Sunday, October 27, 2013

Sunday Morning Insight: Structured Sparsity and Structural DNA Folding Information

In Application of compressed sensing to genome wide association studies and genomic selection, one realizes that connecting GWAS and phenotypes is difficult. One of the underlying reason may lie in part due to the loss of structural information thanks to linear DNA sequencing (such as nanopore sequencing). To comprehend the structural information better, I gathered several figures from the interwebs in a series of figures below. As can be seen, the same DNA can be folded differently and yield different outcomes because non-DNA elements such as histones have a direct impact on allowing certain parts of the DNA to be active (or not). The folding itself may also be behind the reason why some diseases are connected to a large number of genes. Given all this, one wonders if a structured sparsity approach to GWAS studies might be more fruitful in that it could potentially highlight elements of the DNA that are closer to each other and therefore pinpoint to folding information. At the very least, there ought to be a trace of the cyclicality induced by the 147 base pairs wrapped into the nucleosomes.

For some related information, we had a small discussion with Mohammed AlQuraishi 's blog entry on CASP10, and the Future of Structure in Biology a while back.

Different scales in the DNA all the way to the chromosome [2]

Different scales in the DNA all the way to the chromosome [4]

More detailed scales in the DNA all the way to the chromosome [2]

Detailed Sketch of the Histone-DNA complex[1]

Nucleosomes can slide along DNA. When nucleosomes are spaced closely together (top), transcription factors cannot bind and gene expression is turned off. When the nucleosomes are spaced far apart (bottom), the DNA is exposed. Transcription factors can bind, allowing gene expression to occur. Modifications to the histones and DNA affect nucleosome spacing. From [3]

Same figure as before but with different scales [5]

In transformed cells, this scenario is disrupted by the loss of the 'active' histone-marks on tumour-suppressor gene promoters, and by the loss of repressive marks such as the trimethylation of K20 of H4 or trimethylation of K27 of histone H3 at subtelomeric DNA and other DNA repeats. This leads to a more 'relaxed' chromatin conformation in these regions. [6]

No comments: