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                                    Strolling with a skeptical biochemist



Last Build Date: Mon, 23 Apr 2018 09:24:20 +0000

 



Required reading for the junk DNA debate

Sat, 07 Apr 2018 17:48:00 +0000

This is a list of scientific papers on junk DNA that you need to read (and understand) in order to participate in the junk DNA debate. It's not a comprehensive list because it's mostly papers that defend junk DNA and refute arguments for massive amounts of function. The only exception is the paper by Mattick and Dinger (2013).1 It's the only anti-junk paper that attempts to deal with the main evidence for junk DNA. If you know of any other papers that make a good case against junk DNA then I'd be happy to include them in the list.If you come across a publication that argues against junk DNA, then you should immediately check the reference list. If you do not see some of these references in the list, then don't bother reading the paper because you know the author is not knowledgeable about the subject.Brenner, S. (1998) Refuge of spandrels. Current Biology, 8:R669-R669. [PDF]Brunet, T.D., and Doolittle, W.F. (2014) Getting “function” right. Proceedings of the National Academy of Sciences, 111:E3365-E3365. [doi: 10.1073/pnas.1409762111]Casane, D., Fumey, J., et Laurenti, P. (2015) L’apophénie d’ENCODE ou Pangloss examine le génome humain. Med. Sci. (Paris) 31: 680-686. [doi: 10.1051/medsci/20153106023] [The apophenia of ENCODE or Pangloss looks at the human genome]Cavalier-Smith, T. (1978) Nuclear volume control by nucleoskeletal DNA, selection for cell volume and cell growth rate, and the solution of the DNA C-value paradox. Journal of Cell Science, 34(1), 247-278. [doi: PDF]Doolittle, W.F. (2013) Is junk DNA bunk? A critique of ENCODE. Proc. Natl. Acad. Sci. (USA) published online March 11, 2013. [PubMed] [doi: 10.1073/pnas.1221376110]Doolittle, W.F., Brunet, T.D., Linquist, S., and Gregory, T.R. (2014) Distinguishing between “function” and “effect” in genome biology. Genome biology and evolution 6, 1234-1237. [doi: 10.1093/gbe/evu098]Doolittle, W.F., and Brunet, T.D. (2017) On causal roles and selected effects: our genome is mostly junk. BMC biology, 15:116. [doi: 10.1186/s12915-017-0460-9]Eddy, S.R. (2012) The C-value paradox, junk DNA and ENCODE. Current Biology, 22:R898. [doi: 10.1016/j.cub.2012.10.002]Eddy, S.R. (2013) The ENCODE project: missteps overshadowing a success. Current Biology, 23:R259-R261. [10.1016/j.cub.2013.03.023] Graur, D. (2017) Rubbish DNA: The functionless fraction of the human genome Evolution of the Human Genome I (pp. 19-60): Springer. [doi: 10.1007/978-4-431-56603-8_2 (book)] [PDF]Graur, D. (2017) An upper limit on the functional fraction of the human genome. Genome Biology and Evolution, 9:1880-1885. [doi: 10.1093/gbe/evx121]Graur, D., Zheng, Y., Price, N., Azevedo, R. B., Zufall, R. A., and Elhaik, E. (2013) On the immortality of television sets: "function" in the human genome according to the evolution-free gospel of ENCODE. Genome Biology and Evolution published online: February 20, 2013 [doi: 10.1093/gbe/evt028Graur, D., Zheng, Y., and Azevedo, R.B. (2015) An evolutionary classification of genomic function. Genome Biology and Evolution, 7:642-645. [doi: 10.1093/gbe/evv021]Gregory, T. R. (2005) Synergy between sequence and size in large-scale genomics. Nature Reviews Genetics, 6:699-708. [doi: 10.1038/nrg1674]Haerty, W., and Ponting, C.P. (2014) No Gene in the Genome Makes Sense Except in the Light of Evolution. Annual review of genomics and human genetics, 15:71-92. [doi:10.1146/annurev-genom-090413-025621]Hurst, L.D. (2013) Open questions: A logic (or lack thereof) of genome organization. BMC biology, 11:58. [doi:10.1186/1741-7007-11-58]Kellis, M., Wold, B., Snyder, M.P., Bernstein, B.E., Kundaje, A., Marinov, G.K., Ward, L.D., Birney, E., Crawford, G. E., and Dekker, J. (2014) Defining functional DNA elements in the human genome. Proc. Natl. Acad. Sci. (USA) 111:6131-6138. [doi: 10.1073/pnas.1318948111]Mattick, J. S., and Dinger, M. E. (2013) The extent of functionality in the human genome. The HUGO Journal, 7:2. [doi: 10.1186/1877-6566-7-2]Five Things You Should Know if You Want to Participate in the Junk DNA DebateMorange, M. (2014) Genome as a Multipurpose Struct[...]



I'm going to a birthday party!

Fri, 06 Apr 2018 18:40:00 +0000

It's Bruce Alberts' 80th birthday party in San Francisco. There will be food, wine, cake, and (probably) dancing but first you go to the symposium on education.


Bruce Alberts’ 80th Birthday Gathering and Symposium

Saturday, April 14
Symposium on Science Education and Science Policy in Honor of Bruce Alberts’ 80th Birthday
(At the Metropolitan Club, 640 Sutter St., San Francisco 94102)

9a Guests arrive and register

10a Introduction by Master of Ceremonies Gregor Eichele

10:10a Session 1 How do we convey the importance of science to the public?
Moderator: Maureen Munn
Panelists: Janet Coffey, Will Colglazier, Janet English, Caroline Kiehle

11:40a Break

12p Buffet Lunch served in the Garden Room

1:30p Session 2 Innovations in Teaching and Learning in Higher Education
Moderators: Doug Kellogg and Kimberly Tanner.
Panelists: Judy Miner, Sally Pasion (one more panelist TBA)

2:30p Coffee and tea break

3p Session 3 Challenges Facing the Next Generation of Scientists
Moderators: Cynthia Fuhrmann and Bill Theurkauf.
Panelists: Marc Kirschner, Barry Selick, Nolan Sigal

4p Break

4:30p Session 4 Science Policy
Moderators: Mary Maxon and Jason Rao
Panelists: Bill Colglazier, Haile Debas, Donna Riordan, Keith Yamamoto

5:30p Elaine Bearer’s Duet for clarinet and viola: “Replication Machine”

6:15p Reception at Metropolitan Club Bar (4th Floor)

7p Buffet Dinner (Metropolitan Club Main Dining Hall — 4th Floor) Ending at 9:30p.

Sunday, April 15

10a - 2p Drop-in Brunch for all hosted at Beth Alberts’ home


Photo: Bruce Alberts with his first three graduate students: Glenn Herrick (right), Keith Yamamoto (left), Larry Moran (middle right), Bruce Alberts (middle left).



Cafe Scientific Mississauga: The Good, Bad, & Natural

Fri, 06 Apr 2018 15:34:00 +0000

Dan Riskin: The Good, Bad, & Natural: What Mother Nature says
about morality?


Thursday, April 12, 2018
7:30 - 10:00 pm
The Franklin House
263 Queen Street S
Streetsville (Mississauga), Ontario, Canada

"People often act like “natural” is synonymous with “good.” Using heinous examples from the scientific literature, Dan Riskin will blow the hinges off that misconception. Then he’ll give some thoughts about where, if not from nature, the roots of human morality might lie.

Dan Riskin, PhD, is a television personality, scientist, author, and podcaster. He is best known as the co-host of Discovery's flagship science program, Daily Planet, and as the host of Animal Planet's show about parasites, Monsters Inside Me. To make science accessible and interesting to wide audiences, Dan has appeared as a guest on The Tonight Show with Jay Leno, The Late Late Show with Craig Ferguson, The Dr. Oz Show, and on several news outlets, including CP24, CTV, CNN, and CBS. Dan has published more than 20 papers in scientific journals, and his first popular book, Mother Nature is Trying to Kill You was a Canadian bestseller.

IMPORTANT:
This meetup starts 30 minutes later than our regular meeting time to give Dan time to drive to Mississauga from Scarborough.
You are welcome to come at 7 or 7:30, but don't expect the talk to begin before 8 pm. It will definitely be worth it.
"





Subhash Lakhotia: The concept of 'junk DNA' becomes junk

Thu, 05 Apr 2018 21:15:00 +0000

Continuing my survey of recent papers on junk DNA, I stumbled upon a review by Subash Lakhotia that has recently been accepted in The Proceedings of the Indian National Science Academy (Lakhotia, 2018). It illustrates the extent of the publicity campaign mounted by ENCODE and opponents of junk DNA. In the title of this post, I paraphrased a sentence from the abstract that summarizes the point of the paper; namely, that the 'recent' discovery of noncoding RNAs refutes the concept of junk DNA.Lakhotia claims to have written a review of the history of junk DNA but, in fact, his review perpetuates a false history. He repeats a version of history made popular by John Mattick. It goes like this. Old-fashioned scientists were seduced by Crick's central dogma into thinking that the only important part of the genome was the part encoding proteins. They ignored genes for noncoding RNAs because they didn't fit into their 'dogma.' They assumed that most of the noncoding part of the genome was junk. However, recent new discoveries of huge numbers of noncoding RNAs reveal that those scientists were very stupid. We now know that the genome is chock full of noncoding RNA genes and the concept of junk DNA has been refuted. Here's the abstract ...Major discoveries like the one gene-one enzyme hypothesis, demonstration of DNA as the genetic material and finally the elucidation of the double helical structure of DNA in 1940s and early 1950s set the stage for emergence of molecular biology. Parallel cell biological studies during this period also indicated a correlation between rate of protein synthesis in a cell and the amount of cytoplasmic RNA. Following the proposal of George Gamow, a physicist, about the triplet genetic code and possible involvement of RNA in the transfer of information from DNA to proteins, Crick proposed the 'central dogma of molecular biology' to suggest the paths of information transfer between nucleic acids and proteins, with the limitation that the information cannot flow back from protein to nucleic acids. With emphasis on proteins as the central phenotypic determinants and the continuing enigma of heterochromatin, which largely appeared to be ‘gene desert’, enriched in repetitive DNA sequences and claimed to be inert in transcription, the many observations in 1960s of a large variety of heterogeneous nuclear RNAs remained ignored. Curiosity in the nuclear RNAs that do not see the face of cytoplasm appeared to be quelled by concepts of ‘selfish’ or ‘junk’ DNA in the early 1980s, notwithstanding the fact that active transcription of typical heterochromatin regions and repetitive and other noncoding DNA sequences was well demonstrated in 1960s and 1970s. With a few exceptions like the hsrω and roX transcripts in Drosophila and the Xist RNAs in mammals, the noncoding RNAs remained largely ignored for nearly two decades. The discovery of RNA interference and sequencing of different eukaryotic genomes, including the human genome, led to revisits to possible significance of noncoding RNAs (ncRNAs) in the new millennium. The occasional identification of ncRNAs in early 2000s has in recent years transformed into a ‘tsunami’, resulting in concepts of ‘selfish’ or ‘junk’ DNA themselves becoming junk. There is now increasing realization that the subtle and large phenotypic effects of heterochromatin and the existence of diverse nucleus-limited RNAs reported through painstaking genetic and biochemical studies that were undertaken before molecular biology had grown fully, can be largely related to the enormous diversity of short and long ncRNAs now known to be produced by all genomes. Although Crick’s proposal of the Central Dogma was only about the directions of information transfer, its mis-interpretation due to the great emphasis on the central roles of proteins and the reductionist linear approach of molecular biology that led to widespread belief in concepts of 'selfish' or 'junk' DNA, delayed the apprecia[...]



Peter Larsen: "There is no such thing as 'junk DNA'"

Thu, 05 Apr 2018 21:01:00 +0000

The March 2018 issue of Chromosome Research is a Special Issue on Transposable Elements and Genome Function. I found it as I was doing my routine search for papers on junk DNA in order to see whether scientists are finally beginning to understand the issue. Peter Larsen (guest editor) wrote the introduction to the special issue. He says ... There is no such thing as “junk DNA.” Indeed, a suite of discoveries made over the past few decades have put to rest this misnomer and have identified many important roles that so-called junk DNA provides to both genome structure and function (this special issue; Biémont and Vieira 2006; Jeck et al. 2013; Elbarbary et al. 2016; Akera et al. 2017; Chen and Yang 2017; Chuong et al. 2017). Nevertheless, given the historical focus on coding regions of the genome, our understanding of the biological function of non-coding regions (e.g., repetitive DNA, transposable elements) remains somewhat limited, and therefore, all those enigmatic and poorly studied regions of the genome that were once identified as junk are instead best viewed as genomic “dark matter.”This is very disappointing. Anyone working on transposons should know that more than half of our genome is composed of various bits and pieces of defective transposons. Nobody has ever provided convincing evidence that most of that flotsam and jetsam is functional. The default explanation is that it is junk and that makes a lot of sense since it certainly looks like junk. Larsen proposes that transposable elements are involved in the third and fourth dimensions of the genome. The third dimension is DNA & chromatin structure and the fourth dimension is time-related biological processes. He provides no evidence that half of our genome plays a functional role in these "dimensions."There is evidence that some transposon-related sequences have been co-opted to perform regulatory and structural roles but that doesn't mean that all of them do. That crazy form of argument has been ridiculed so many times that I'm surprised to see it resurface in 2018. It's almost as though the scientists who use it don't even read the literature on junk DNA.Five Things You Should Know if You Want to Participate in the Junk DNA DebateFurthermore, the evidence for junk DNA is not confined to speculation about the role of transposon fragments. There's lots of other data that must be refuted before you announce the death of junk DNA. If you don't know what that evidence is, then you have no business writing about the subject. width="560" height="315" src="https://www.youtube.com/embed/h_bNO7MelXI?rel=0&start=82" frameborder="0" allow="autoplay; encrypted-media" allowfullscreen>I'm also annoyed about sloppy use of the term "dark matter." As far as I can tell, it's an attempt to: (1) shift the burden of proof, and (2) glamorize ignorance. The default explanation for transposon fragments is junk. The burden of proof is on those who want to prove function. By saying that it's "dark matter" they ignore the default explanation and shift the burdon of proof on to those who say it's junk DNA. The glamorous part is due to associating the term with the dark matter of the universe. There's plenty of evidence for the existence of that kind of dark matter even though astronomers don't know exactly what it's composed of. The idea here is that by referring to the 'dark matter' of the genome you imply that there really is something mysterious and important going on but we just don't know what it is. That's not true. We know a lot about genomes and there are no great mysteries [What's In Your Genome? - The Pie Chart]. We know that most of the human genome is junk in spite of what Peter Larsen says. Can someone explain what's going on? There really isn't much of a controversy any more. Knowledgeable scientists have examined the data and concluded that about 90% of our genome is junk. How can you write about junk DNA without mentioning that data and how does an a[...]



What's In Your Genome? - The Pie Chart

Tue, 27 Mar 2018 19:37:00 +0000

Here's my latest compilation of the composition of the human genome. It's depicted in the form of a pie chart.1 [UPDATED: March 29, 2018]

There are several ways of estimating the amount of functional DNA and the amount of junk DNA. All of them are approximations but they only differ by a few percent. Note that several categories overlap. For example, introns and pseudogenes contain substantial amounts of DNA derived from transposons. The total amount of transposon-related sequence is about 60% when you include this fraction.

Here's the list of DNA sequences that are known or presumed to have a function (i.e. they are not junk).
  • functional parts of protein-coding genes (mostly coding regions): 1%
  • functional parts of genes for likely noncoding RNAs: 1%
  • regulatory sequences: 0.2%
  • scaffold attachment regions (SARs): 0.3%
  • origins of replication: 0.3%
  • centromeres: 1%
  • telomeres: 0.1%
  • functional virus sequences: 0.1%
  • functional transposons: 0.1%
  • conserved sequences of unknown function: ~3.9% (maximum)
This adds up to 8% of the genome. The remaining 92% is junk.

Most of the junk consists of: (1) very obvious examples of broken genes (pseudogenes 5%); (2) bits and pieces of transposon sequences that used to be capable of transposing but have mutated over time (45%); and (3) ancient viral sequences that have degenerated (9%). That's 59% of the genome that's clearly junk DNA. In addition, there's plenty of evidence that most intron sequences are dispensable. That accounts for another 28% of the genome. The total amount of junk DNA is at least 87%.

Note that protein-coding genes take up about 23% of the genome (1% exons, 22% introns). Genes for functional noncoding RNAs take up an additional 7% of the genome (1% exons, 6% introns). (Much of the functional region of noncoding RNA genes consists of 300 copies of ribosomal RNA genes (0.4%).) The important point is that roughly 30% of the genome is genes when we define a gene as a DNA sequence that's transcribed. A lot of this is junk within introns.

Also keep in mind that the well-characterized functional parts of the genome account for about 4% of the total but the functional regions of genes are only half of this total. Thus, we know that genes make up less than half of the total functional DNA in the human genome. This fact is not widely known even though the data is half-a-century old. I guess it takes some scientists a long time to learn the facts about the human genome.


1. I have to use a pie chart because they were invented by my wife's ancestor, William Playfair. (image)



What is "dark DNA"?

Sun, 18 Mar 2018 19:29:00 +0000

Some DNA sequencing technologies aren't very good at sequencing and assembling DNA that's rich in GC base pairs. What this means is that some sequenced genomes could be missing stretches of GC-rich DNA if they rely exclusively on those techniques. This difficult-to-sequence DNA was called "dark DNA" in a paper published last summer (July 2017).The paper looked at some missing genes in the genome of the sand rat Psammomys obesus. The authors initially used a standard shotgun strategy in order to sequence the sand rat genome. They combined millions of short reads (<200 bp) to assemble a complete genome. A large block of genes seemed to be missing—genes that were conserved and present in the genomes of related species (Hargraves et al., 2017). They knew the genes were present because they could detect the mRNAs corresponding to those genes. Hargraves et al. isolated GC-rich DNA and sequenced it using a different technique. This revealed the missing DNA and the missing genes. As expected, the entire block of DNA, containing 88 genes, had a high percentage of GC base pairs relative to AT base pairs. The authors attribute this to insertion of GC-rich repeats and to a phenomenon known as "gene conversion." Gene conversion, or more appropriately, biased gene conversion, is associated with recombination. Recombination results in stretches of DNA containing mismatched base pairs such as A:C or G:T. The mismatches must be repaired to restore the normal GC and AT base pairs. There's plenty of evidence showing a bias in the repair process such that the final product favors GC pairs over AT pairs. This is biased gene conversion.1 Biased gene convesion leads to a gradual increase in GC content in regions of the genome that are hotspots for recombination. This is a well-understood and reasonable explanation of the GC-rich region in the sand rat genome. Biased gene conversion and GC-rich regions are not new. What's new in the paper is the idea that large regions of the genome may be missing from a genome assembly because of limitations of standard sequencing technology. This is "dark DNA." A species related to the sand rat also has a high GC content in the same region suggesting that the shift to high GC content occurred before their last common ancestor. GC-rich genes are missing from the chicken genome assembly suggesting that dark DNA may be more common than anyone suspected.If that's all there is to the story we probably wouldn't have head about it. However, the lead author of the paper, Adam Hargreaves, is mainly interested in how changes in the genome can lead to innovation and adaptation. He wrote an article last summer for The Conversation in which he emphasized the possible role of dark DNA in evolution [Introducing ‘dark DNA’ – the phenomenon that could change how we think about evolution]. He said,Most textbook definitions of evolution state that it occurs in two stages: mutation followed by natural selection. DNA mutation is a common and continuous process, and occurs completely at random. Natural selection then acts to determine whether mutations are kept and passed on or not, usually depending on whether they result in higher reproductive success. In short, mutation creates the variation in an organism’s DNA, natural selection decides whether it stays or if it goes, and so biases the direction of evolution.But hotspots of high mutation within a genome mean genes in certain locations have a higher chance of mutating than others. This means that such hotspots could be an underappreciated mechanism that could also bias the direction of evolution, meaning natural selection may not be the sole driving force.So far, dark DNA seems to be present in two very diverse and distinct types of animal. But it’s still not clear how widespread it could be. Could all animal genomes contain dark DNA and, if not, what makes gerbils and birds so unique? The most[...]



Making Sense of Genes by Kostas Kampourakis

Tue, 13 Mar 2018 19:03:00 +0000

Kostas Kampourakis is a specialist in science education at the University of Geneva, Geneva (Switzerland). Most of his book is an argument against genetic determinism in the style of Richard Lewontin. You should read this book if you are interested in that argument. The best way to describe the main thesis is to quote from the last chapter.Here is the take-home message of this book: Genes were initially conceived as immaterial factors with heuristic values for research, but along the way they acquired a parallel identity as DNA segments. The two identities never converged completely, and therefore the best we can do so far is to think of genes as DNA segments that encode functional products. There are neither 'genes for' characters nor 'genes for' diseases. Genes do nothing on their own, but are important resources for our self-regulated organism. If we insist in asking what genes do, we can accept that they are implicated in the development of characters and disease, and that they account for variation in characters in particular populations. Beyond that, we should remember that genes are part of an interactive genome that we have just begun to understand, the study of which has various limitations. Genes are not our essences, they do not determine who we are, and they are not the explanation of who we are and what we do. Therefore we are not the prisoners of any genetic fate. This is what the present book has aimed to explain.If you are interested in real facts about genes and the history of gene definitions, then you will be sorely disappointed because the author has fallen for the ENCODE hype. Similarly, if you want to know about genomes and junk DNA then don't read this book. The author takes his cues from Junk DNA by Nessa Carey and The Deeper Genome by John Parrington. Genomes and junk are the topics that interest me so let's look at some other excerpts from the book, keeping in mind that the main part of the book is about genetic determinism and the large-scale phenotypic effects of genes and alleles. The concept of a "gene" was poorly defined in the first part of the twentieth century. That fuzzy definition is still common today. It imagines a gene as a nebulous entity responsible for some visible trait. It's the way most people still think of a gene and it's the way students are often taught when they study genetics. Kostas Kampourakis does a pretty good job of describing the history of this idea up until 1953. The next stage is something he calls the "molecularization" of genes. That's the transformation from a gene as the subject of genetics to the idea that a gene is the subject of biochemistry and molecular biology. This is an important shift and the author is justified in emphasizing the transformation. From this point on, the book gets pretty confusing. The part I like is that the author doesn't get bogged down in the old-fashioned idea that genes only encode proteins. From fairly early on in the book he recognizes that a gene can specify either a protein or a functional RNA.1 So far, so good.The problems begin when he starts describing all the things that make a precise definition of a gene so difficult. Rather than treat these as exceptions that can be accommodated by a good working definition [What Is a Gene?], he focuses on the problems ...Regulatory sequences, discontinuous genes, overlapping genes, trans-splicing, RNA editing, among other things, have made impossible the structural individualization of genes on DNA. Looking more closely into the phenomena presented in this chapter might make one argue that the RNA transcript should be considered as the "true" gene. ... The important conclusion from all these phenomena is that DNA does not contain distinct segments corresponding to the genes it is supposed to contain, or, in other words, that genes cannot be structurally individuated. These phenomena can therefo[...]



Is evolutionary psychology a deeply flawed enterprise?

Mon, 12 Mar 2018 16:12:00 +0000

We were discussing the field of evolutionary psychology at our local cafe scientific meeting last week. The discussion was prompted by watching a video of Steven Pinker in conversation with Stephen Fry. I pointed out that the field of evolutionary psychology is a mess and many scientists and philosophers think it is fundamentally flawed. The purpose of this post is to provide links to back up my claim.There are several good sources of information that can be consulted. The Wikipedia articles note the controversial nature of evolutionary psychology [Evolutionary Psychology] [Criticism of evolutionary psychology]. The article by Stephen M. Downes on the Stanford Encyclopedia of Philosophy site is very comprehensive. It include an extensive discussion of the potential flaws in evolutionary psychology [Evolutionary Psychology]. Downes says ....I said in my introduction that there is a broad consensus among philosophers of science that evolutionary psychology is a deeply flawed enterprise and some philosophers of biology continue to remind us of this sentiment (see e.g. Dupre 2012). However the relevant consensus is not complete, there are some proponents of evolutionary psychology among philosophers of science. I think there's a broad consensus among evolutionary biologists as well. The critique from biologists is summarized by Robert C. Richardson (a philosopher) in his book Evolutionary Psychology as Maladapted Psychology.The claims of evolutionary psychology may pass muster as psychology; but what are their evolutionary credentials? Richardson considers three ways adaptive hypotheses can be evaluated, using examples from the biological literature to illustrate what sorts of evidence and methodology would be necessary to establish specific evolutionary and adaptive explanations of human psychological traits. He shows that existing explanations within evolutionary psychology fall woefully short of accepted biological standards. The theories offered by evolutionary psychologists may identify traits that are, or were, beneficial to humans. But gauged by biological standards, there is inadequate evidence: evolutionary psychologists are largely silent on the evolutionary evidence relevant to assessing their claims, including such matters as variation in ancestral populations, heritability, and the advantage offered to our ancestors. As evolutionary claims they are unsubstantiated. Evolutionary psychology, Richardson concludes, may offer a program of research, but it lacks the kind of evidence that is generally expected within evolutionary biology. It is speculation rather than sound science—and we should treat its claims with skepticism.You may disagree with these criticisms of evolutionary psychology but there's no denying that the discipline is being attacked. In fact, it's hard to think of any other academic discipline whose fundamental validity is being questioned so openly [Evolutionary Psychology Deserves Criticism] [How Valid Is Evolutionary Psychology? ] [Four Fallacies of Pop Evolutionary Psychology] [A Critique of Evolutionary Psychology] [A critique of evolutionary psychology]. The field of evolutionary psychology is full of hyper-adaptationist thinking. It's primary task is explaining modern features of human behavior as adaptations that took place in primitive human populations. From an evolutionary perspective, this requires that the behavior has strong enough genetic components to be subject to evolution by natural selection. It requires that primitive populations contained alleles for the modern behavior as well as alleles for a different behavior that reduced fitness. Finally, it requires that selection for the modern behavior is strong enough to lead to fixation in just a few hundred thousand years.All of these assumptions require supporting evidence that is almost always missing in evolutiona[...]



Can the Dunning-Kruger effect be reversed?

Wed, 07 Mar 2018 17:26:00 +0000

The Dunning-Kruger Effect was first proposed in a classic 1999 paper (Kruger and Dunning, 1999).1 People suffering from this effect show one of two characteristics. If they are not knowledgeable about a subject they tend to overestimate their ability. If they are experts in a subject they tend to underestimate their ability (see figure).The phenomenon is more significant in people who overestimate their ability because it includes a large number of people who are making decisions on subjects that they know little about. Because of the Dunning-Kruger effect, they are confident that their decisions are based on facts and evidence. That's bad enough, but there's another aspect to this problem—why do these people seem to be incapable of recognizing that they are suffering from the Dunning-Kruger effect? Here's how Kruger and Dunning explain this ...We argue that when people are incompetent in the strategies they adopt to achieve success and satisfaction, they suffer a dual burden: Not only do they reach erroneous conclusions and make unfortunate choices, but their incompetence robs them of the ability to realize it. ... they are left with the mistaken impression that they are doing just fine. ... as Charles Darwin (1871) sagely noted over a century ago, "ignorance more frequently begets confidence than does knowledge."We all know examples of people who are overly confident and we are familiar with the other end of the spectrum; namely, experts who worry about how little they know. We, ourselves, are very likely guilty at both ends of the Dunning-Kruger effect. We would all like to believe that we can correct our ignorance with facts and evidence but if we are truly incompetent then we might be resistant to evidence. Here's what Kruger and Dunning have to say about that,One puzzling aspect is how the incompetent fail, through life experience, to learn that they are unskilled. This is not a new puzzle. Sullivan, in 1953, marveled at "the failure of learning which has left their capacity for fantastic, self-centered, delusions so utterly unaffected by a life-long history of educative events." With that observation in mind, it is striking that our student participants overestimated their standing on academically oriented tests as familiar to them as grammar and logical reasoning. Although our analysis suggests that incompetent individuals are unable to spot their poor performances themselves, one would have thought negative feedback would have been inevitable at some point in their academic career. So why have they not learned?The authors propose several reasonable explanations. Most people don't get negative feedback because their friends are reluctant to point out how incompetent they are.In some situations here's no opportunity to recognize that you are incompetent.Even if people receive negative feedback, they may not accept it. This is because they usually blame someone, or something, else for their failure.Incompetent individuals may be unable to benefit from constructive criticism because they lack the ability to change. The very flaws that cause them to be incompetent in the first place are what prevent them from improving their reasoning skills and knowledge.That last point is important. It's what the authors were referring to in the first quotation.There's one aspect of the problem that isn't covered in the work on the Dunning-Kruger effect. That's the problem faced by experts when they fail to make an impression on the unknowledgeable. It must be very frustrating to try and teach people who suffer from unjustified overconfidence in their abilities. For example, imagine that you are an expert on international trade, the global economy, and macroeconomics. You are hired by a wealthy businessman to teach him about these subjects but you find it impossible to get anywher[...]



Junk DNA and selfish DNA

Wed, 28 Feb 2018 20:31:00 +0000

Selfish DNA is a term that became popular with the publication of a series of papers in Nature in 1980. The authors were referring to viruses and transposons that insert themselves into a genome where they exist solely for the purposes of propagating themselves. These selfish DNA sequences are often thought, incorrectly, to be the same as the Selfish Genes of Richard Dawkins1 [Selfish genes and transposons]. In fact, "selfish genes" refers to the idea that some DNAs enhance fitness and the frequency of these genes will increase in a population through their effect on the vehicle that carries them. It's an adaptationist view of evolution. The selfish DNA of transposons and viruses is quite different. These sequences only propagate themselves—the fitness of the organism is largely irrelevant. These elements do not contribute directly to the adaptive evolution of the species.Transposons and integrated viruses are are subjected to mutation just like the rest of the genome. Deleterious mutations cannot be purged by natural selection because inactivating a transposon has no effect on the fitness of the organism.2 As a result, large genomes are littered with defective transposons and bits and pieces of dead transposons. This is not selfish DNA by any definition. It is junk DNA [What's in Your Genome?]. It's important to remember that real selfish DNA makes up only a tiny percentage of the human genome. This is a fact that was not widely known in 1980 although some of the discussion back then alluded to the possibility.This brings me to a recent article by Itai Yanai and Martin Lercher [Life doesn’t make trash]. They are the authors of The Society of Genes. I wrote a short review of this book where I said that my main beef was their over-emphasis on The Selfish Gene and their adaptationist approach to evolution [Human genome books]. The article in Eon continues the emphasis on selfish genes and adaptation. Read it yourself to see if Yanai and Lercher are adaptationists or not. Most of the article is about junk DNA. You have to read very carefully to see that the authors have gotten the basic facts correct. They conclude that about 10% of our genome is functional based on the criterion that it is conserved—although I'm not sure that point comes across very clearly. They say,There is good evidence for this 10 per cent. If we compare our genome to that of other mammals, we find that 90 per cent of the genome was free to change through random mutations. Those DNA letters apparently did not contribute to the efficiency of the survival machine, us. By contrast, mutations in the remaining 10 per cent were weeded out by natural selection because they would have compromised the DNA sequences’ ability to spread – either by damaging the survival machine’s functioning, or by reducing the sequences’ freeloading capacity. This is the definition of function that has traditionally been used by evolutionary biologists as well as by philosophers of science: if something is conserved by natural selection, then it is functional. Function, then, is identified as the feature that ensures the spread or maintenance of a particular DNA sequence.So far, so good. I disagree with their description of the rest of the genome. They imply that most of it is selfish DNA composed of transposons like Alu's and LINE-1 sequences. I wish they had put more emphasis on the fact that much of our genome consists of defective transposons and viruses that are junk, plain and simple. They aren't selfish DNA today, although they once were in the past. 1. The confusion stems from the fact that Dawkins briefly mentioned these selfish DNAs in his book The Selfish Gene. 2. Strictly speaking, this isn't true. There may be some fitness advantage to eliminating transposons. In species w[...]



Human genome books

Sun, 18 Feb 2018 16:35:00 +0000

ThemeGenomes& Junk DNAI'm trying to read all the recent books on the human genome and anything related. There are a lot of them. Here's a list with some brief comments. You should buy some of these books. There are others you should not buy under any circumstances.The Deeper Genome: Why there is more to the human genome than meets the eyeby John ParringtonOxford University Press (2015)ISBN 978-0-19-968873-9John Parrington is an Associate Professor in Molecular and Cellular Pharmacology at the University of Oxford (UK). He claims that most of our genome is functional (not junk) based largely on the results of the ENCODE study. He ignores most of the scientific evidence in favor of junk DNA. This is a very bad book [Georgi Marinov reviews two books on junk DNA] [John Parrington discusses genome sequence conservation].Junk DNA: A journey Through the Dark Matter of the Genomeby Nessa CareyColumbia University Press (2015)ISBN 978-0-231-53941-8Nessa Carey is former researcher in epigenetics. She is currently a science writer based in the United Kingdom. She claims that recent discoveries have revealed that most of the mysterious “dark matter” of the genome (formerly junk DNA) is actually required for the regulation of gene expression. This book is even worse than Parrington’s [Georgi Marinov reviews two books on junk DNA] [Teaching about genomes using Nessa Carey's book: Junk DNA] [Nessa Carey doesn't understand junk DNA]. It's even worse than the book written by ID proponent Jonathan Wells (see below). In fact, it's a classic example of everything that's wrong with modern science writing [On explaining science to the general public].The Myth of Junk DNAby Jonathan WellsDiscovery Institute Press (2011)ISBN 978-1-9365990-0-4Jonathan Wells has a Ph.D. in Molecular & Cell Biology from the University of California, Berkeley. He is a leading advocate of intelligent design. According to Wells, the idea that most of our genome is junk is a myth promoted by Darwinian scientists. The science in this book is far superior to the first two books on the list. Wells acknowledges and deals with the main evidence for junk DNA but he still reaches the wrong conclusion [The Myth of Junk DNA by Jonathan Wells]. Human Evolution: Genes, Genealogies and Phylogeniesby Graeme FinlayCambridge University Press (2013)ISBN 978-1-107-04012-0Graeme Finlay is a professor in the Department of Molecular Medicine and Pathology at the University of Auckland, Auckland, New Zealand. This is an excellent book on retroviruses, transposons, pseudogenes, and new (de novo) genes. Those topics are very well described at a fairly sophisticated level with an emphasis on their adaptive roles. Junk DNA is not discussed even though most of the sequences Finlay discusses are junk. The emphasis is on the possible evolutionary significance of co-opted sequences of pseudogenes giving the impression that they aren't junk [Human Evolution: Genes, Genealogies and Phylogenies by Graeme Finlay]. I agree with Norman Johnson when he says that the book is hyperadaptationist in tone [Making sense of the human genome]. Ancestors in Our Genome: The new science of human evolutionby Eugene E. HarrisOxford University Press (2015)ISBN 978-0-19-997803-8Eugene Harris is a professor of Biological Sciences and Geology at City University of New York, New York (USA). He has written an excellent analysis of modern human evolution from a molecular evolution perspective. His description of some complex techniques; such as selective sweeps and coalescence are very good. His explanation of the difference between gene trees and species trees is excellent. The science is well above the level of some of the dumbed-down books at the top of this list. This is the best book I've ever read on the subject [...]



Test your irony meter

Wed, 14 Feb 2018 16:30:00 +0000

The irony meter was a running joke on the newsgroup talk.origins back in the last century. Our irony meters were supposed to protect us from the craziness of creationists but as soon as we built a really good irony meter a new bit of creationist crazy came along and fried it. Apparently Jesus and Mo have the same problem.





Scientists fight back against fake news and pseudoscience

Mon, 12 Feb 2018 20:06:00 +0000

You probably know that climate change is real and humans are a major cause of global warming. You probably know that life has evolved and the Biblical story of creation is false. Scientists have been actively promoting these ideas for decades and they've been relatively successful in most countries. What you may not know is that these are just two of the many controversial claims that scientists are fighting. You may even have been tricked into believing some of the other pseudoscientific claims that are out there.Do you think genetically-modified organisms are dangerous? Do you think vaccines are a threat to your child's well-being? Do you consult a naturopath or a homeopath? How about a chiropracter? Do you take daily vitamin supplements? Do you avoid gluten or lactose? Do you think hamburgers and fries are unhealthy? Poutine? Have you ever had acupuncture? Have you ever been detoxified? Are you afraid of free radicals? Is Round-Up a deadly poison? Do you spend extra money buying "organic" food? Are you afraid of fluoride? Are preservatives always bad? Is Diet Coke gonna kill you? Do skinny people live longer? Are whole wheat bagels better for you than the regular kind? Do you take probiotics? Do you even know what they are? Can you avoid cancer by eating healthy and working out every day?1 If you answered "yes" to any of those questions then chances are you've fallen for some fake science. It's more common than you might think. I have many friends who take vitamin supplements, for example, in spite of the fact there's no scientific evidence that they do any good. They've been sucked in by the fake "health" food industry who are more than willing to take your money. Last year the so-called "health and wellness" industry raked in a trillion dollars [Health and Wellness the Trillion Dollar Industry in 2017]. Fortunately, there are a few scientists out there who are fighting back and, even more importantly, the legitimate press is beginning to pay attention. This is important because those scientists are fighting a trillion dollar industry and they're mostly doing it for free. Today I was pleased to read the following article in Toronto Star: Scientists, researchers fight against online plague of nutrition pseudoscience. This group is collectively working to debunk the most egregious health myths with evidence-based, factual information.It always a good thing when proponents of evidence-based facts get as much attention as the proponents of pseudoscience. One of the scientists highlighted in the article is Timothy Caulfield, a professor at the University of Alberta Health Law Institute. He's the author of Is Gwyneth Paltrow Wrong About Everything? (Spoiler Alert! - the answer is "yes.") Finding health information online is easy. Cutting through the clutter and getting facts is very difficult. There’s a cacophony of voices, each saying something different. The confusion worsens when charlatans provide false hope and bad advice.But there is a glimmer of hope. Scientists and researchers are working to debunk the most egregious health myths and educate readers with evidence-based, factual information. Let’s call them skeptics, myth-busters or debunkers. In any case, this group is collectively using science to fight back against the pseudoscience (such as fad diets and quack cancer cures). It's fun to debunk the claims of pseudoscience but let's not forget that the important goal is to teach critical thinking in our schools so that our children grow up armed with the tools to avoid falling for false claims in the first place. 1. If I haven't found at least one question that makes you want to post an angry rebuttal then please let me know and I will add some others.[...]



Dirty bacteria

Mon, 12 Feb 2018 18:16:00 +0000

Did you know that the dirt in your local park is full of bacteria? Each scoop of soil contains millions of bacteria. And it's not just in your local park, soil bacteria are everywhere. This is part of the reason why the total mass of bacteria on the planet outweighs all of the eukayotes combined, including elephants and whales.

There are hundreds of different species of bacteria in your local dirt. They are as different from each other as moose and mushrooms.

Did you ever wonder whether the bacteria in Australian soil are similar to the bacteria in Austrian soil? Delgado-Baquerizo and his colleagues did, so they tested soils from all over the world. The results are published in a recent issue of Science (Delgado-Baquerizo et al., 2018).

The answer is yes ... and no. They looked at 237 locations on all continents except Antarctica. Most samples had about 1000 different species—the authors call them "phylotypes" because it's hard to define what a species is in bacteria. Only a small number of species (phylotypes) were found in all locations (511 out of 25,224 = 2%) but they accounted for almost half of the total mass. Here's how the authors describe their result ...
Together, our results suggest that soil bacterial communities, like plant communities, are typically dominated by a relatively small subset of phylotypes.
Most of those 511 dominant phylotypes fall into two large and diverse clades (phyla?): Proteobacteria and Actinobacteria. The distribution is shown in Figure 1 of the paper (left). It illustrates a little-known fact about bacteria; namely, that they are a very diverse group. Scientists are only beginning to explore this diversity. Only 18% of the 511 dominant phylotypes were previously known to science!




Image Credit: Bacillus Sp. soil bacteria from The ecology of soil-borne human diseases

Delgado-Baquerizo, M., Oliverio, A.M., Brewer, T.E., Benavent-González, A., Eldridge, D.J., Bardgett, R.D., Maestre, F.T., Singh, B.K., and Fierer, N. (2018) A global atlas of the dominant bacteria found in soil. Science, 359(6373), 320-325. doi: doi: 10.1126/science.aap9516




Happy Darwin Day 2018!

Mon, 12 Feb 2018 16:46:00 +0000

Charles Darwin, the greatest scientist who ever lived, was born on this day in 1809 [Darwin still spurs tributes, debates] [Happy Darwin Day!] [Darwin Day 2017]. Darwin is mostly famous for two things: (1) he described and documented the evidence for evolution and common descent and (2) he provided a plausible scientific explanation of evolution—the theory of natural selection. He put all this in a book, The Origin of Species by Means of Natural Selection published in 1859—a book that spurred a revolution in our understanding of the natural world.

Modern evolutionary theory has advanced well beyond Darwin's theory but he still deserves to be honored for being the first to explain evolution and promote it in a way that convinced others. Here's one passage from the introduction to Origin of Species.
Although much remains obscure, and will long remain obscure, I can entertain no doubt, after the most deliberate and dispassionate study of which I am capable, that the view which most naturalists entertain, and which I formerly entertained—namely, that each species has been independently created—is erroneous. I am fully convinced that species are not immutable; but that those belonging to what are called the same genera are lineal descendants of some other and generally extinct species, in the same manner as the acknowledged varieties of any one species are the descendants of that species. Furthermore, I am convinced that Natural Selection has been the main but not exclusive means of modification.





One philosopher's view of random genetic drift

Mon, 12 Feb 2018 15:46:00 +0000

Random genetic drift is the process whereby some allele frequencies change in a population by chance alone. The alleles are not being fixed or eliminated by natural selection. Most of the alleles affected by drift are neutral or nearly neutral with respect to selection. Some are deleterious, in which case they may be accidentally fixed in spite of being selected against. Modern evolutionary theory incorporates random genetic drift as part of population genetics and modern textbooks contain extensive discussions of drift and the influence of population size. The scientific literature has focused recently on the Drift-Barrier Hypothesis, which emphasizes random genetic drift [Learning about modern evolutionary theory: the drift-barrier hypothesis].Most of the alleles that become fixed in a population are fixed by random genetic drift and not by natural selection. Thus, in a very real sense, drift is the dominant mechanism of evolution. This is especially true in species with large genomes full of junk DNA (like humans) since the majority of alleles occur in junk DNA where they are, by definition, neutral.1 All of the data documenting drift and confirming its importance was discovered by scientists. All of the hypotheses and theories of modern evolution were, and are, developed by scientists. Nothing in biology makes sense except in the light of population genetics.Michael LynchYou might be wondering why I bother to state the obvious; after all, this is the 21st century and everyone who knows about evolution should know about random genetic drift. Well, as it turns out, there are some people who continue to make silly statements about evolution and I need to set the record straight.One of those people is Massimo Pigliucci, a former scientist who's currently more interested in the philosophy of science. We've encountered him before on Sandwalk [Massimo Pigliucci tries to defend accommodationism (again): result is predictable] [Does Philosophy Generate Knowledge?] [Proponents of the Extended Evolutionary Synthesis (EES) explain their logic using the Central Dogma as an example]. I looks like Pigliucci doesn't have a firm grip on modern evolutionary theory.His main beef isn't with evolutionary biology. He's mostly upset about the fact that science as a way of knowing is extraordinarily successful whereas philosophy isn't producing many results. He loves to attack any scientist who points out this obvious fact. He accuses them of "scientism" as though that's all it takes to make up for the lack of success of philosophy. His latest rant appears on the Blog of the American Philosophers Association: The Problem with Scientism. I'm not going to deal with the main part of his article because it's already been covered many times. However, there was one part that caught my eye. That's the part where he lists questions that science (supposedly) can't answer. The list is interesting. Pigliucci says, Next to last, comes an attitude that seeks to deploy science to answer questions beyond its scope. It seems to me that it is exceedingly easy to come up with questions that either science is wholly unequipped to answer, or for which it can at best provide a (welcome!) degree of relevant background knowledge. I will leave it to colleagues in other disciplines to arrive at their own list, but as far as philosophy is concerned, the following list is just a start:In metaphysics: what is a cause?In logic: is modus ponens a type of valid inference?In epistemology: is knowledge “justified true belief”?In ethics: is abortion permissible once the fetus begins to feel pain?In aesthetics: is there a meaningful dif[...]



We live in the age of bacteria

Sat, 10 Feb 2018 22:18:00 +0000

I'm sad because we now have almost a whole generation of young people who know very little about Stephen Jay Gould. (He died of cancer in 2002.) I was thinking of this yesterday as I was preparing a post on bacteria. Gould's 1996 book, Full House, is about fundamental misconceptions of evolution and progress and it contains the following passage (p. 176) ...

We live now in the "Age of Bacteria." Our planet has always been in the "Age of Bacteria," ever since the first fossils—bacteria, of course—were entombed in rocks more than three and a half billion years ago.

On any possible, reasonable, or fair criterion, bacteria are—and always have been—the dominant forms of life on earth.
Listen to him make this point twenty years ago ...

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Junior scientist snowflakes

Fri, 09 Feb 2018 18:35:00 +0000

A recent letter in Nature draws attention to a serious (?) problem in modern society; namely, the persecution of junior scientists by older scientists who ask them tough questions. Anand Kumar Sharma warns us: "Don’t belittle junior researchers in meetings". Here's what he says, ...The most interesting part of a scientific seminar, colloquium or conference for me is the question and answer session. However, I find it upsetting to witness the unnecessarily hard time that is increasingly given to junior presenters at such meetings. As inquisitive scientists, we do not have the right to undermine or denigrate the efforts of fellow researchers — even when their reply is unconvincing.It is our responsibility to nurture upcoming researchers. Firing at a speaker from the front row is unlikely to enhance discussions. In my experience, it is more productive to offer positive queries and suggestions, and save negative feedback for more-private settings.I wasn't going to comment on this but Neuroskeptic blogged about it and supported the idea that junior scientists need special protection when they present their work at meetings and conferences [Hostile Questions at Scientific Meetings]. He says,In my view, a conference is not a place to be making critical comments. For one thing, it is very difficult to critically appraise a conference presentation, because they don’t provide the full details of the study. It is also unlikely that putting a presenter on the spot with a hard question is going to elicit a useful answer. It’s better to wait until the paper is published, and then critique that, giving the authors time to respond properly.I recognize that there are abuses from time to time but I take the opposite position. I don't think there's enough harsh criticism at scientific meetings. I think that too many scientists get away with making ridiculous claims that go unchallenged out of politeness and political correctness. I think we need MORE hostile questions not fewer. Why should a scientist be allowed to make stupid statements at a conference presentation on the grounds that they can't be criticized because the work isn't published?Should we treat junior scientists any differently than senior scientists? Should we allow junior scientists the privilege of saying stupid things without being challenged as long as they are under 40 years old? Let's hear from some younger scientists 'cause I'm pretty sure that all of us old curmudgeons don't hold back from criticizing our younger colleagues. When I was younger—yes, that's me on the left—I would have been insulted to be told that I was being treated as a child, not an equal, by my senior colleagues.[...]



Are splice variants functional or noise?

Fri, 09 Feb 2018 17:42:00 +0000

This is a post about alternative splicing. I've avoided using that term in the title because it's very misleading. Alternative splicing produces a number of different products (RNA or protein) from a single intron-containing gene. The phenomenon has been known for 35 years and there are quite a few very well-studied examples, including several where all of the splice regulatory factors have been characterized. The number of known examples is quite small in any given species. In contrast, the number of different splice variants is enormous. Most human genes, for example, are associated with a dozen or so different variants that have been detected over the years. Almost of of these splice variants have been rejected by genome annotators because they are very rare, never leave the nucleus, and are never present in sufficient quantities to be functional. They are undoubtedly junk RNA produced by the sloppy spliceosome. This kind of noise should not be called alternative splicing because that term should be restricted to real examples that produce functional variants by some sort of regulatory mechanism. This seems like common sense to me but, unfortunately, most scientists disagree. They continue to refer to any example of splice variants as alternative splicing even though they might be just splicing errors. In fact, most of these scientists don't even consider the possibility of splicing errors. See the following posts for a more thorough discussion of this problem. Debating alternative splicing (part I)Debating alternative splicing (part II)Debating alternative splicing (Part III)Debating alternative splicing (Part IV)A recent paper by John Mattick and his collaborators highlights the problem (Deveson et al., 2017). Recall that Mattick is a prominent opponent of junk DNA. He thinks that most of the genome is devoted to producing regulatory RNAs. His "proof" is pervasive transciption. He claims there are thousands and thousands on long nocoding RNAs that have a function [John Mattick still claims that most lncRNAs are functional].His most recent paper employs the latest technology for detecting RNAs in a cell. The authors highlight the fact that they can detect very low abundance RNAs. They apply the technique to map all the RNAS complementary to the DNA on human chromosome 21. They choose three tissues; testis, brain, and kidney. Two of these tissues are well-known examples of noisy transcription.The results are not unexpected. They detected an enormous number of different transcripts covering most of the non-repetitive DNA in chromosome 21. Each protein-coding gene matched to dozens of different splice variants in addition to the standard mRNA. Although the authors make passing reference to the controversy over splicing, it's clear that they treat all of these mRNA variants as examples of true alternative splicing. But that's not the main point of their paper. The main point is that the rest of the chromosome specifies a large number of noncoding RNAs and those RNAs exhibit an enormous diversity of splice variants. The result is nicely captured in their summary image (right).The old RNA-Seq view is shown in the upper-right part of the image. A typical protein-coding gene produces a number of splice variants that I assume are examples of splicing errors. Mattick and his colleagues assume they are due to alternative splicing. The noncoding part of the genome is complementary to another set of transcipts with a limited set of splice variants. Mattick assumes these regions are genes and the RNAs are functional, a[...]



The Salzburg sixty discuss a new paradigm in genetic variation

Wed, 07 Feb 2018 19:18:00 +0000

Sixty evolutionary biologists are going to meet next July in Salzburg (Austria)to discuss "a new paradigmatic understanding of genetic novelty" [Evolution – Genetic Novelty/Genomic Variations by RNA Networks and Viruses]. You probably didn't know that a new paradigm is necessary. That's because you didn't know that the old paradigm of random mutations can't explain genetic diversity. (Not!) Here's how the symposium organizers explain it on their website ...For more than half a century it has been accepted that new genetic information is mostly derived from random‚ error-based’ events. Now it is recognized that errors cannot explain genetic novelty and complexity.Empirical evidence establishes the crucial role of non-random genetic content editors such as viruses and RNA-networks to create genetic novelty, complex regulatory control, inheritance vectors, genetic identity, immunity, new sequence space, evolution of complex organisms and evolutionary transitions....This new empirically based perspective on the evolution of genetic novelty will have more explanatory power in the future than the "error-replication" narrative of the last century.Wow! Who knew? The lead organizer is Günther Witzany, a philosopher of science and a prominent member of The Third Way [The Third Way: Günther Witzany]. We've encountered him before on Sandwalk: Here's why you can ignore Günther Witzany. Just about anyone can misunderstand molecular biology but it takes a philosopher of science to really screw it up. Witzany says ...The older concepts we have now for a half century cannot sufficiently explain the complex tendency of the genetic code. They can't explain the functions of mobile genetic elements and the endogenous retroviruses and non-coding RNAs. Also, the central dogma of molecular biology has been falsified -- that is, the way is always from DNA to RNA to proteins to anything else, or the other "dogmas," e.g., replication errors drive evolutionary genetic variation, that one gene codes for one protein and that non-coding DNA is junk. All these concepts that dominated science for half a century are falsified now. ...Here's a summary of where my views differ ...The fundamental concepts in evolution and molecular biology were worked out in the middle of the last century and thery have been steadily improved and modified since then. They are fully capable of explaining mobile genetic elements, endogenous retroviruses, and non-coding RNAs. Read any textbook.The Central Dogma of Molecular Biology says that once information is transferred to protein it can't go back to nucleic acids [Central Dogma of Molecular Biology]. It's blatantly obvious that Günther Witzany doesn't understand the Central Dogma. It's obvious that he hasn't read Crick's papers.The idea that replication errors create genetic variation has not been falsified. It is by far the most important source of mutation.The idea that one gene codes for one protein is a false strawman version of our current understanding of a gene [What Is a Gene?]. No knowledgeable scientist ever thought that all genes produced proteins and no knowledgeable scientist since 1980 was unaware of genes encoding multiple proteins. Read a textbook. No knowledgeable scientist ever said that all non-coding DNA is junk. They do, however, say that most of the DNA in the human genome is junk. That's a concept that was formed in the middle of the last century and has become more and more true as evidence accumulates in the 21st century. It has not been falsified as [...]



How many lncRNAs are functional?

Tue, 06 Feb 2018 20:55:00 +0000

There's solid evidence that 90% of your genome is junk. Most of it is transcribed at some time but the transcripts are transient and usually confined to the nucleus. They are junk RNA [Functional RNAs?]. This is the view held by many experts but you wouldn't know that from reading the scientific literature and the popular press. The opposition to junk DNA gets much more attention in both venues.There are prominent voices expressing the view that most of the genome is devoted to producing functional RNAs required for regulating gene expression [John Mattick still claims that most lncRNAs are functional]. Most of these RNAs are long noncoding RNAs known as lncRNAs. Although most of them fail all reasonable criteria for function there are still those who maintain that tens of thousands of them are functional [How many lncRNAs are functional: can sequence comparisons tell us the answer?]. There are very few serious reviews that address the controversy over function (but see Palazzo and Lee, 2015 ... the figure is from their paper). That's why I want to highlight a review that's just been published in Cell. It's a review that recognizes the controversy over function and points to the possibility that most putative lncRNAs may be junk (Kopp and Mendell, 2018). I'm going to quote directly from the introduction and the conclusion to show you how scientific reviews are supposed to be written.There is a broad range of estimates for the number of lncRNA genes in mammals, ranging from less than 20,000 to over 100,000 in humans. Nevertheless, the function and biological relevance of the vast majority of lncRNAs remain enigmatic. Given that transcriptional regulatory elements, such as enhancers and promoters, are now known to initiate transcription bi-directionally, it is likely that many lncRNAs—if not the majority—actually represent RNAs that initiate at enhancers or promoters but do not perform sequence-specific functions. This conclusion is further suggested by the fact that many lncRNAs are localized to the nucleus with low expression levels and little primary sequence conservation. Recent reports of local gene regulation by lncRNA loci reinforce this notion and suggest that in many cases, the act of transcription or DNA elements within the lncRNA locus are more likely to be the source of regulatory activity than the actual lncRNA itself. Given these observations, it is clear that the mere existence or production of an RNA does not automatically imply its functionality. Indeed, we must assume until proven otherwise that of the tens of thousands of annotated lncRNAs, those that function independently of the DNA sequence from which they are transcribed represent a small minority. Nevertheless, even if a small percentage of lncRNAs are functional, they would still constitute a major gene class with hundreds or possibly thousands of members.The best available data shows that less than 500 putative lncRNAs have a well-defined function. When I'm calculating the amount of functional DNA in the human genome I usually assume 5,000 genes for noncoding RNAs—most of them are not lncRNAs. I still think that's a good estimate.The act of transcription around promoter regions may play a role in regulation. In such cases, the sequence of the transcript may be irrelevant but the transcribed region of the genome has a function. There aren't very many proven examples of this type of function. In most cases it looks like the transcripts are just due to sloppy initiation. Kopp a[...]



ENCODE's false claims about the number of regulatory sites per gene

Mon, 05 Feb 2018 21:24:00 +0000

Some beating of dead horses may be ethical, where here and there they display unexpected twitches that look like life.Zuckerkandl and Pauling (1965)I realize that most of you are tired of seeing criticisms of ENCODE but it's important to realize that most scientists fell hook-line-and-sinker for the ENCODE publicity campaign and they still don't know that most of the claims were ridiculous.I was reminded of this when I re-read Brendan Maher's summary of the ENCODE results that were published in Nature on Sept. 6, 2012 (Maher, 2012). Maher's article appeared in the front section of the ENCODE issue.1 With respect to regulatory sequences he said ... The consortium has assigned some sort of function to roughly 80% of the genome, including more than 70,000 ‘promoter’ regions — the sites, just upstream of genes, where proteins bind to control gene expression — and nearly 400,000 ‘enhancer’ regions that regulate expression of distant genes ... But the job is far from done, says [Ewan] Birney, a computational biologist at the European Molecular Biology Laboratory’s European Bioinformatics Institute in Hinxton, UK, who coordinated the data analysis for ENCODE. He says that some of the mapping efforts are about halfway to completion, and that deeper characterization of everything the genome is doing is probably only 10% finished.We knew back in 2012 that there were only about 25,000 genes so why are there 70,000 promoters? And if this is only 10% of the total then how can there be 700,000 promoters?Similarly, if there really are 400,000 enhancers (what ever they are) then that's 16 per gene. Throw in the unknown 90% that have yet to be discovered and you have 160 per gene. Really?The main ENCODE claim is that a substantial percentage of the genome is devoted to regulation ...… even using the most conservative estimates, the fraction of bases likely to be involved in direct regulation, even though incomplete, is significantly higher than that ascribed to protein codon exons (1.2%), raising the possibility that more information in the human genome may be important for gene regulation than for biochemical function. (ENCODE, 2012 p. 71)Their value for coding region is too high but let's parse what they mean based on the idea that regulatory sequences account for more than 1.2% of the genome. That works out to 38 Mb of DNA. If we take a generous estimate of 10 bp per regulatory site then there must be 3.8 million sites or 152 sites per gene. That makes no sense. If makes even less sense if Birney is right and this is only 10% of all functional sites. ENCODE never seriously considered the possibility that most of their sites have no function. We now know this was a serious error that tainted their conclusions. It's very common for papers to be retracted when the authors make mistakes that invalidate their conclusions. I'm sure we aren't going to see any retractions but it would be really nice if Nature (and Science) would at least publish an article admitting that they were duped by Ewan Birney and the other ENCODE researchers. 1. Brendan Maher published an online news article on the Nature website on Sept. 6, 2012. He acknowledges that many of us were highly critical of the ENCODE hype but he still defends the idea that much of the genome is functional (Fighting about ENCODE and junk). In that post, he claims that at least 20% of the genome could be devoted to regulation. ENCODE Project Consortium (2012) An integrated encycloped[...]



What's in Your Genome?: Chapter 5: Regulation and Control of Gene Expression

Sat, 03 Feb 2018 20:51:00 +0000

I'm working (slowly) on a book called What's in Your Genome?: 90% of your genome is junk! The first chapter is an introduction to genomes and DNA [What's in Your Genome? Chapter 1: Introducing Genomes ]. Chapter 2 is an overview of the human genome. It's a summary of known functional sequences and known junk DNA [What's in Your Genome? Chapter 2: The Big Picture]. Chapter 3 defines "genes" and describes protein-coding genes and alternative splicing [What's in Your Genome? Chapter 3: What Is a Gene?]. Chapter 4 is all about pervasive transcription and genes for functional noncoding RNAs [What's in Your Genome? Chapter 4: Pervasive Transcription].Chapter 5 is Regulation and Control of Gene Expression. Chapter 5: Regulation and Control of Gene ExpressionWhat do we know about regulatory sequences?The fundamental principles of regulation were worked out in the 1960s and 1970s by studying bacteria and bacteriophage. The initiation of transcription is controlled by activators and repressors that bind to DNA near the 5′ end of a gene. These transcription factors recognize relatively short sequences of DNA (6-10 bp) and their interactions have been well-characterized. Transcriptional regulation in eukaryotes is more complicated for two reasons. First, there are usually more transcription factors and more binding sites per gene. Second, access to binding sites depends of the state of chromatin. Nucleosomes forming high order structures create a "closed" domain where DNA binding sites are not accessible. In "open" domains the DNA is more accessible and transcription factors can bind. The transition between open and closed domains is an important addition to regulating gene expression in eukaryotes.The limitations of genomicsBy their very nature, genomics studies look at the big picture. Such studies can tell us a lot about how many transcription factors bind to DNA and how much of the genome is transcribed. They cannot tell you whether the data actually reflects function. For that, you have to take a more reductionist approach and dissect the roles of individual factors on individual genes. But working on single genes can be misleading ... you may miss the forest for the trees. Genomic studies have the opposite problem, they may see a forest where there are no trees. Regulation and evolutionMuch of what we see in evolution, especially when it comes to phenotypic differences between species, is due to differences in the regulation of shared genes. The idea dates back to the 1930s and the mechanisms were worked out mostly in the 1980s. It's the reason why all complex animals should have roughly the same number of genes—a prediction that was confirmed by sequencing the human genome. This is the field known as evo-devo or evolutionary developmental biology.            Box 5-1: Can complex evolution evolve by accident?Slightly harmful mutations can become fixed in a small population. This may cause a gene to be transcribed less frequently. Subsequent mutations that restore transcription may involve the binding of an additional factor to enhance transcription initiation. The result is more complex regulation that wasn't directly selected.Open and closed chromatin domainsGene expression in eukaryotes is regulated, in part, by changing the structure of chromatin. Genes in domains where nucleosomes are densely packed into compact structures are essentially i[...]



Sex isn't as beneficial as you might think

Thu, 01 Feb 2018 22:27:00 +0000

One of the most interesting topics in my molecular evolution class was the discussion over the importance of sex. Most students seem to think the problem is solved. They were taught that sex increases variation in a population and this gives sexual populations an evolutionary advantage. The fact that sex (recombination) breaks up as many linkages as it creates makes the explanation much less viable. The fact that there's very little evidence to support the claim comes as quite a surprise to my students. Sex is still one of the greatest mysterious in evolutionary biology [What did Joe Felsenstein say about sex?] [Everything you thought you knew about sex is probably wrong].It is worth noting that Maynard Smith's argument invalidates the earliest genetic argument for the evolution of recombination, that advanced by East (1918). That argument is also the one commonly found in textbooks, which tend to be a bit out of date (in this case, by over 50 years). East argued that recombination creates new genotypes. So it does. An AB/ab parent will have among its gametes not only the two types that formed it, AB and ab, but also Ab and aB if there is recombination between the two loci. But if the population is in linkage equilibrium, then somewhere else an Ab/aB parent will be undergoing recombination, which will remove Ab and aB gametes and replace them by AB and ab. These two processes will exactly cancel each other if the two types of double heterozygote, coupling (AB/ab) and repulsion (Ab/aB) are equally frequent. This will happen precisely when the population is in linkage equilibrium. In that case no new genotypes arise by recombination....We have that anomalous situation that a detailed population genetic analysis analysis reveals not only that the standard explanation for the evolution of recombination will not work, but also that there is a good evolutionary reason for believing that modifiers will be selected to eliminate recombination. [my emphasis LAM]                        Joe Felsenstein (1988)Richard Lenski decided to test the benefits of sex. He took the twelve cultures from the long-term evolution experiment and added sex to see if they would adapt faster (Maddamsetti and Lenski, 2018). Specifically, he added Escherichia coli strain K12 Hfr (high frequency recombination) to the cultures. This strain promotes conjugation and the exchange of genes.The results are described in the abstract.Maddamsetti, R., and Lenski, R. E. (2017) Analysis of bacterial genomes from an evolution experiment with horizontal gene transfer shows that recombination can sometimes overwhelm selection. PLOS Genetics, January 31, 2018. [doi: 10.1371/journal.pgen.1007199]AbstractFew experimental studies have examined the role that sexual recombination plays in bacterial evolution, including the effects of horizontal gene transfer on genome structure. To address this limitation, we analyzed genomes from an experiment in which Escherichia coli K-12 Hfr (high frequency recombination) donors were periodically introduced into 12 evolving populations of E. coli B and allowed to conjugate repeatedly over the course of 1000 generations. Previous analyses of the evolved strains from this experiment showed that recombination did not accelerate adaptation, despite increasing genetic variation re[...]