Archive for category Quotes
Yet, without a thick skin, the patience of Job, and an enduring sense of humor, the hard-hit small editor would probably not last through a single cycle of his journal, laboring as he must under the curses of author uncomprehension, author uncooperativeness, author irresponsibility,and sometimes even downright stupidity
Soon after the recent set of ENCODE papers came out, several scientists raised concerns regarding the estimates about the fraction of the genome that appears to be functional, that the authors put forward: according to them, ~80% of the human genome is functional.
This, of course, greatly differs to what most of us think, considering, among other things, that the fraction of the genome that is evolutionarily conserved through purifying selection appears to be under 10% (what about the rest? We think it divides between junk DNA and some “unknowns”).
The problem mainly arose from the definition of “functional” that ENCODE used, one that is so loose, that may not be useful at all.
In fact, “according to ENCODE, for a DNA segment to be ascribed functionality it needs to (1) be transcribed or (2) associated with a modified histone or (3) located in an open-chromatin area or (4) to bind a transcription factors or (5) to contain a methylated CpG dinucleotide” (Graur et al., 2013). You would agree that this criteria is very lenient, hence, the 80% estimate.
A recent paper, ruthlessly discusses the ENCODE paper and takes great issue with the “80%” estimate. The authors “detail the many logical and methodological transgressions involved in assigning functionality to almost every nucleotide in the human genome“. The manuscript reviewers could have suggested the authors to tone it down a little, but from what I found out in the web, evolutionary biologists tend to be very strong about their opinions on paper, when discussing the work of others they disagree with.
I encourage you to read the article, which is freely available. In the meantime, here are a few quotes:
The ENCODE results were predicted by one of its authors to necessitate the rewriting of textbooks. We agree, many textbooks dealing with marketing, mass-media hype, and public relations may well have to be
ENCODE adopted a strong version of the causal role definition of function, according to which a functional element is a discrete genome segment that produces a protein or an RNA or displays a reproducible biochemical signature (for example, protein binding). Oddly, ENCODE not only uses the wrong concept of functionality, it uses it wrongly and inconsistently
We identified three main statistical infractions. ENCODE used methodologies encouraging biased errors in favor of inflating estimates of functionality, it consistently and excessively favored sensitivity over specificity, and it paid unwarranted attention to statistical significance, rather than to the magnitude of the effect.
At this point, we must ask ourselves, what is the aim of ENCODE: Is it to identify every possible functional element at the expense of increasing the number of elements that are falsely identified as functional? Or is it to create a list of functional elements that is as free of false positives as possible
Comparative studies have repeatedly shown that pseudogenes, which have been so defined because they lack coding potential due to the presence of disruptive mutations, evolve very rapidly and are mostly subject to no functional constraint (Pei et al. 2012). Hence, regardless of their transcriptional or translational status, pseudogenes are nonfunctional!
For example, according to ENCODE, the putative function of the H4K20me1 modification is “preference for 5’ end of genes.” This is akin to asserting that the function of the White House is to occupy the lot of land at the 1600 block of Pennsylvania Avenue in Washington, D.C.
So, what have we learned from the efforts of 442 researchers consuming 288 million dollars? According to Eric Lander, a Human Genome Project luminary, ENCODE is the “Google Maps of the human genome” (Durbin et al. 2010). We beg to differ, ENCODE is considerably worse than even Apple Maps.
Evolutionary conservation may be frustratingly silent on the nature of the functions it highlights, but progress in understanding the functional significance of DNA sequences can only be achieved by not
ignoring evolutionary principles
High-throughput genomics and the centralization of science funding have enabled Big Science to generate “high-impact false positives” by the truckload (The PLoS Medicine Editors 2005; Platt et al. 2010; Anonymous 2012; MacArthur 2012; Moyer 2012). Those involved in Big Science will do well to remember the depressingly true popular maxim: “If it is too good to be true, it is too good to be true.”
We conclude that the ENCODE Consortium has, so far, failed to provide a compelling reason to abandon the prevailing understanding among evolutionary biologists according to which most of the human genome is devoid of function
(…) according to the ENCODE Consortium, a biological function can be maintained indefinitely without selection, which implies that at least 80 – 10 = 70% of the genome is perfectly invulnerable to
deleterious mutations, either because no mutation can ever occur in these “functional” regions, or because no mutation in these regions can ever be deleterious. This absurd conclusion was reached through various means (…)
Two great comments from T Ryan Gregory at E Birney’s Blog post on ENCODE.
He is replying to someone in the comments section. In the first quote, he again (and correctly) highlights that there was never a period when researchers supposedly dismissed all ncDNA as junk. I’ve quoted him before here stating that.
In the second one, he talks about intelligent design.
What I am talking about is what was actually being said in the primary literature. In that case, it is abundantly clear that there was no widespread dismissal of possible functions for non-coding DNA among the researchers working in the field. I have not been quoting selectively, either — I looked at the papers that first described each type of non-coding DNA elements, for example, or review papers from the period, or news stories in Science and Nature from that time. All of them show that function was a common expectation, or at least a serious question, throughout the supposed period of dismissal.
I personally don’t think non-functional junk DNA is all that relevant to the fight from either side. Why should “intelligent design” assume that nothing is non-functional? Our own intelligently designed artifacts often have crap in them. Who would argue that the computer code for Windows is flawless and without non-functional, redundant, sloppy, or otherwise unnecessary bits? I have never seen a clear articulation of the reason that ID predicts no non-functional DNA (other than the obvious “God don’t make no junk” — and even then, why not?).
In light of the recent ENCODE papers, several researchers have questioned some of their conclusions and the way the authors have described their findings (“These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions” -that’s from one of the articles….-), not only in the primary articles, but also in interviews and press releases.
Michael Eisen has discussed some of these issues on his blog, and this is a brief extract from one of his posts:
But if you think about this, you will realize that this simply can not be true. As we and many others have now shown, molecular interactions are not rare. Transcripts, transcription factor binding sites, DNA modifications, chromatin modifications, RNA binding sites, phosphorylation sites, protein-protein interactions, etc… are everywhere. This suggests that these kind of biochemical events are easy to create – change a nucleotide here – wham, a new transcription factor binds, an splicing site is lost, a new promoter is created, a glycosylation site is eliminated.
And, as I’ve mentioned before….
Rather than assuming – as so many of the ENCODE researchers apparently do – that the millions (or is it billions?) of molecular events they observe are a treasure trove of functional elements waiting to be understood, they should approach each and every one of them with Kimurian skepticism
Thank you, Michael.
This is an important point. Most of the science education reforms that are being proposed these days focus on style rather than substance.
In the long run, it really doesn’t matter whether you are employing the very latest pedagogical techniques if what you are teaching is crap.
Larry Moran at Sandwalk, discussing an article on curriculum design, published on Biochemistry and Molecular Biology Education.
Percentage-wise, there is less bullshit in specialized journals. But there is still a lot of it there. Notably, the percent of bullshit that draws attention and is dealt with in decisive fashion is definitely higher in glamour mags.
-DK, as a comment to a post discussing peer review.
Quotes from the blogosphere: Patience for publishing in the “right” journal: like trying to get sex at a bar…
I wrote there that my inkling is two tries. Two tries max. First, mama needs some damned publications these days, so I approach publication like trying to get sex at a bar. I might shoot high once and then just get the shit in. Thankfully, my “shoot highs” basically always work, so I need not settle for journal stank…
-Dr. Isis on her blog, commenting on the patience people have for publishing their article on a particular preferred journal.
(…) submitting six times is not like approaching six different girls at six different bars. It’s like approaching the same girl at a different bar each time, over and and over, and saying, “Wanna fuck?” “Wanna fuck?” “Wanna fuck?” “Wanna fuck?” “Wanna fuck?” “Wanna fuck?” “Wanna fuck?” (I think that was seven times). I mean, maybe after seven tries and a couple of cocktails the poor dude gets a pitty fuck, but certainly no one’s coming out the other side feeling great about it. You mostly just end up looking pathetic.
In order to work with a protein that was easy to obtain, we chose the protein lysozyme. (…) Fleming had shown that it occurred in tears and that egg white was also a rich source.
Our main target was egg white but we also tried human tears. Each morning when I came into the laboratory the assistant took a small sample of my tears. Not being an actor, I did not find it easy to weep at will, so my assistant would hold a slice of raw onion underneath one eye. I would hold my head to one side, to make it less easy for the tear to escape down the tear duct, and she would catch the tears with a little Pasteur pipette as they dribbled out of the other side of my eye. Even so, it was difficult to produce more that one or two tears, though I found it helped to think sad thoughts.
Francis Crick, from “What Mad Pursuit” (1988).
To me, anytime I see people demanding that you have at least a 6 log dynamic range to work with, I know immediately they really haven’t performed that much qPCR with low abundance targets, and they also blindly believe that purified amplicon, plasmid or other differently purified target source will magically amplify with exactly the same efficacy as it amplifies within the biological sample extracts we ultimately assess by qPCR.
-JMG (in the Biotechniques forum)
From ”What Mad Pursuit”:
The second criticism is that we may not yet know all the gadgetry that has been evolved to make natural selection work more efficiently. There may still be surprises for us in the tricks that are used to make for smoother and more rapid evolution. Sex is probably an example of such mechanism, and there may, for all we know, be other as yet undiscovered. Selfish DNA -the large amounts of DNA in our chromosomes with no obvious function- may turn out to be part of another. It is entirely possible that this selfish DNA may play an essential role in the rapid evolution of some of the complex genetic control mechanisms essential for higher organisms
Francis Crick, 1988.