The Human Genomic Melting Map

In a living cell, the antiparallel double-stranded helix of DNA is a dynamically changing structure. The structure relates to interactions between and within the DNA strands, and the array of other macromolecules that constitutes functional chromatin. It is only through its changing conformations that DNA can organize and structure a large number of cellular functions. In particular, DNA must locally uncoil, or melt, and become single-stranded for DNA replication, repair, recombination, and transcription to occur. It has previously been shown that this melting occurs cooperatively, whereby several base pairs act in concert to generate melting bubbles, and in this way constitute a domain that behaves as a unit with respect to local DNA single-strandedness. We have applied a melting map calculation to the complete human genome, which provides information about the propensities of forming local bubbles determined from the whole sequence, and present a first report on its basic features, the extent of cooperativity, and correlations to various physical and biological features of the human genome. Globally, the melting map covaries very strongly with GC content. Most importantly, however, cooperativity of DNA denaturation causes this correlation to be weaker at resolutions fewer than 500 bps. This is also the resolution level at which most structural and biological processes occur, signifying the importance of the informational content inherent in the genomic melting map. The human DNA melting map may be further explored at http://meltmap.uio.no.: In a living cell, DNA both is an information carrier and carries out important structural tasks, such as organizing its replication and distributing the chromosomes to the daughter cells. DNA is frequently depicted as an antiparallel double-stranded helix, but DNA may rather be viewed as having a dynamically changing structure. This is because in performing most of these tasks, it is necessary for the DNA helix to become single-stranded locally, or unwound, thereby creating “bubbles” in the double strand, much as what happens when a twisted rope with two strands is untwisted. In the cell, this happens by the aid of the enzymatic machinery, but it may also be observed in experiments when a gradual increase in temperature produces bubbles. Our calculations in producing a melting map are based on temperature changes, but may be viewed as a map of bubble formation tendencies along the genome. In DNA, an opening bubble does not open one base at a time, but rather as a cooperative event, in that several base pairs act in concert to form a bubble, and we use an algorithm that takes this aspect into consideration. We then explore the correlations between the melting map and many known features of the human genome. We also demonstrate the extent of cooperativity, and find that the melting map carries information otherwise not available. Once the melting map is calculated, a number of more detailed studies of relationships to DNA structure and function are made possible, as well as improvements of algorithms for modelling DNA with associated proteins as they occur in the natural cellular environment.