Monday, February 1, 2010

GWAS under attack?, historical evolutionary constraints, and a lot more, in my picks of the week from RB

Another week has gone by and some very interesting molbio blog posts have been aggregated to Every week [see my opening post on the matter], I'll select some blog posts I consider particularly interesting in the field of molecular biology [see here to get a sense of the criteria that will be used], briefly describe them and list them here for you to check out.

This week's Picks encompass posts from both last week and the week before, as last week no Picks were posted. Also, this will be the last "Picks of the Week" till March (written by me), as I'm sort of going on vacation (at the very least, I'm going to take some time off from the lab).

Note that I'm only taking into consideration the molbio-related blog posts aggregated under "Biology".

Congratulations to everyone who got their post selected.

1) Drug-induced side effects resulting from secondary targets are an important limitation in drug development. Indeed, “one third of potential therapeutic compounds fail in clinical trials or are later removed from the market due to unacceptable side effects often caused by off-target binding”.
Sometimes, however, a compound binding multiple targets or sites (“polypharmacology”) can be an advantage: a single drug could be used for the treatment of two or three different diseases. Also,

The rational design of drugs that act via polypharmacological mechanisms can produce compounds that exhibit increased therapeutic potency and against which resistance is less likely to develop
Thus, having a way to predict and identify secondary targets of known molecules, is something useful. Iddo Friedberg at Byte Size Biology discusses a recent paper published in PLoS Computational Biology reporting:

a multidimensional strategy for the identification of secondary targets of known small-molecule inhibitors in the absence of global structural and sequence homology with the primary target protein.
Using this approach, the authors predicted a few secondary targets for a compound that inhibits a protein responsible for RNA processing in Trypanosoma brucei and validated some of them.

2) The early atmosphere, the one who witnessed the origin of life, differs greatly from the one present today, the former probably being characterized by very little oxygen and an abundance of carbon dioxide.
The rise of atmospheric oxygen, as stated by Sessions et al., “was an epic event for both the biosphere and geosphere, and paved the way for the evolution of animal life” [Current Biology, 19:R567-R574].

LabRat describes the atmospheric scenery where this marvellous phenomenon took place, billions of years ago, and speculates on the time it took multicellularity to arise from the “blob phase”.

3) After some hard and arduous work, Psi Wavefunction at Skeptic Wonder, a blogger who usually surprises us with fantastic stories from the bizarre and ever-surprising world of protists, now unveils her very own tree of Eukaryotes based on an impressive body of work. You should definitely check it out!

From the post, here’s one of the blogger’s reasons for composing this tree…

Remember how I often refer to the Keeling et al 2005 tree when pointing out where some obscure organism lies on the 'map'? Well, that tree is 5 years out of date now. In fields like molecular biology and genomics, a lot can change in five years; compounded with how the protistan phylogeny was still in murky, squishy swamp of a mess only about 10-15 years ago, the current tree is far from static.

4) A recent study using two vertebrate species (zebrafish and mouse), suggests that genes expressed early during development have a more dramatic effect when knocked out or mutated, and also are more likely to revert to single copy after whole genome duplication, than genes expressed late.

It then appears that constraints are high in early stages of vertebrate development, and that the timing of expression during development, constrains a gene’s "evolvability”

Lucas Brouwers at Thoughtomics comments on a recent paper addressing the following question: are these developmental and genomic constraints associated to the age of origin of the corresponding genes?

5) There has been a lot of fuzz regarding a new paper published in PLoS Biology recently that, according to “various articles around the internet”, supposedly undermines GWAS studies. But does it really?

The only real solid claim in the paper is that, if you do not include rare SNPs in your genome-wide association study, and rare SNPs of large effect are contributing to disease, then you will sometimes pick up more common SNPs as associated, because they are in Linkage Disequilibrium with the rare SNPs.
The paper makes no attempt to say whether this IS happening, just says that it CAN happen, and that we should be AWARE of it.
Luke Jostins at Genetic Interference takes a critical stand against this paper and makes some interesting points, particularly in the comments section.

I have a lot of issues with this paper, but I will be brief and stick to my main objection; the authors attempt to demonstrate that common associations can be caused by sets of rare variants, and in doing so inadvertantly show they most of them are not.[my emphasis]

That's it for this week. Stay tuned for more MolBio Research Highlights!

ResearchBlogging.orgSome of the articles discussed in this week's selected posts:

Durrant, J., Amaro, R., Xie, L., Urbaniak, M., Ferguson, M., Haapalainen, A., Chen, Z., Di Guilmi, A., Wunder, F., Bourne, P., & McCammon, J. (2010). A Multidimensional Strategy to Detect Polypharmacological Targets in the Absence of Structural and Sequence Homology PLoS Computational Biology, 6 (1) DOI: 10.1371/journal.pcbi.1000648

Falkowski PG (2006). Evolution. Tracing oxygen's imprint on earth's metabolic evolution. Science (New York, N.Y.), 311 (5768), 1724-5 PMID: 16556831

KEELING, P., BURGER, G., DURNFORD, D., LANG, B., LEE, R., PEARLMAN, R., ROGER, A., & GRAY, M. (2005). The tree of eukaryotes Trends in Ecology & Evolution, 20 (12), 670-676 DOI: 10.1016/j.tree.2005.09.005

Milinkovitch, M., Helaers, R., & Tzika, A. (2009). Historical Constraints on Vertebrate Genome Evolution Genome Biology and Evolution, 2010, 13-18 DOI: 10.1093/gbe/evp052

Dickson, S., Wang, K., Krantz, I., Hakonarson, H., & Goldstein, D. (2010). Rare Variants Create Synthetic Genome-Wide Associations PLoS Biology, 8 (1) DOI: 10.1371/journal.pbio.1000294

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