Junk DNA

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Susumu Ohno is usually credited for coining the term “junk DNA” for segments of DNA that have no known biological function; specifically he was referring to pseudogenes. However, Dan Graur did a bit of detective work[1] and found out that the idea of "junk" DNA had been around before Ohno's article[2]. The bottom line is that:

“The term ‘junk DNA’ became popular in the 1960s (e.g., Ehret and de Haller 1963). It was formalized by Susumu Ohno in 1972.”

Non-coding DNA

Non-coding DNA sequences are components of an organism's DNA that do not encode protein sequences.

http://en.wikipedia.org/wiki/Noncoding_DNA

http://en.wikipedia.org/wiki/C-value_enigma

Related to TFBS

The Majority of Primate-Specific Regulatory Sequences Are Derived from Transposable Elements - http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003504

Exaptation of Transposable Elements into Novel Cis-Regulatory Elements: Is the Evidence Always Strong? - http://mbe.oxfordjournals.org/content/30/6/1239

Evolution of the mammalian transcription factor binding repertoire via transposable elements - http://genome.cshlp.org/content/early/2008/10/03/gr.080663.108

Transposable elements and the evolution of regulatory networks - http://www.nature.com/nrg/journal/v9/n5/full/nrg2337.html

Popular media

On Howard Chang's research: http://www.nytimes.com/2016/01/22/science/telling-jewels-from-junk-in-dna.html (and related to Xist http://www.nytimes.com/2014/01/21/science/seeing-x-chromosomes-in-a-new-light.html)

Below are notes from http://www.nytimes.com/2015/03/08/magazine/is-most-of-our-dna-garbage.html

  • Gregory believes that while some noncoding DNA is essential, most probably does nothing for us at all, and until recently, most biologists agreed with him.
  • Instead, he champions an idea first developed in the 1970s but still startling today: that the size of an animal’s or plant’s genome has essentially no relationship to its complexity, because a vast majority of its DNA is — to put it bluntly — junk.
  • Gould and Lewontin did not deny that natural selection was a powerful force, but they stressed that it was not the only explanation for why species are the way they are. Male nipples are not adaptations, for example; they’re just along for the ride.
  • Gould and Lewontin called instead for a broader vision of evolution, with room for other forces, for flukes and historical contingencies, for processes unfolding at different levels of life — what Gould often called “pluralism.”
  • Any two people may have millions of differences in their genomes. Most of those differences aren’t a result of natural selection’s guiding force; they just arise through random mutations, without any effect for good or ill.
  • The Human Genome Project team declared that our DNA consisted of isolated oases of protein-coding genes surrounded by “vast expanses of unpopulated desert where only noncoding ‘junk’ DNA can be found.” Junk DNA had started out as a theoretical argument, but now the messiness of our evolution was laid bare for all to see.
  • Rinn ran a series of experiments on skin cells to figure out what, if anything, hotair was doing. He carefully pulled hotair molecules out of the cells and examined them to see if they had attached to any other molecules. They had, in fact: they were stuck to a protein called Polycomb.
  • Polycomb belongs to a group of proteins that are essential to the development of animals from a fertilized egg. They turn genes on and off in different patterns, so that a uniform clump of cells can give rise to bone, muscle and brain. Polycomb latches onto a number of genes and muzzles them, preventing them from making proteins. Rinn’s research revealed that hotair acts as a kind of guide for Polycomb, attaching to it and escorting it through the jungle of the cell to the precise spots on our DNA where it needs to silence genes.
  • Rinn’s research revealed that hotair acts as a kind of guide for Polycomb, attaching to it and escorting it through the jungle of the cell to the precise spots on our DNA where it needs to silence genes.
  • They bred engineered mice that lack the hotair gene, for example, and found that the mice developed a constellation of deformities, like stunted wrists and jumbled vertebrae.
  • The experiments that Rinn’s team has run on firre suggest that it performs a spectacular lasso act, grabbing onto three different chromosomes at once and drawing them together. Rinn suspects that there are thousands of RNA molecules encoded in our genomes that perform similar feats: bending DNA, unspooling it, bringing it in contact with certain proteins and otherwise endowing it with a versatility it would lack on its own.
  • Gregory likens the search for useful pieces of noncoding DNA to using a metal detector to find gold buried at the beach. “The idea of combing the beach is a great idea,” he says. But you have to make sure your metal detector doesn’t go off when it responds to any metal. “You’re going to find bottle caps and nails,” Gregory says.
  • Scientists at the University of Oxford have measured evolutionary change over the past 100 million years at every spot in the human genome. “I can today say, hand on my heart, that 8 percent, plus or minus 1 percent, is what I would consider functional,” Chris Ponting, an author of the study, says. And the other 92 percent? “It doesn’t seem to matter that much,” he says.
  • He was frustrated to see how many of his readers thought he was arguing that natural selection was the only force behind life’s diversity. “Great is the power of steady misrepresentation,” Darwin grumbled when he updated the book for its sixth edition in 1872.
  • To subtract junk, meanwhile, would require swarms of proteins to chop out every single dead gene or transposable element — without chopping out an essential gene. A genome evolving away its junk would lose the race to sloppier genomes, which left more resources for fighting diseases or having children.

Blog posts

Stephen Jay Gould and Sydney Brenner Agree on Junk DNA: http://sandwalk.blogspot.jp/2012/09/stephan-jay-gould-and-sydney-brenner.html (The difference between "junk DNA", which can't be explained by any adaptive mechanism, and "selfish DNA," which isn't junk and has a Darwinian explanation.)

Junk DNA gets Wired: http://www.genomicron.evolverzone.com/2007/06/junk-dna-gets-wired/ (We don't have junk DNA because some day it will prove to be useful. Sure enough some of these junk get coopted but that's not the reason why we have them in our genomes.)

Discussions at the Human Genetic Information: Science, Law and Ethics conference in 1989: http://www.genomicron.evolverzone.com/2014/12/quotes-of-interest-brenner-1990-and-discussion/ (Brenner argues that most of the human genome is junk because of we must have an upper limit to the number of functional elements due to the rate of mutation. In addition, he does not dismiss that all junk DNA is non-functional.)

Genomic Junk And Transcriptional Noise: http://www.science20.com/adaptive_complexity/genomic_junk_and_transcriptional_noise (We should expect random transcription, i.e. non-specific transcription, as a large pool of RNA polymerase are available and unbound.)

Calculation of genetic load http://judgestarling.tumblr.com/post/106833397831/if-encode-nih-is-right-each-of-us-should-have

Functional RNAs? Transcription factors and RNA polymerase can bind at many sites in the genome that have nothing to do with transcription of a normal gene. http://sandwalk.blogspot.jp/2015/01/functional-rnas.html

A collection of posts on Sandwalk that are related to genomes and junk DNA: http://sandwalk.blogspot.jp/2008/02/theme-genomes-junk-dna.html

Calculating the percentage of junk in the genome, assuming that the majority of the intronic sequence is junk, only exonic sequences are functional, and regulatory regions for a gene is roughly ~1,000 long: http://sandwalk.blogspot.jp/2008/02/junk-in-your-genome-protein-encoding.html

We have junk DNA because we can't get rid of it and junk DNA isn't transcribed because it might be useful but because RNA polymerase and TFs just happen to transcribed them: http://sandwalk.blogspot.jp/2014/09/are-lncrnas-really-mrnas-in-waiting.html

We can tolerate an estimated number of 130 mutations each generation because of synonymous mutations and the fact that most of our genome is non-functional: http://sandwalk.blogspot.de/2009/11/genetic-load-neutral-theory-and-junk.html

Arguments in favour of junk DNA: genetic load (see above), C-Value paradox, modern evolutionary theory, pseudogenes and broken genes are junk, and most of the genome is not conserved: http://sandwalk.blogspot.ca/2013/07/five-things-you-should-know-if-you-want.html

Discussion between Georgi and Larry on the goals of ENCODE and on TF binding: http://sandwalk.blogspot.co.uk/2013/09/dark-matter-is-real-not-just-noise-or.html

DNA Binding Proteins http://sandwalk.blogspot.jp/2008/09/dna-binding-proteins.html (The point is that even for a highly specific DNA binding protein like lac repressor, most of the protein is bound to other sites most of the time. This can also be true for RNA polymerases, thus creating a lot of spurious transcripts.)

How RNA Polymerase Binds to DNA http://sandwalk.blogspot.ca/2008/09/how-rna-polymerase-binds-to-dna.html (This post is a continuation of the post above. Unlike the lac repressor, the core polymerase binds DNA non-specifically since it needs to bind to various promoters. Since the holoenzyme molecules are capable of initiating transcription on their own, a small number of the non-specifically bound molecules will accidentally transcribe short stretches of DNA.)

http://www.genomicron.evolverzone.com/2008/02/junk-dna-quotes-of-interest-series/

Flesh-Eating Plant Cleaned Junk From Its Minimalist Genome by Ed Yong http://phenomena.nationalgeographic.com/2013/05/12/flesh-eating-plant-cleaned-junk-minimalist-genome/ (The bladderwort has 82 million letters in its genome. By sequencing the bladderwort genome, Enrique Ibarra-Laclette from the CINESTAV institute in Mexico City has shown that it’s largely junk-free. Repetitive stretches of DNA make up just 3 percent of its genome, compared to 10 and 60 percent in most other plants. See http://www.nature.com/nature/journal/v498/n7452/full/nature12132.html)

The case for junk DNA by Carl Zimmer http://phenomena.nationalgeographic.com/2014/05/09/the-case-for-junk-dna/

http://www.michaeleisen.org/blog/?p=1167 and http://www.genomicron.evolverzone.com/2012/09/michael-eisens-take-on-encode-theres-no-junk/

http://selab.janelia.org/people/eddys/blog/?p=683

http://thefinchandpea.com/2012/09/06/encode-media-fail/

http://genomeinformatician.blogspot.jp/2012/09/encode-my-own-thoughts.html (I really hate the phrase “biological noise” in this context. I would argue that “biologically neutral” is the better term, expressing that there are totally reproducible, cell-type-specific biochemical events that natural selection does not care about.)

http://thefinchandpea.com/2013/07/17/using-a-null-hypothesis-to-find-function-in-the-genome/ and http://thefinchandpea.com/2013/07/18/finding-function-in-the-genome-part-2-all-function-is-local-almost/

http://aeon.co/magazine/science/does-our-genetic-heritage-lie-under-a-pile-of-junk-dna/

In favour of widespread functionality

Pervasive transcription of the eukaryotic genome: functional indices and conceptual implications http://www.ncbi.nlm.nih.gov/pubmed/19770204

The extent of functionality in the human genome - http://www.thehugojournal.com/content/7/1/2

In favour of partial functionality

Functionality or transcriptional noise? Evidence for selection within long noncoding RNAs - http://www.ncbi.nlm.nih.gov/pubmed/17387145

Signatures of adaptive evolution within human non-coding sequence - http://www.ncbi.nlm.nih.gov/pubmed/16987880

8.2% of the Human Genome Is Constrained: Variation in Rates of Turnover across Functional Element Classes in the Human Lineage - http://www.ncbi.nlm.nih.gov/pubmed/25057982

Signatures of adaptive evolution within human non-coding sequence - http://www.ncbi.nlm.nih.gov/pubmed/16987880

On the turnover rate of noncoding DNA

What fraction of the human genome is functional? - http://www.ncbi.nlm.nih.gov/pubmed/21875934

Rapid Turnover of Long Noncoding RNAs and the Evolution of Gene Expression - http://www.ncbi.nlm.nih.gov/pubmed/22844254

Massive turnover of functional sequence in human and other mammalian genomes - http://www.ncbi.nlm.nih.gov/pubmed/20693480

Evidence for turnover of functional noncoding DNA in mammalian genome evolution - http://www.ncbi.nlm.nih.gov/pubmed/15475259

Rapid Turnover of Functional Sequence in Human and Other Genomes - http://www.ncbi.nlm.nih.gov/pubmed/21721940

Editorials

Existence of RNA 'dark matter' in doubt - http://www.nature.com/news/2010/100518/full/news.2010.248.html and Genomics: Not-so-dark genome - http://www.nature.com/nature/journal/v465/n7297/full/465401a.html (Editorials on the "Most 'Dark Matter' Transcripts Are Associated With Known Genes" paper. It discusses how the authors performed tiling array and RNA-Seq experiments on the same tissues and found that the arrays had much more noise, whereas the RNA-Seq transcripts were all associated to known genes. Kapanov commented that he had contrasting results with his RNA-Seq experiments.)

Dark matter transcripts: sound and fury, signifying nothing? - http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1000370 (A synopsis of http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.1000371)

On functionality

Defining functional DNA elements in the human genome - http://www.ncbi.nlm.nih.gov/pubmed/24753594 (Discusses the discrepancy between genetic, molecular, and evolutionary approaches, and how biochemical assays are the most useful approach for estimating the functional portion of the genome.)

Conceptual and empirical challenges of ascribing functions to transposable elements - http://www.ncbi.nlm.nih.gov/pubmed/24921597

Journal articles

Selfish genes, the phenotype paradigm and genome evolution - http://www.ncbi.nlm.nih.gov/pubmed/6245369

Selfish DNA: the ultimate parasite - http://www.ncbi.nlm.nih.gov/pubmed/7366731

Transcribed dark matter: meaning or myth? - http://www.ncbi.nlm.nih.gov/pubmed/20798109

Can ENCODE tell us how much junk DNA we carry in our genome? http://www.ncbi.nlm.nih.gov/pubmed/23268340

The ENCODE project: Missteps overshadowing a success - http://www.ncbi.nlm.nih.gov/pubmed/23578867

The C-value paradox, junk DNA, and ENCODE http://www.ncbi.nlm.nih.gov/pubmed/23137679

The Case for Junk DNA - http://www.ncbi.nlm.nih.gov/pubmed/24809441

The evolution of gene regulation, the RNA universe, and the vexed questions of artefact and noise. - http://www.ncbi.nlm.nih.gov/pubmed/20653929 (Are regulatory RNAs or the combinatorics of proteins the drivers of complexity?)

Pervasive transcription

Pervasive transcription refers to the observation that a large percentage of mammalian genomes are transcribed. However, is the observation simply that of RNA Pol II randomly colliding with chromatin thus forming biological noise? Or is the transcription observed in a regulated manner? Transcription factors will also bind to random sequence of DNA, when a random piece of DNA just happens by chance to have a sequence that resembles the transcription factor binding site.

However, uncontrolled transcription needs to be contained as this would be wasteful and may interrupt other cellular processes. One role of chromatin is to prevent RNA polymerase from being able to access DNA, since the amount of information required to initiate transcription is quite low. In addition, inappropriately transcribed DNA are rapidly eliminated by degradation.

We applied RNA-Seq to generate a high-resolution transcriptome map of the yeast genome and demonstrated that most (74.5%) of the nonrepetitive sequence of the yeast genome is transcribed.

Experiments in S. cerevisiae, showed that mutating two chromatin remodelling factors, Spt6p and Spt16p, provoked spurious intragenic transcription from cryptic promoters within gene bodies.

The absence of Rrp6p, a nuclear-specific catalytic subunit of the S. cerevisiae 3'-5' exoribonucleolyatic and endoribonucleolytic RNA exosome, exposed a layer of "hidden transcription" that generates so-called "cryptic unstable transcripts" (CUTs), which are normally not allowed to accumulate to detectable levels in wild-type cells. Pervasive transcripts less sensitive to Rrp6p activity were termed "stable unannotated transcripts" (SUTs). Loss of another ribonuclease, the cytoplasmic 5'-3' exoribonuclease Xrn1p, revealed another case called "Xrn1-sensitive unstable transcripts" (XUTs).

CUTs, SUTs, and XUTs are all transcribed by RNAPII; CUTs and SUTs almost exclusively originate from nucleosome-depleted regions (NDRs) at the 5' and 3' ends of genes.

Related blog post on this paper http://sandwalk.blogspot.jp/2010/05/junk-rna-or-imaginary-rna.html

http://sandwalk.blogspot.jp/2013/08/the-junk-dna-controversy-john-mattick.html

http://thefinchandpea.com/2013/07/31/10654/

References