial and temporal patterns of allele frequency changes indicates that the multiple steps of the allelic series are adaptive. Further, a DDT association study shows that the most resistant allele, Cyp6g1-[BP], is greatly enriched in the top 5% of the phenotypic distribution and accounts for ~16% of the underlying phenotypic variation in resistance to DDT. In contrast, copy number variation for another candidate resistance gene, Cyp12d1, is not associated with resistance. Thus the Cyp6g1 locus is a major contributor to DDT resistance in field populations, and evolution at this locus features multiple adaptive steps occurring in rapid succession.

Acting alone to act together: diversifying approaches to North Korea

Strategic discussions about North Korea’s proliferation comprise a number of dimensions. The core assumption underlying this article is that the ideational aspects of North Korea’s decision making are important and give rise to a range of strategic considerations. This is not to underplay the strategic, materialist elements in North Korea’s provocative and at times belligerent behaviour. Rather, it is to argue that Australia is well placed to concentrate on the social dimensions of strategic discussions. As a less important middle power, a regional player, yet geographically distant from the threat, Australia is in a position to provide a point of differentiation from other, more entrenched players such as the United States or the Republic of Korea (ROK). A good starting point for developing this sort of engagement is to enhance non-state, track two cooperation between the two countries, which has been stalled since the early 2000s. In this article I will first canvass the ongoing debate taking place in Australian academic and policy circles regarding Australia’s place in the world. Of particular concern, is the question how Australia should balance its most important strategic relationship – that with the United States – with geographic and economic realities. I then sketch some of the limitations of current thinking, concentrating particularly on discourse that portrays North Korea as a rogue state and finish with a discussion of how non-state activity can act as a helpful precursor to more constructive relationships between states, and the types of creative engagement strategies currently taking place in the United States, despite the volatile political environment.