When I read a new paper I immediately test it against my model of how things are supposed to work. If the conclusions of the paper don't fit with my views, I tend to be very skeptical of the paper. Of course I realize that my model could be wrong and I'm always on the lookout for new results that challenge the current dogma, but, in most cases, if the paper conflicts with current ideas then it's probably flawed.
This is what people mean when they talk about making sense of biology. The ENCODE papers don't make sense, according to my model of how genomes work so I was immediately skeptical of the reported claims. The arseniclife paper conflicted with my understanding of the structure of DNA and how it evolved so I knew it was wrong even before Rosie Redfield pointed out the flaws in the methodology.
What this means in practice is that it requires a great deal of wisdom and experience in order to really make sense of the scientific literature. If that's true, then undergraduates are not in a good position to benefit from the primary scientific literature without the guidance of an experienced instructor. They need a lot more instruction on basic principles and concepts so they can construct, and have confidence in, a good working model of various processes. This goes against the grain of what you find in the pedagogical literature where there's a great deal of emphasis on getting senior undergraduates to experience the primary scientific literature. I'm very skeptical of this emphasis.
All this is by way of introducing a blog post from last September [Transcription Initiation Sites: Do You Think This Is Reasonable?]. I was commenting on a paper by Venters and Pugh (2014) on the number of potential transcription start sites in the human genome. They estimated that there were about 500,000 transcription start sites and most of them would be functional.
This conflicts with my model of the number of genes in the human genome so I assumed that the paper was flawed in spite of the fact that it was published in Nature. I wondered how many other people were skeptical. Not many, according to the comments.
Now a reader, Rui Lopes, tells me that the paper has been retracted!!!! (See his comment on the original post.)
Matthias Siebert and Johannes Söding of the Ludwig-Maximilians-Universität in Munich (München), Germany published a paper criticizing the Vincent and Pugh results (Siebert and Söding, 2014). Here's the abstract ...
How cells locate the regions to initiate transcription is an open question, because core promoter elements (CPEs) are found in only a small fraction of core promoters1, 2, 3, 4. A recent study5 measured 159,117 DNA binding regions of transcription factor IIB (TFIIB) by ChIP-exo (chromatin immunoprecipitation with lambda exonuclease digestion followed by high-throughput sequencing) in human cells, found four degenerate CPEs—upstream and downstream TFIIB recognition elements (BREu and BREd), TATA and initiator element (INR)—in nearly all of them, and concluded that these regions represent sites of transcription initiation marked by universal CPEs. We show that the claimed universality of CPEs is explained by the low specificities of the patterns used and that the same match frequencies are obtained with two negative controls (randomized sequences and scrambled patterns). Our analyses also cast doubt on the biological significance of most of the 150,753 non-messenger-RNA-associated ChIP-exo peaks, 72% of which lie within repetitive regions. There is a Retraction accompanying this Brief Communication Arising by Venters, B. J. & Pugh, B. F. Nature 511, http://dx.doi.org/10.1038/nature13588 (2014).The retraction by Venters and Pugh (2014) says,
We reported the presence of degenerate versions of four well known core promoter elements (BREu, TATA, BREd and INR) at most measured TFIIB binding locations found across the human genome. However, it was brought to our attention by Matthias Siebert and Johannes Söding in the accompanying Brief Communication Arising (Nature 511, E11–E12, http://dx.doi.org/10.1038/nature13587; 2014) that the core-promoter-element analyses that led to this conclusion were not correctly designed. Consequently, the individual core promoter elements were not statistically validated, and therefore there is no evidence of specificity for most reported core-promoter-element locations. To the best of our knowledge, the raw and processed human TFIIB, TBP and Pol II ChIP-exo data are valid, but subject to standard false discovery considerations. We therefore retract the paper. We sincerely apologize for adverse consequences that may have arisen from the error in our analyses.
Siebert, M. and Söding, J. (2014) Universality of core promoter elements? Nature 511:E11–E12 (24 July 2014) [doi:10.1038/nature13587]
Venters, B.J. and Pugh, B.F. (2013) Genomic organization of human transcription initiation complexes. Nature Published online 18 September 2013 [doi: 10.1038/nature12535] [PubMed] [Nature]
Venters, B.J. and Pugh, B.F. (2014) Retraction: Genomic organization of human transcription initiation complexes. Nature, published online July 23, 2014 [doi: 10.1038/nature12535]