Science Friday: A Molecular Biology & Evolution Sampler

Posted on by

My favorite subject-specific journal is Molecular Biology and Evolution (MBE).  This journal publishes on topics primarily related to molecular evolution and evolutionary genomics, which are among my favorite subjects in biology. I’m happy to report that the latest issue of MBE is out today, and there are lots of great articles that I think will be of interest to folks here, many of which are open-access.

I sadly don’t have time to write up any of these articles, but I thought it might be useful to “sample” a few in case any any of you would like to read and discuss them.  Here are a handful that seem particularly interesting:

Population Structure Shapes Copy Number Variation in Malaria Parasites (open-access)

Abstract:

If copy number variants (CNVs) are predominantly deleterious, we would expect them to be more efficiently purged from populations with a large effective population size (Ne) than from populations with a small Ne. Malaria parasites (Plasmodium falciparum) provide an excellent organism to examine this prediction, because this protozoan shows a broad spectrum of population structures within a single species, with large, stable, outbred populations in Africa, small unstable inbred populations in South America and with intermediate population characteristics in South East Asia. We characterized 122 single-clone parasites, without prior laboratory culture, from malaria-infected patients in seven countries in Africa, South East Asia and South America using a high-density single-nucleotide polymorphism/CNV microarray. We scored 134 high-confidence CNVs across the parasite exome, including 33 deletions and 102 amplifications, which ranged in size from <500 bp to 59 kb, as well as 10,107 flanking, biallelic single-nucleotide polymorphisms. Overall, CNVs were rare, small, and skewed toward low frequency variants, consistent with the deleterious model. Relative to African and South East Asian populations, CNVs were significantly more common in South America, showed significantly less skew in allele frequencies, and were significantly larger. On this background of low frequency CNV, we also identified several high-frequency CNVs under putative positive selection using an FST outlier analysis. These included known adaptive CNVs containing rh2b and pfmdr1, and several other CNVs (e.g., DNA helicase and three conserved proteins) that require further investigation. Our data are consistent with a significant impact of genetic structure on CNV burden in an important human pathogen.

No Accumulation of Transposable Elements in Asexual Arthropods (open-access)

Abstract:

Transposable elements (TEs) and other repetitive DNA can accumulate in the absence of recombination, a process contributing to the degeneration of Y-chromosomes and other nonrecombining genome portions. A similar accumulation of repetitive DNA is expected for asexually reproducing species, given their entire genome is effectively nonrecombining. We tested this expectation by comparing the whole-genome TE loads of five asexual arthropod lineages and their sexual relatives, including asexual and sexual lineages of crustaceans (Daphnia water fleas), insects (Leptopilina wasps), and mites (Oribatida). Surprisingly, there was no evidence for increased TE load in genomes of asexual as compared to sexual lineages, neither for all classes of repetitive elements combined nor for specific TE families. Our study therefore suggests that nonrecombining genomes do not accumulate TEs like nonrecombining genomic regions of sexual lineages. Even if a slight but undetected increase of TEs were caused by asexual reproduction, it appears to be negligible compared to variance between species caused by processes unrelated to reproductive mode. It remains to be determined if molecular mechanisms underlying genome regulation in asexuals hamper TE activity. Alternatively, the differences in TE dynamics between nonrecombining genomes in asexual lineages versus nonrecombining genome portions in sexual species might stem from selection for benign TEs in asexual lineages because of the lack of genetic conflict between TEs and their hosts and/or because asexual lineages may only arise from sexual ancestors with particularly low TE loads.

 

Evolution of Prdm Genes in Animals: Insights from Comparative Genomics (open-access)

Abstract:

Prdm genes encode transcription factors with a subtype of SET domain known as the PRDF1-RIZ (PR) homology domain and a variable number of zinc finger motifs. These genes are involved in a wide variety of functions during animal development. As most Prdm genes have been studied in vertebrates, especially in mice, little is known about the evolution of this gene family. We searched for Prdm genes in the fully sequenced genomes of 93 different species representative of all the main metazoan lineages. A total of 976 Prdm genes were identified in these species. The number of Prdm genes per species ranges from 2 to 19. To better understand how the Prdm gene family has evolved in metazoans, we performed phylogenetic analyses using this large set of identified Prdm genes. These analyses allowed us to define 14 different subfamilies of Prdm genes and to establish, through ancestral state reconstruction, that 11 of them are ancestral to bilaterian animals. Three additional subfamilies were acquired during early vertebrate evolution (Prdm5, Prdm11, and Prdm17). Several gene duplication and gene loss events were identified and mapped onto the metazoan phylogenetic tree. By studying a large number of nonmetazoan genomes, we confirmed that Prdm genes likely constitute a metazoan-specific gene family. Our data also suggest that Prdm genes originated before the diversification of animals through the association of a single ancestral SET domain encoding gene with one or several zinc finger encoding genes.

This next one is on a topic that comes up here from time to time, and I think it will be of interest to many of you.  Sadly, it’s paywalled, but if you don’t have access through a university library, feel free to send me a pm.

Are Human Translated Pseudogenes Functional?

Abstract:

By definition, pseudogenes are relics of former genes that no longer possess biological functions. Operationally, they are identified based on disruptions of open reading frames (ORFs) or presumed losses of promoter activities. Intriguingly, a recent human proteomic study reported peptides encoded by 107 pseudogenes. These peptides may play currently unrecognized physiological roles. Alternatively, they may have resulted from accidental translations of pseudogene transcripts and possess no function. Comparing between human and macaque orthologs, we show that the nonsynonymous to synonymous substitution rate ratio (ω) is significantly smaller for translated pseudogenes than other pseudogenes. In particular, five of 34 translated pseudogenes amenable to evolutionary analysis have ω values significantly lower than 1, indicative of the action of purifying selection. This and other findings demonstrate that some but not all translated pseudogenes have selected functions at the protein level. Hence, neither ORF disruption nor presence of protein product disproves or proves gene functionality at the protein level.

There are a lot of other interesting papers in this issue, but for the sake of brevity, I’ll stop here.  Happy reading!

205 thoughts on “Science Friday: A Molecular Biology & Evolution Sampler”

  1. stcordova: Why would anyone expect we would deploy histones and DNA the same way onions do?

    Because half a century of genetics says we do. DNA stores genetic information, in the form of regulatory sequence and protein coding genes. It is packed up to take less space in the cell nucleus by winding around histone proteins. This is true for all Eukaryotes.

    Regardless, why would one species of onion (Whatever you think onions do with their histones) need five times more than another, highly similar species of onion?

    Why would the puffer fish get by basically without junk DNA? Why would spiny pufferfish need a genome twice the size of smooth pufferfish?

    Genome size evolution in pufferfish: an insight from BAC clone-based Diodon holocanthus genome sequencing

    Another striking characteristic of the genome size is that it can vary greatly among different taxonomic categories and even among closely related species. Genome size varies 250-fold in arthropods, 350-fold in fish, 1,000-fold in angiosperms, 5,000-fold in algae, and 5,800-fold in protozoans, and more than 200,000-fold in eukaryotes as reviewed by Gregory [5]. Genome size variation among closely related species is also prevalent and significant. For example, the fly genus Drosophila displays a twofold variation in genome size [6], whereas variation of genome size can achieve ninefold in a plant genus Crepsis [7].

    Genome size variation appears to have resulted from a number of different processes over evolution time. In the short run, genome doubling or large-scale sequence duplication might be one of the most straightforward mechanisms underlying genome size variation [1, 8]. The gain and loss of non-coding DNA are considered to be the main force behind the gradual accumulation of genome size variation over evolution time. For example, the correlation between genome size and transposable element amplification [9, 10], and intron size variation [11–14], and gene duplication and pseudogenization [15] have been widely studied and verified across a broad phylogenetic range. Study has revealed that a massive loss of ancestral protein-coding genes has contributed to the reduction in the size of the chicken genome [16]. Overall, genome size variation is now recognized as reflecting the net effects of a collection of mechanisms that sometimes work antagonistically to expand and contract the genome, and is the result of that many forces affect collectively and operate heterogeneously among genomic regions [17, 18].

    Notice how nobody ever makes the useless inference you want to saddle them with “Oh gee we have no idea how this shit works, that must mean it’s junk because, you know, evilusion hurr durr”.

  2. stcordova: No you don’t understand. Fewer histones means fewer histones available for regulation.

    The histones have cell-type, tissue specific, developmental stage histone states which means different regulatory profiles per cell.

    Which would be true regardless of genome size.

    No, YOU don’t understand.

  3. stcordova,

    If one assumes evolution, then the inference that the Alu’s are junk seems to follow quite well from that assumption. If however we find widespread function in existing Alu’s and then find damage from newly inserted Alu’s this would be a paradox

    That would be no more a paradox than finding widespread ‘functional mutations’, yet finding that new mutations are generally damaging. Which I know Creationists find paradoxical, but it isn’t.

  4. Mung,

    Onions don’t tell us squat about the human genome.

    At what point did that become the sole focus of the debate?

    But one could say the same about Arabidposis, Saccharomyces, Mus, C. elegans, Drosophila and all other model organisms. All we ever learnt about the human genome was gained by sticking people in a mincer – science’s dirty secret. We had no choice; they aren’t related to anything else.

  5. The genome size variations between the Asian and African lion is:
    http://www.genomesize.com/results.php?page=1
    Panthera leo African lion C-value: 2.95
    Panthera leo persica Asian lion C-value: 3.83

    That’s just a handpicked example of two extremely similar species of mammals with a large difference in genome size (roughly one billion base-pairs). Go through the list, explain all of them.

    Prediction: You can’t.

    Unless you infer it’s random variations in junk due to fluctuations in genome size by transposable elements, deletion and duplication mutations and pseudogenization over evolutionary time. Simply put the junk-hypothesis has the greatest explanatory power because it explains all the evidence. The alternative would be that you’d have to hand-craft an ad-hoc hypothesis for every genome in every single species on the planet, which would be absurd. Why would you do this? What could possibly motivate a desire to claim that every individual species has some unique biochemical processes operating inside them that explains their huge variations in genome size, other than some a priori commitment to “perfect creations” and rejection of the idea of accumulation of mutations and changing transpositional activity over time? You are all conclusion first, ad-hoc reasoning second.

  6. The Orangutan genome looks to be a bit bigger than the Human genome. Do Orangutans remember better? Maybe they do.

  8. Rumraket,

    This bastard has three times the genome size of humans

    From the photo, it’s clearly front-loaded for evolving into a kiwi. That extra capacity does not come for free.

  9. Which would be true regardless of genome size.

    No, YOU don’t understand.

    False. There needs to be a place where information of different cells is stored so that we have different expression levels of proteins, alternative splices, and who knows what else in terms of being able to differentiate 100 trillion adult cells from each other. Even differentiating 100 billion brain cells and 100 trillion connections and keeping them centrally organized requires an accounting mechanism and memory storage to manage it all, and I provided at least a few place in the DNA that can help provide the necessary memory storage to do the job.

    I just provided evidence of where some of that information is stored, provided even data from evolutionary biologists regarding transposable elements, and all you can do is nay-say and insist we KNOW it’s junk.

    Ok, believe what you want, but don’t pretend it’s actually based on experiments like the experiments which provided the cytosine graphs here in the non-coding regions:

    Science Friday: A Molecular Biology & Evolution Sampler

    or the data on the histones located in supposed junk of transposable elements here:

    Science Friday: A Molecular Biology & Evolution Sampler

    Or the data on how human memories recruit histone memory, etc.

    All you have is your argument from ignorance, “gee, we don’t know how onions can use so much DNA in a different way, so human DNA must be junk.” That’s a pretty lame argument, imho. It does compare with the abundant data points I provided that may hint otherwise.

    Such a nay-saying attitude is bad for medical science, that’s why the NIH and medical community chose to commit at least half a billion dollar studying what you call junk and just basically turn its back on such arguments from willful ignorance and nay-saying. Patients suffering heritable diseases of defects in non-coding DNA shouldn’t be impressed with the nay-saying, argument-from-ignorance, onions-have-too-much DNA arguments.

  11. Well, damn, Sal, if it causes disease, it’s functional. Now the question is, what percentage of the human genome has function.

  12. Now the question is, what percentage of the human genome has function.

    No one knows for sure, but Rumraket insists he knows because the onion genome size is sooo big, therefore most human DNA must be junk. I’d say that’s a bit premature and also a bit of a non-sequitur given the last common ancestor of an onion and a human was some ????missing link???…..

  13. stcordova: No one knows for sure, but Rumraket insists he knows because the onion genome size is sooo big,

    That’s a fucking lie, Sal.

  14. Sal,
    Thanks for the link that fascinating Nature paper on methylation patterns during development. The concluding paragraph of the main body of the text seems worth quoting in full (with my emphasis):

    Furthermore, we explored how DNA methylation contributes to the repression of transposable elements. We found that the expression levels of SINE/variable number of tandem repeats/Alu elements (SVAs) increased sharply from the 4-cell stage to morula stage (Extended Data Fig. 10a). This indicates that after the genome-wide demethylation of transposable elements at the 2-cell stage, the transcriptional activities of SVAs increase markedly for a short period but decrease back to the basal level before the genome-wide re-methylation, probably due to repression mechanisms other than DNA methylation (Extended Data Fig. 10b). SINEs, LINEs and long terminal repeats retained relatively abundant transcripts before the 8-cell stage, following which their transcripts gradually decreased to the basal level in post-implantation embryos (Fig. 4a, b and Extended Data Fig. 10c). Moreover, we found that SINEs and LINEs with different evolutionary ages show different demethylation patterns (Fig. 4a–d and Extended Data Fig. 10d–f). For example, both LINE-1 (L1) and LINE-2 (L2) belong to the LINE family of transposable elements, with L1 being evolutionarily younger than L2 (ref. 25). The younger L1 shows a higher methylation level than L2 in oocytes, whereas they show a comparable level of methylation in sperm. More importantly, we found that during the genome-wide demethylation process, the evolutionarily younger L1 retains higher levels of residual methylation than L2. L1 was also re-methylated to a higher methylation level after implantation (Fig. 4d). This pattern persists when further subdividing L1 into sub-groups, such as L1PA and L1ME with different evolutionary ages (Fig. 4e and Extended Data Fig. 10e, f). Similar patterns were also found for Alu elements and mammalian-wide interspersed repeats (MIR), two subfamilies of SINEs with younger and older evolutionary ages, respectively (Fig. 4a, b). This indicates that the evolutionarily young transposable elements with higher transcriptional activity tend not to be demethylated to the same extent as older elements and also retain higher levels of remnant methylation, probably to maintain stronger repression of their transcription and activity by DNA methylation (Extended Data Fig. 10).

  15. Rumraket:

    1. knowing the actual sequence and being able to see that it is mostly dead transposable elements,

    Clearly? Just in 2011 I provided a paper that showed the histone regulatory influence seated right there on transposable elements — which forced the researchers to change their evolutionary story to some sort of exaptation (but then they didn’t even use that word).

    I provided data on Line-1 transposable elements enabling somatic cell neuron DNA to have slight variation apparently necessary so that those 100 trillion connections in our brain can route signals of our memory.

    Yet, you are so sure transposable elements are dead. Just because transposable elements may not transpose in the germline doesn’t mean they are dead. The have been experimentally shown to transpose in the somatic lines and by doing so provide important function to brain development of a cellular network as complex as the global internet.

    I provided evidence of regulatory roles of the histones that build a home on transposable elements in order to regulate coding regions — but you just keep saying they are dead. That’s an argument from ignorance — that is ignorance due to unwillingness to look at contrary data, that’s not an argument from experimental and direct observational data which I’ve pointed to.

    You want to believe LINE-1’s transposable elements are junk, that’s up to you, but you’ll have to continue to keep ignoring what is popping up in the labs. If that is your attitude, how can you claim you are being pro-science. To me that smacks of being pro close-your-eyes-to-experiment-and-direct-observation. Such an attitude looks pretty anti-science to me.

  16. Sal,
    Thanks for the link that fascinating Nature paper on methylation patterns during development. The concluding paragraph of the main body of the text seems worth quoting in full (with my emphasis):

    You’re welcome. I have far less problem with the evolutionary interpretation that you bolded than one that insists the DNA doesn’t have functional role.

    I know you are somewhat non-committal on the junk DNA issue, but lots of the evolutionists at the NIH don’t view evolutionary theory as necessarily in conflict with high levels of function in the genome.

    I suspect you have some ideas about how those methylation patterns have evolutionary significance, and I actually don’t have a problem with that since I think the interspecies patterns tell us something about expected methylation levels just by interspecies genome comparisons. That is actually medically valuable data!

  18. stcordova: False.There needs tobe a place where information of different cells is stored so that we have different expression levels of proteins, alternative splices, and who knows what else in terms of being able to differentiate 100 trillion adult cells from each other.

    Why the fuck do you think every one of those 100 trillion adult cells need to be differentiable from each other? They don’t. The skin on your butt works just as well if transferred to a burn on your face or your chest. There are cell-types and hundreds of them, but it isn’t subidivisible into 100 trillion different tissues.

    If you want to know how cells differentiate, look at what we already know about regulation. You don’t need three gigabases of regulatory elements for that and we know that because we know of plenty of species with similar levels of complexity and tissues with one tenth the amount of DNA we have.

    There are roughle 20.000 known protein coding genes, another roughly 10.000 known RNA’s and then there are regulatory sequences associated with all of these. How many combinations can you make with 30.000 “genes” and their assoicated regulatory sequences? Much much more than 30.000.

    I just provided evidence of where some of that information is stored, provided even data from evolutionary biologists regarding transposable elements, and all you can do is nay-say and insist we KNOW it’s junk.

    Nobody is nay-saying anything. It is entirely possible to me that there’s some kind of histone-related DNA accessing mechanism that serves as a kind of memory. But there’s a difference between saying such a mechanism might exist and saying that mechanism is in effect over the entire fucking genome.

    Ok, believe what you want,

    This isn’t about what I want to believe. Why the fuck would anyone WANT to believe in junk DNA? I couldn’t give any less of a fuck. I already believe there are thousands of species with very little to NO junk-DNA, such as the pufferfish, all the prokaryotes and others, and I believe evolution explain them too.

    but don’t pretend it’s actually based on experiments like the experiments which provided the cytosine graphs here in the non-coding regions:

    http://theskepticalzone.com/wp/science-friday-a-molecular-biology-evolution-sampler/comment-page-3/#comment-113534

    or the data on the histones located in supposed junk of transposable elements here:
    http://theskepticalzone.com/wp/science-friday-a-molecular-biology-evolution-sampler/comment-page-3/#comment-113529

    Oh for fucks sake Sal, even the junk regions need to be wrapped up in histones to conserve space. That’s why you find histones targeting junk regions and histone markers in the junk. That doesn’t make it functional (or RAM), it just make it wrapped up like all the other DNA.

    Or the data on how human memories recruit histone memory, etc.

    And then we bring the onion test and your entire line of ad-hoc reasoning goes out the window. Large genome size variations even between mammals runs a freight-train through the idea that the entire genome is the size it is because of some obscure histone-related mechanism of memory.

    All you have is your argument from ignorance, “gee, we don’t know how onions can use so much DNA in a different way, so human DNA must be junk.”

    Why make it just about human? Are you going to invent a 35 million ad-hoc hypotheses, one for every single species on the planet, to explain why their genomes vary so much in size?

    See, the problem isn’t that we can’t explain why Onions have “so much DNA” – therefore junk. Rather the problem for you is that junk actually DOES explain the genome size variations and that no other competing hypothesis does. So now you have to come up with 35 million ones so you can explain the genome sizes for all these species, and why they vary so much even between closely related ones.

    The two water fleas I showed pictures of, why does one need 10 times the DNA of the other? Does it have an additional 50 trillion differentiation stages it needs to control? Sounds unlikely to me.

    That’s a pretty lame argument, imho.It does compare with the abundant data points I provided that may hint otherwise.

    But you have provided NO data that hints otherwise. All you have provided is hints that a mechanism exists but nothing that says the entire genome serves as some kind of memory. Again, the entire genome will unavoidably be wrapped in histones and that unavoidably produces local histone-mediated methylation and so on.

    Such a nay-saying attitude is bad for medical science, that’s why the NIH and medical community chose to commit at least half a billion dollar studying what you call junk and just basically turn its back on such arguments from willful ignorance and nay-saying.

    Yes yes bla bla bla you’ve invented this caricature now several times. It was false to begin with, it is still false now.

    Patients suffering heritable diseases of defects in non-coding DNA shouldn’t be impressed with the nay-saying, argument-from-ignorance, onions-have-too-much DNA arguments.

    Why are you suddenly blathering about non-coding DNA? Everybody with more than 2 braincells and a biochemistry textbook knows non-coding DNA isn’t junk merely because it’s non-coding. There’s plenty of functional but non-coding DNA.

    Hey Sal, isn’t weird how the papers you’ve been citing are by evolutionary biologists, molecular biologists and biochemists trying to work out how the genome works? Where ARE all these strawmen biologists you keep hinting at who say studying how the genome works, isn’t worth doing because it’s mostly junk?

  19. stcordova: The have been experimentally shown to transpose in the somatic line

    How many of them? Prove it! And then prove that the transpositional activity is part of an important organismal function.

  20. petrushka: Well, damn, Sal, if it causes disease, it’s functional.

    Even this doesn’t follow. It is possible that a mutation in a junk-region can produce a transcript that interferes with normal cellular function. Does that make the junk functional?

  21. stcordova,

    Yet, you are so sure transposable elements are dead. Just because transposable elements may not transpose in the germline doesn’t mean they are dead.

    This line of reasoning is getting stale. There are means by which active transposons can be distinguished from dead ones. There are excellent theoretic and practical grounds to think that the majority are dead. You seem to think that, in thrall to the junk DNA paradigm, no-one has looked. You’d better hope they’re dead, because these things seriously fuck with genes and promoters when unrestrained. Genetic meltdown is nothing compared to one of these going wild.

    You are so determined to believe that the entire genome is functional that even the slightest crumb of comfort to that view is siezed upon. So what proportion of transposons do you really think are functional? Forget ‘maybe’. Your swipes at people for being ‘unscientific’ in their assessment would be less irritating if your own bias weren’t so prominently on display.

    Meanwhile, the biggest genome of all is Amoeba dubia. It’s 220 times as big as ours. Does it really need all that to control differential expression in its multicellular … oh, hang on …

  24. Allan Miller,

    Previous studies have revealed that intron size variation is positively correlated with genome size variation [11, 12, 22]. Compared with human, the compact genome of T. rubripes is suggested to correlate positively with intron size shrinking [13, 36]. In our analysis, we observed a correlation between the size of genome and intron length in pufferfish, with the smooth pufferfish having both smaller genomes and shorter introns compared with D. holocanthus having relative larger genome size and long introns. Statistical analysis showed that the difference of the average intron length between D. holocanthus (mean of 566 bp) and the smooth pufferfish (mean of 435 bp) was statistically significant. Although only a tiny fraction of the introns was sampled in our analysis, the nearly identical length distribution patterns (Figure 3) compared with that in the T. rubripes genome [13] suggested that our sampled data were not biased and the result was robust.

    This is from the paper the Rumraket posted. Do you have any thoughts why intron length would correlate with Genome size?

  25. Well, for one thing it would explain why larger genomes generally have larger introns? It’s almost tautological 😛

    But seriously, if genome size is at least partially explained by transpositional activity, combined with an on-average higher rate of deletions, that would also affect intron sequences. So the mechanisms that affect overall genome size, whatever their nature, also affect average intron length for the same reasons.

    In genomes with high transpositional activity, transposons copy themselves a lot and bloat the genome. In genomes with low transpositional activity deletions happen frequently enough to keep the genome size down. Both transposons and deletions are known to affect introns.

    That would be my initial guess.

  26. “Larger genomes have larger introns” actually seems to me to be an argument that most of a genome is junk, that is that the processes (leaving aside for the moment what those processes are) that change genome size are operating throughout the genome without regard for what role the sequence they’re affecting plays. If the genome is big because there are lots of transposon insertions, there are lots of transposon insertions randomly scattered through the genome, including within introns. If small deletions happen at a high rate, lots of small deletions will happen within introns. And so on. Nothing is being fine-tuned for a particular role except for those few bits under selection, and a transposon insertion within (for example) an exon will be selected against and will not attain high frequency in the population.

  27. colewd,

    Do you have any thoughts why intron length would correlate with Genome size?

    Yes, as Rumraket and John H have said, one would expect introns to be subject to the same patterns as the bulk of the genome if they were junk. After selection, mechanisms adding and removing bases will preferentially show up in areas where they do least harm, and that would tend to avoid sequence-critical regions.

    Introns are not, I should note, equally tolerant throughout their length. Anything that disrupts excision will make a right mess. But provided the integrity of intron start and end is maintained, the middle is pretty much up for grabs. It would be interesting to see if there is any significant nesting – once one sequence has inserted nonfatally, another is free to insert anywhere within it.

    On the other hand, I can’t think of a functional explanation for this pattern. “Just because you can’t think of one doesn’t mean there isn’t one” is true, but on present evidence, I’d say intron length – as opposed to intron presence – is mostly explained by the junk argument, beyond that sequence which is critical to excision.

  29. Rumraket:

    Sal, even the junk regions need to be wrapped up in histones to conserve space. That’s why you find histones targeting junk regions and histone markers in the junk. That doesn’t make it functional (or RAM), it just make it wrapped up like all the other DNA.

    You’re understanding is so obsolete even after I put two diagrams to help you see the epiproteomic postranslations modifications that are reversible read-write memory on the histones. The histones are memory devices, not just a means of wrapping DNA tightly. You’ve got it backwards, the DNA is partly there for the histones, not the histones there just solely for the DNA.

    From prestigious scientific journal nature that shows histone function as a memory device that can be written to and read, not just some barrel to wrap DNA around:

    http://www.nature.com/ni/journal/v11/n7/images/ni0710-565-F1.jpg

  30. Sa, if you’re going to cite something in support, please don’t just cite a picture; give a citation to the whole article. Each of those words, “writing”, “erasing”, “reading”, should be in scare quotes. Metaphor.

  31. Each of those words, “writing”, “erasing”, “reading”, should be in scare quotes. Metaphor.

    You’re certainly welcome to tell the editors of the most prestigious scientific journal that their picture should have scare quotes. 🙂

    They need scare quotes since it might make people think histones implement something that looks like Random Access Memory of a computer which might make them think a cell is a computer which might make them think… ahem, let’s not go there.

    I mean, now look at the picture of all those histones inside nucleosome beads that look like an array of memory devices, I mean DANG this looks like almost a conceptual VLSI array from an computer memory chip. The prestigious scientific journal nature shoulnd’t be publishing stuff like this since it makes the histone array look like RAM:

    http://www.nature.com/nrm/journal/v13/n7/images/nrm3382-f6.jpg

  32. stcordova: You’re understanding is so obsolete even after I put two diagrams to help you see the epiproteomic postranslations modifications that are reversible read-write memory on the histones.

    Let’s get something straight: That is a suggestion for how it might work, not an actual demonstration that the entire genome is actually used and functioning in this way.

    The mere fact that this kind of methylation editing takes place isn’t a demonstration that the process is playing any sort of important organismal function everywhere it takes place. Just like transcription. The entire genome is at some point transcribed somewhere in some cell in some tissue too, but that is predicted from first principles whether the entire genome is functional or not. If histone wrapping unavoidably causes DNA methylation and a mechanism exists to erase these methylations, that mechanism will take place in junk and functional DNA, whether it is junk or functional.

  33. stcordova: You’re certainly welcome to tell the editors of the most prestigious scientific journal that their picture should have scare quotes.

    Oooh, the “most prestigious journal”. Where is that intense adoration when Nature publishes another 50 papers demonstrating the truth of evolution and the age of the Earth?

    Your selectively applied adoration and rethorical devices are looking a bit pathetic to be honest.

  34. stcordova,

    Once again, please don’t just post only a picture or link to a picture. Post a citation to the article the picture came from, at a minimum.

    I too find your highly selective appeals to authority amusing.

  35. Rumraket:

    Let’s get something straight: That is a suggestion for how it might work, not an actual demonstration that the entire genome is actually used and functioning in this way.

    Well, from peer-reviewed literature:

    Histone acetylation and disease.

    Cell Mol Life Sci. 2001; 58(5-6):728-36 (ISSN: 1420-682X)

    Timmermann S; Lehrmann H; Polesskaya A; Harel-Bellan A
    CNRS UPR 9079, IFC-01 André Lwoff, Villejuif, France.

    Differential acetylation of histones and transcription factors plays an important regulatory role in developmental processes, proliferation and differentiation. Aberrant acetylation or deacetylation leads to such diverse disorders as leukemia, epithelial cancers, fragile X syndrome and Rubinstein-Taybi syndrome. The various groups of histone acetyltransferases (CBP/p300, GNAT, MYST, nuclear receptor coactivators and TAFII250) and histone deacetylases are surveyed with regard to their possible or known involvement in cancer progression and human developmental disorders. Current treatment strategies are discussed, which are still mostly limited to histone deacetylase inhibitors such as trichostatin A and butyrate.
    .

    You think the histones that are associated with disease (and therefore function when in the healthy state) are located solely in the coding regions? I already provided evidence there is gene regulation by histones that are located on non-coding regions!

    You seem to be under the mistaken impression that for a histones to regulate a gene, the gene has to be wound around the set of regulating histones. Not so. I provided scientific evidence, you just ignored it.

    Look at a real picture of histones/nucleosome beads. The DNA almost just looks like wires connecting these memory devices, eh?

    https://beyondthedish.files.wordpress.com/2012/08/chromatin-fiber.jpg

  36. stcordova:
    You think the histones that are associated with disease (and therefore function when in the healthy state) are located solely in the coding regions?I already provided evidence there is gene regulation by histones that are located on non-coding regions!

    Once again you seem to believe that in the literature “non-coding” is used as a synonym for “junk”. Please stop making this equation.

    Look at a real picture of histones/nucleosome beads. The DNA almost just looks like wires connecting these memory devices, eh?

    Also please stop using “a picture I saw makes two things look similar” as an argument.

  37. Once again you seem to believe that in the literature “non-coding” is used as a synonym for “junk”. Please stop making this equation.

    I don’t believe that because and I don’t care about mincing words. tRNA’s are non-coding, I don’t think they are junk, no one today thinks they are. I wonder if anyone thought that once upon a time.

    So do you think histones that regulate genes can be located in non-coding regions like say those “junk” transposable elements. 🙂

  38. stcordova: I don’t believe that because and I don’t care about mincing words.tRNA’s are non-coding, I don’t think they are junk, no one today thinks they are.I wonder if anyone thought that once upon a time.

    There are words missing in that. If you don’t think “non-coding” is a synonym for “junk”, then why did you say “So do you think histones that regulate genes can be located in non-coding regions like say those “junk” transposable elements”, in which you equate non-coding with junk? Putting a smiley next to it doesn’t make it OK.

    Do histones regulate genes, or does their modification make the difference between euchromatin and regions of less dense packing that allows access to the gene-regulating molecules?

  39. ERRATA:

    147 bp was the figure I cited for nucleosome length, but nucleosomes are liked by linker DNA form 20bp to 90 bp.

    The 147 figure is an estimate, some recent numbers are 145-147 for an average of 146. If we add the linker DNA we get a DNA to nucleosome density of about

    (146+20) to (146+90).

    That affects my numbers above. I was hoping for a little better peer-review from you guys. You should have caught my oversight. 🙂

  42. Do histones regulate genes, or does their modification make the difference between euchromatin and regions of less dense packing that allows access to the gene-regulating molecules?

    If the histone regulates the regulator of a gene then it regulates the gene.

    At least one way histones regulate expression of genes through chromatin remodeling right at the gene (promoter region). It can also regulate at the enhancer region. It can also regulate ncRNAs that regulate genes since histones regulate transcription of ncRNAs through chromatin remodeling.

    The histone marks are what the readers of the remodeling complexes see.

    Examples of histones regulating genes from non-coding regions:

    http://www.nature.com/nature/journal/v459/n7243/full/nature07829.html

    enhancers are marked with highly cell-type-specific histone modification patterns, strongly correlate to cell-type-specific gene expression programs on a global scale, and

    and

    H3K4me1 was the first histone modification globally linked to distal regulatory regions through genomic studies (Heintzman et al., 2007). Analyses of histone modifications over 1% of the human genome conducted in the initial phase of the ENCODE project associated presence of H3K4me1 with distal enhancer regions, in contrast to H3K4me3, which is present at active promoters (Heintzman et al., 2007). This pioneering work provided the first indication that histone modification patterns can be used for genome-wide and cell type-specific annotation of distal enhancers. It is important to note, however, that presence of H3K4me1 is not unique to enhancers, as it also coincides with large 5′ portions of actively transcribed genes. Moreover, even in the context of non-coding sequences, H3K4me1 is widely distributed and generally covers substantially broader regions than the underlying genetic enhancer elements.

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3857148/#R40

    Ah, so histones don’t have to be on the genes that they regulate. Just as I said.

    And speaking of the absence of scare quote:

    https://en.wikipedia.org/wiki/Histone_code

    Structural determinants of histone recognition by readers, writers and erasers of the histone code are revealed by a growing body of experimental data.[11]

    Me, being selective? This is mainstream stuff, you’re arguing from obsolete viewpoints. Oh, they use the word “code” with no scare quotes. You want to write to the scientists who wrote papers on the histone code to put scare quotes too?

    There is really not a universal histone code since the coding and convention is gene dependent.

    Btw,

    Every nucleosome in a cell can therefore have a different set of modifications, raising the question of whether common patterns of histone modifications exist. A recent study of about 40 histone modifications across human gene promoters found over 4000 different combinations used, over 3000 occurring at only a single promoter. However, patterns were discovered including a set of 17 histone modifications that are present together at over 3000 genes.[10] Therefore, patterns of histone modifications do occur but they are very intricate, and we currently have detailed biochemical understanding of the importance of a relatively small number of modifications.

    See that bolded portion, histones are complex memory devices! 3000 histone combinations at a single promoter. Bwhaha!

  43. The presence of thousands of modification types in a singe promoter suggests to me not that there’s some incredibly complex code but that the precise pattern isn’t strong controlled and that many different states are more or less equivalent. Nor does the location seem all that specific. Your triumph at finding someone on Wikipedia using some of the same words you do is faintly amusing.

  44. This is the pervasive transcription discussion all over again. Transcription takes place, you’d get a heatmap similar to the methylation heatmap that changes from tissue to tissue and sporadically covers the entire genome. That doesn’t prove that merely because it happens it is functional everywhere it happens.

  45. Ah yes, speaking of enhancers, yet another class of junk DNA that is no longer junk.

    Enhancer RNA more powerful than previously thought
    …
    This study started with the existence of regions of DNA that created RNA that could enhance the production of protein – facilitating rapid genetic response to stimulus. It showed that this type of RNA, eRNA, has a much wider effect than was previously suspected. In fact, eRNA may be one of the more important mechanisms for directing cell growth – although that is an area for new research. This is part of what seems to be an ever widening pattern discovered by molecular biology – it includes the active areas in what used to be considered ‘junk’ DNA, the role of proteins in epigenetics, and newly discovered forms of RNA involved in the complex feedback system that is a living cell.

    http://scitechstory.com/2010/04/21/enhancer-rna-erna-more-powerful-than-previously-thought/

  46. stcordova,

    You’re certainly welcome to tell the editors of the most prestigious scientific journal that their picture should have scare quotes.

    Yes, I guess you could tell the editors of the most prestigious scientific journal that you have compelling evidence that the earth is 6,000 years old too … 🙂

  48. stcordova,

    So do you think histones that regulate genes can be located in non-coding regions like say those “junk” transposable elements.

    What percentage of the histones associated with noncoding DNA would you hazard are involved in regulating the 1-2% coding region?

  49. stcordova,

    Ah yes, speaking of enhancers, yet another class of junk DNA that is no longer junk.

    What percentage of the genome codes for enhancer RNA?

  50. stcordova: Ah yes, speaking of enhancers, yet another class of junk DNA that is no longer junk.

    Nobody ever thought enhancers were Junk. There can’t be a change of opinion if the first opinion was never held by anyone.

Leave a Reply