klmr

Because it’s just stochastic. There’s no mechanism for systematic, guided DNA changes to mutate some genes more than others, which is exactly what I wrote in my initial comment that you took umbrage at. “It can be selected” for only through the blind process of chance, which isn’t really selection at all.

GC content (the local ratio of G and C nucleotides, i.e. (#C + #G) / (#A + #C + #G + #T)) varies in patches across certain mammalian genomes. GC content correlates with stability because stacked C–G base pairs are chemically more stable than A–T base pairs. However, while gene density correlates with GC content, gene function is uncorrelated. This means that genes (which tend to be in high-GC regions) in general tend to be (very, very slightly) less susceptible to mutations than non-genic DNA (by contrast, they are vastly less susceptible to mutation than non-genic DNA due to negative selection^1). But the difference in GC content between different genes is purely stochastic, and there’s no mechanism for changing the GC content of a given gene, except by random (!) mutation. This can happen, and it indeed improves the stability of a gene, but the same is true for all genes to the same extent, and it isn’t directed.

^1 I’ve never seen anybody explicitly quantify this but the relative impact of GC content and negative selection on mutation rate must be several orders of magnitude different … at a guess at least thousandfold, more likely millionfold.

It was a reason, yes. But more generally I started a new job at the time (~ 2 years ago) that took me out of biological research altogether for the moment.

You fundamentally misunderstand the article you cite. It describes population-level events, and it’s entirely compatible with what I’ve said: variable mutation rates, in modern evolutionary biology, are entirely explained by variable selective pressure (see “purifying selection”, which is what I’ve described in my previous comment using your example).

As for the second article, I’ve made reference to that in my previous comment, too (that’s GC bias). And, as mentioned, this isn’t relevant here.

Yes, I’m well aware of TEI, it being my former field of research. However, as your link (4) shows there are all kinds of caveats, and usual epigenetic inheritance isn’t transgenerational (in fact, it’s a ubiquitous, “mundane” biological mechanism to maintain cellular state). Your first example — agouti mouse coat colour — is essentially the only firmly established example of TEI in mammals. And, as I explained in another comment, TEI tends to attenuate over generations, and it probably functions very differently in non-mammalian organisms. To date, the existence of pervasive TEI in mammals remains a point of contention. Outside of the agouti locus there’s almost no high-quality, replicated evidence for its existence, and the hypothesis is fundamentally hindered by the lack of a plausible mechanism [1]. Most epigenetics research focuses on other things, and there’s general scepticism that TEI in mammals is all that important [2].

[1] https://www.theguardian.com/science/sifting-the-evidence/201...

[2] https://twitter.com/ewanbirney/status/1014494822525296640

> Why are we significantly less likely to have mutations on our mitochondria than in our fingers?

I’m afraid this is simply not a biologically meaningful statement to begin with. Mitochondria are subcellular organelles. Fingers are complex organs that are formed from spatial arrangements of multiple cell types. Furthermore, mutations happen on the level of DNA, not on the level of either organelles or organs.

Apart from that, mutation rate is (not quite, but more or less) uniform across the whole genome (the exceptions, due to e.g. GC bias, are not relevant here). Viable mutations are not uniformly distributed because of selection; that’s precisely the striking insight that Darwin had (though he was unaware of DNA and genes). Importantly, this does not require a guided error correction mechanism. Simply put, even slight variations in the oxidative phosphorylation pathway of the mitochondrion are likely to kill you during gestation; whereas similarly extreme variations in finger morphogenesis, at worst, make you unable to hold a tool.

> some subsystems are more stringently error corrected than others

This is virtually certainly not the case, because of what I’ve just described. Selection is sufficient to describe the outcome, and there is no evidence whatsoever to point to the mechanism you postulate.

> I would be incredibly surprised if a crocodile, who has been in a state of relative homeostasis for millions of years, has the same rate of mutation as a human.

Evolutionary mutation rate is governed by effective population size and generation time. That’s why fruit flies evolve fast and crocodiles evolve slowly. This, too, doesn’t require variable mutability of different traits, and no biologist has yet seriously suggested such a mechanism.

> Isn't there a similar mechanism in humans though?

No. That review paper doesn’t discuss an actual mechanism, with good reason: the authors don’t have a mechanism. At the risk of sounding harsh, the underlying research has been throughly rubbished by the community [1, 2]. It uses a tiny sample size, tenuous correlation and, as mentioned, utterly fails at highlighting a plausible mechanism. It’s bunk: there’s absolutely no need to invoke the spectre of epigenetics to explain why children of traumatised parents may likewise be jumpy, just as there’s no need to invoke epigenetics to explain why children of English parents speak English. In fact, even the review you link to acknowledges as much:

> studies in humans have not yet demonstrated that the effects of trauma are heritable through non‐genomic (i.e., epigenetic) mechanisms

[1] http://sciblogs.co.nz/code-for-life/2015/08/28/epigenetics-a...

[2] https://www.theguardian.com/science/blog/2015/sep/11/why-im-...

Sure, and that happens all the time in unicellular organisms. But it’s fundamentally different in multicellular organisms because they have distinct cells forming the germ line. So any (random) changes to DNA in other cells won’t be transmitted. And while mutations in the germ line do happen, they are also random. So far there’s no known mechanism for systematic, guided DNA changes, and no good reason to assume that such mechanisms exist (on the contrary). Furthermore, the article is discussing epigenetic changes which, by definition, are not encoded in DNA and are instead transient (and thus not inherited trans-generationally).

Furthermore, it has nothing to do with epigenetics. It’s good old genetics.

Rupert Sheldrake is an esoteric quack and pseudoscientist. He has not done any relevant work in this field, and his theoretical claims are fundamentally unsound.

Nick is a former colleague, and I’ve co-authored one of the relevant papers with Isabelle, and with the greatest respect to the two of them I need to caution anybody against taking away the wrong message from this misleading article: these findings are fundamentally not translatable to humans — and even in most cases to mammals, research in mice notwithstanding.

Furthermore, most, if not all, transgenerational effects of epigenetic inheritance even in C. elegans is transient. Meaning, the effect attenuates over just a few generations and then vanishes completely.

To be absolutely clear: Learning is not inherited in humans. There are good reasons to make this a categorical statement. What’s called “learning” in C. elegans is completely different from “learning” in humans, and adaptive changes in mouse behaviour are, so far, still not clearly demonstrated to be caused by epigenetics, and there are good reasons to be sceptical, as summarised by Kevin Mitchell: http://www.wiringthebrain.com/2013/01/the-trouble-with-epige..., and by Bernhard Horsthemke: https://www.nature.com/articles/s41467-018-05445-5

I agree with your comment in principle but the specific example of Roundup is rather weak. Yes, glyphosate is usually studied in isolation rather than as a commercial formulation including surfactants etc., but we have decades’ worth of epidemiological studies showing that proper use of Roundup has, at most, a marginal effect on tumour incidence. Conversely, the most-discussed studies that purport to show Roundup’s carcinogenicity have well-known, glaring methodological flaws (including some that formed the basis of the IARC report). The case of Roundup is made more complicated by the fact that Monsanto/Bayer has been caught red-handed skewing the publication record without disclosure of conflict of interest, and lobbying scientific journals. But the same is true for the opposition: for instance, the now-retracted 2012 Séralini study also failed to disclose the authors’ conflict of interest. And beyond improper publication practices (which, yes, is serious), there’s no evidence that Monsanto/Bayer actually falsified information.

In sum, I’d rank the risk of Roundup being carcinogenic on roughly the same level as that of 5G: possible but unlikely, given the best available evidence.

Being such a person is totally fine (I’m one myself). What’s damning is the fact that this list is largely composed of just such people (plus some that are less qualified).

> * Whether it is made in good faith or not is a red herring and does not change anything.*

That’s true only if we indeed know nothing about 5G, and that’s demonstrably not the case. In fact, the pretend open-mindedness is tantamount to denialism, if we accept that findings on ≤4G translate to 5G, and there are good scientific reasons for thinking so, based on our established understanding of physics and biology. It’s possible that 5G changes the picture, and I am indeed open to the possibility. But at the same time intellectual honestly compels me to describe the chance of this happening as low, given what we generally know about the biological effects of non-ionising radiation.

Put differently: Given what we know, it’s honest to say that 5G might carry risks, but that there is currently no good reason to assume so. It is not honest to claim, as the article does, that “we have no reason to believe 5G is safe”.

Careful, you’re misinterpreting the document. The two studies you’ve picked are listed as “neither evidence of an effect or a null finding”, they are not included in the “more than 500 studies” finding harmful effects. Those studies are prefixed by “P” in the document and, although I haven’t counted, a rough estimate based on the number of pages makes it plausible that there are > 500.

That said, given the scientific consensus from rigorous meta-analyses, I expect that these “positive” studies are mostly of low quality and/or limited sample size. And scepticism is generally warranted when advocates start listing large numbers of studies instead of referring to a few meta-studies. As it happens, the best available meta-studies come to the opposite conclusion (namely, that there’s probably no harm from mobile EMF), so this long list is essentially bogus.

> The leading independent organization on cancer causes says that current cell phones are "possible carcinogens"

It is crucial to understand what this actually means. the IARC classifications are valid but — particularly to lay people — incredibly misleading and pretty much useless. All that “possible carcinogen” means is that we haven’t yet collected sufficient evidence to discount harm. It’s not evidence of carcinogenicity at all. If anything it’s the opposite, because it means that, despite the existence of relevant studies, there hasn’t been any consistent demonstration of carcinogenic effect.

Furthermore, IARC only classifies risk itself, not hazard [1], nor dosage effects.

For context, IARC classifies sunlight exposure and processed meat consumption as “definitely carcinogenic” [2]. Despite this, regular exposure to sunlight is crucial for your health, and regular meat consumption is known to have little absolute effect on cancer risk (in other words, although red meat does have an effect, the effect size is tiny).

[1] https://worksmart.org.uk/health-advice/health-and-safety/haz... [2] https://monographs.iarc.fr/list-of-classifications/

> That's a very reasonable general approach.

If made in good faith, yes. I’m not convinced that this is the case here, however, given that the author is fundamentally at odds with the scientific consensus on 2G, 3G and 4G safety, without acknowledging that he’s in the clear minority. In fact, he claims that the majority of relevant experts have signed the 5G moratorium, and this seems to not actually be the case. I actually think that disagreeing with the consensus, based on limited but potentially valid evidence, is completely acceptable. But he goes further and pretends to be in the majority, and that contrary evidence only marginally exists.

In sum, he makes demonstrably false claims about the current state of the scientific consensus, which makes me sceptical of everything else he says.

Unfortunately a few developers are morons who misuse features, and browser vendors try hard to work around them. Case in point, lots of websites used to put `autocomplete="off"` on password boxes, which breaks some password managers. IIRC that’s why Chrome (and other browsers) decided to sometimes ignore the `autocomplete` attribute in the first place. Of course that doesn’t justify ignoring it completely (just for password fields) but maybe a similar reason is at play.

While you’re right, it’s unfortunately not that simple because macOS updates really do break a lot of stuff (especially for developers) and, on older hardware, degrade performance to the point of un-usability. I’ve got an MBP from 2012, and I’ve stopped updating macOS with Sierra (10.12) due to ever degrading performance. I’ll be forced to throw away the (perfectly functional!) laptop at some point once I stop receiving security updates.

> I don't think the GDPR solves much or anything, iff you want to play on the internet, almost … all of the time you'll have to click "I agree".

That in itself is a GDPR violation. If you care enough, report it. That said, this is not what happens “almost all of the time” at all. In my experience most websites are completely or partially usable when you disagree with being tracked. At worst (and also in violation of GDPR), the tracking dialog makes it intentionally difficult to refuse being tracked.

> It's a hamburger after all, it's not meant to be healthy.

Hamburgers aren’t inherently unhealthy (though I’ll concede that in practice they often are). A well-made hamburger contains part protein, vegetables and carbs. It’s a whole meal. A bit too heavy on the carbs maybe, but not extremely so. It can stand on its own with very few additional flavour components, and has the potential of being a more wholesome meal than many others.

The issue, rather, is twofold. First, almost all burgers skimp on the veggies and generally use low-quality ingredients, instead relying on other flavour components (i.e. too much sugar and salt, and often added fat in the form of low-quality cheese and bacon). And secondly, burgers are umami bombs and lead people to overeat, both in terms of quantity (serving size) and frequency.

> So basically you concede the original point then.

I’m not “conceding” anything because I’m not arguing against it (I didn’t write the grandparent comment). My comment is intended to provide all the relevant information, not argue against the comment I replied to.

> Citation?

I’ll refer you to the discussion on Wikipedia [1], which is fairly exhaustive. The long and the short of it is that we don’t know for certain either way, and all estimates have large uncertainties attached. However, the (tentative) prevalent opinion amongst experts can be fairly summarised as “The reported increase is largely attributable to changes in diagnostic practices, referral patterns, availability of services, age at diagnosis, and public awareness”. However, it also needs to be said that “largely” here refers to the effect size: most of the increase is probably not due to actually increased incidence. But some of it probably is.

[1] https://en.wikipedia.org/wiki/Epidemiology_of_autism#Changes...

> This is surprising because individual tRNA abundance varies by cell state and type, so that would have been the obvious (but apparently wrong) explanation.

tRNA gene expression varies by cell state, but isoacceptor abundance is in fact very stable (at least in mammals). Meaning, if you have a set of tRNA genes which all code for, say, Ala_AGC, the sum of the gene expression of all these genes is relatively stable, even if their individual expression varies (http://dx.doi.org/10.1101/gr.176784.114l; full disclosure: I’m an author on this and one of the previously linked papers).

Why individual tRNA gene expression varies, and how the cell regulates the overall stability, is unclear (my personal pet theory is that secondary tRNA function as regulatory RNA, in the form of tRNA-derived fragments, causes the need to regulate tRNA genes, see e.g. http://dx.doi.org/10.1016/j.cell.2017.06.013).

> It's doubly surprising because a number of single celled organisms utilize the mismatch between codon preference and tRNA availability in order to regulate protein translation

It’s not that surprising: gene regulation happens fundamentally differently in eukaryotes and prokaryotes, and even differently in different classes of eukaryotes. The effective population size (= evolvability) and genome complexity seems to play a role here. Simply put, higher animals have much more powerful and precise ways of controlling gene expression (enhancers and histone control). Regulation at the translation level is comparatively slow and wasteful (it’s several steps further down the line of the gene->protein production process).

Some people argue that the moon is made of cheese. I don’t think that merits a mention either.

I misunderstood both your and the grandparent comment. You’re right. I’ve amended my other comment.

> but the tree of life isn't a tree

That’s correct but I don’t see what this has to do with my comment. It’s still a fact that all modern life, at some point, came through the same individual organism (EDIT: this should be population) which, furthermore, already possessed the fundamental machinery of DNA replication, RNA transcription and protein synthesis (amongst other things).

EDIT: I misunderstood. Yes, you’re right: due to lateral gene/molecule transfer, it’s not certain that the last universal common ancestor was an individual cell, and at that time the label “individual” probably didn’t make much sense (although the paper I linked argues strongly that it was in fact one single cell).

> but that doesn't mean it's been proven through experimentation, does it? isn't it just an assumption?

It’s not an assumption, it’s backed up by excellent evidence — see the paper I linked.

> what if there's something akin to mathematical uniqueness in the mechanics of the core machinery?

Well that’s clearly not the case, we can trivially (…) design self-replicating machines that have completely different mechanics, as a thought experiment. More to the point, we can change parts of the machinery. For instance, we can take the universal genetic code and, with effort, change it into something completely different (by just swapping all codons around). The result is just as viable, but doesn’t exist in nature. In fact, the observed universality of the genetic code, in itself, is already seen as sufficient evidence for common descent (and then some).

“Essential” amino acids are those that humans can’t synthesise. Other life forms can, which is why we ingest them with our food.

As for how early life started, presumably with a strongly reduced set of amino acids. Some of these are simple enough chemicals which form spontaneously given the right conditions (technically all of them can, but probably at very low rates). This was famous established by the Miller–Urey experiment (https://en.wikipedia.org/wiki/Miller–Urey_experiment).

> But it sounds unlikely that a) there really was that single origin cell

This is just a fact. All life that we know of has the same origin. Common descent is a core tenet, and one of the best established facts, of modern biology (https://doi.org/10.1038%2Fnature09014). For there to have been multiple distinct ancestors, we would need to see some relevant differences in the core machinery of life. And the fact is that, despite minor variations, we simply don’t see any. The odds of there being multiple distinct ancestors is astronomical, and would fundamentally impact our understanding of modern biology.

> and b) no organism has drifted in the millions of years of evolution

Organisms have drifted. That’s what evolution is. But evolution plays by rules, it can’t just change things willy-nilly. Changes to the core machinery would presumably either break it outright, or be so strongly detrimental as to be purified away almost immediately. Of course many genetic changes are deleterious to some extent but most effects can either be buffered for a short time because they are minor, or they confer some other advantage. In the core machinery of the cell this is much (!) less tolerated because even tiny chemical inefficiencies would immediately be amplified millionfold. Odds are, the DNA/RNA core machinery of all life sits in a steep local optimum. It’s not necessarily a global optimum but it’s essentially impossible to evolve out of because any individual change, or even a handful of coincidental changes, would leave the organism a lot worse off.