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Theory Suggests That All Genes Affect Every Complex Trait
- zfrenchee 8y agoThe original paper is https://www.cell.com/cell/fulltext/S0092-8674(17)30629-3 https://www.cell.com/cell/fulltext/S0092-8674(17)30629-3 There was a nice follow up last week https://www.cell.com/cell/abstract/S0092-8674(18)30714-1 https://www.cell.com/cell/abstract/S0092-8674(18)30714-1 There's a lot of good theoretical biology to be done here. I don't think any of us systems biologists are surprised about this result, but pinning down exactly the structure of the genetic basis for complex traits is going to be an interesting enterprise.
- dekhn 8y agoYou might want to check out the evo-devo community. They've been doing that for some time.
- api 8y agoHaving studied biology and genetics this is common sense to me. Genetic systems are probabilistic chemical systems where everything influences everything to varying degrees in parallel. They are nothing like the linear assemblies of modules that humans prefer to engineer.
- stochastic_monk 8y agoWhich explains why gene regulatory network inference by expression patterns is garbage. My first time in graduate school I worked on it, and the model worked just as well using random genes instead of annotated transcription factors. There was no science in it, so I took a master’s, worked in industry, and am now doing real science in a CS PhD program.
- fizx 8y agoCommon sense from the machine learning side too! (that said, the ex-physicist in me would like to remind everyone that science and reality are not required to match your common sense) If true, this means that evolution could look more like stochastic gradient descent, and less like brute force luck plus survival of the fittest.
- onychomys 8y agoFrom an evolution point of view, it actually just means that selection happens at the organismal level, not the gene level.
- fizx 8y agoYou misunderstand my point... larger ratio of base pairs to behavior means that the behavior is likely more robust to noise, and the original evolution of the behavior would have been smoother (i.e. proceeded in less of a step-wise manner, because each step would be a much smaller fraction of the required change than previously thought).
- politician 8y agoTraits embedded into a dense vector space encoded as DNA base pairs is a pretty radical deviation from the one-hot vector approach we were taught in school. Wouldn't it be lovely if we found that vector addition worked similarly in this domain?
- aphextron 8y ago>Having studied biology and genetics this is common sense to me. Genetic systems are probabilistic chemical systems where everything influences everything to varying degrees in parallel. They are nothing like the linear assemblies of modules that humans prefer to engineer. I'm really glad that this mental model I've built up seems to reflect reality. The idea of neatly editing specific genes to produce a desired result always sat with me as the pinnacle of human hubris. The more I learn about Biology the more I just throw up my hands and say "magic".
- bookofjoe 8y ago>The idea of neatly editing specific genes to produce a desired result always sat with me as the pinnacle of human hubris. See, for example: Gene Therapy in a Patient with Sickle Cell Disease https://www.nejm.org/doi/full/10.1056/NEJMoa1609677 https://www.nejm.org/doi/full/10.1056/NEJMoa1609677
- aphextron 8y agoI literally can't understand a single word on that page. Care to explain?
- bookofjoe 8y ago"We describe our first patient treated with lentiviral vector–mediated addition of an antisickling β-globin gene into autologous hematopoietic stem cells."
- politician 8y ago"We describe our first patient treated with <a technique that injected> <DNA to counteract the disease> into <stem cells>. <which were then injected into the patient>."
- bookofjoe 8y agoOr you could simply say "We performed a chemistry...":-)
- deegles 8y agoI wonder if years from now we'll look back at the "selfish gene" the way we look at Freudian ideas about psychology.
- api 8y agoDefinitely. I am generally unimpressed by Dawkins.
- gwern 8y agoR.A. Fisher was right, as usual.
- toasterlovin 8y agoOff topic: I see you on here commenting on discussions related to evolution pretty frequently, so I figured I'd ask you: Are there any communities like HN, but focused on evolution, population genetics, etc. that you would recommend?
- gwern 8y agoNot really, with the exception of genetics Twitter.
- spruciefic399 8y agoThis is a paper that I'm glad was published (maybe not Cell, but somewhere), because it presents an interesting and pretty clear theory. At the same time, it seems like it's fairly clearly falsifiable almost on its face, because there are many genetic disorders involving clear, substantial mutations (in a chromosomal topography sense) that are circumscribed in their effects, at least to one extent or another. I think some variant of this might be true, where traits are influenced by a very very large number of genes (like thousands or hundreds of thousands or more), possibly interacting or in more complex chaotic effects. But this is basically a variant of the polygenic hypothesis, which has been a major paradigm for years. This model seems like the dominant paradigm pushed to its limit, rather than something fundamentally new. Maybe I'm misrepresenting my sense of the field, but I doubt that many people doing GWASes believe in a relatively limited number of genes affecting traits. I think this has been true for several years now at least. I've been wrong in my assumptions about the field before though.
- asimpletune 8y agoDid you mean false instead of falsifiable?
- deleted 8y ago[deleted]
- jjeaff 8y agoThe top comment on this post addresses the one gene, one trait evidence. In essence, just because changing one gene mutation fixes the problem, that doesn't mean that only one gene was responsible for the problem in the first place. "The "one gene = one protein" dogma of molecular biology (expanded: "one trait selectable in breeding experiments = one compact locus of the chromosome") was a priori wrong, but it's taken us decades to undo the damage. We were led astray because there are traits that do map to a single locus, or single mutations that were found to be able to control a trait, which is not the same thing as the trait."
- madhadron 8y agoThere's a couple of things that are slowly changing in the thinking of biologists related to this: 1. Genes are not loci. The "one gene = one protein" dogma of molecular biology (expanded: "one trait selectable in breeding experiments = one compact locus of the chromosome") was a priori wrong, but it's taken us decades to undo the damage. We were led astray because there are traits that do map to a single locus, or single mutations that were found to be able to control a trait, which is not the same thing as the trait. 2. Distributed representation. If I point to a sentence and ask "where is the sarcasm?" (assuming the sentence is sarcastic), there is no answer. It's certainly a trait of the sentence, just as, say, being red headed is a trait of the organism. But a linear model showing each word's contribution to sarcasm isn't helpful. 3. Perhaps a corollary of (2), humans have the concept of abstraction. There are many situations where you can get something like an abstraction from evolution. If a human engineered it, we'd call it a leaky abstraction, but please don't get caught up on that. Evolution doesn't abstract. But there are structures that emerge that can have similar properties, especially from repeated exaptation. Consider the MAP kinase pathways. Lots and lots of cell responses involve them, in all kinds of subtly different ways. We don't try to claim that a MAP kinase is the gene for anything in particular, any more than we would claim that the interrupt for triggering a system call on 32 bit Linux is the cause of certain behavior that a program is supposed to have in a particular domain.
- jds375 8y agoVery interesting comment, thanks! Could you elaborate on what you mean by ‘evolution doesn’t abstract’? I did not totally understand what the example given had to do with abstraction
- frgtpsswrdlame 8y agoThese kinds of strange findings are going to keep occurring because these researchers are too far invested into a mode of research (genetics) that won't actually find the determinism they desire. It's the environment not the genes.
- reptation 8y agoOne reason for this dependence could be that DNA exists within a confined space in the nucleus. The locations of the genes are not random. eg. https://www.sciencedirect.com/science/article/pii/S1367593114000647 https://www.sciencedirect.com/science/article/pii/S136759311...
- jcims 8y agoI was hoping CRISPR/Cas9 (or some similar system) was going to answer many prayers. Maybe this means it's less likely?
- Analemma_ 8y agoI imagine CRISPR/Cas9 still has great potential for addressing specific genetic disorders (which are usually localized to a single, known gene), but the more transhumanist stuff about making smarter, longer-lived people is still a ways off.
- meowface 8y agoI don't think this significantly changes expectations. CRISPR and similar systems will still be immensely beneficial for simple traits (e.g. traits determined by a very small number of genes). Some diseases can be eliminated by changing a single gene. CRISPR and similar systems could someday be helpful for dealing with complex traits, but we first need to understand exactly what genes contribute to them and how, and for many traits, that will take a very long time. In some sense, CRISPR is just a dumb cutting tool. Knowing where to cut was always the hard part, and it always will be.
- empath75 8y agoEven if the cause of a particular disorder is spread across the genome it could be the case that changing one particular gene is enough to cure it in some cases.
- polski-g 8y agoNo it just means more than one gene would be needed to be modified. Don't know who was ever thinking that traits weren't polygenic. If they were monogenic then there would be no variance in traits.
- ancorevard 8y agoTwo things: 1. The theory of "junk DNA" of which the authors received Nobel Price is increasingly looking like...well...junk. 2. The recent discovery of Epigenetics adds a whole other dimension for understanding traits and genetics. Lots of biological science needs to be rewritten/updated in the years to come.
- speby 8y ago#2 is perhaps one of the most confounding recent areas of research that really starts complicating the study of DNA and how changes to it map to an organism's outcome in the real world over time and in different environments. As new studies emerge on identical twins/triplets/etc., it has become clear that even identical DNA does not at all have 100% clone of the person, even if they do in fact share the same DNA. Ranging from things like height differences, leg lengths, intelligence levels, and a host of other characteristics, "identical" DNA does not mean physically identical creatures that look and behave exactly the same, even if they are far more similar than different.
- xyhopguy 8y agoEh I disagree. It's been known for a while that you need something other than just DNA to get the heterogeneity of cellular phenotypes. Remember that your Iris and toenails have the same DNA, yet wildly different gene expression profiles. Without cellular memory that would be impossible and we would all still be single celled organisms :)
- adrianN 8y agoI think the interesting discovery has been that epigenetic traits can be inherited to some degree.
- NegativeLatency 8y agoNeo-Neo-Lamarckism ;)
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- woodandsteel 8y agoA couple of comments from a non-biologist. It seems to me that this is an example of a common pattern in biological research. A simple explanation is developed for a phenomena, but then as time goes on, it turns out that in at least some important ways things are much more complicated than originally thought. Also, the article talks about the controversy between the view that all genes make tiny causal contributions versus some are core and other peripheral. But perhaps it is, at least in some cases, a matter of what I would call complex conditionality. So for instance maybe disease X happens if there are mutations in genes A, B and C, or C, D and E, or G, H and I, but not any other combination. Certainly we find things like that in other areas of reality.
- SubiculumCode 8y agoAnd that pattern in science is not a bad thing. Find a general pattern and use it to make predictions. Eventually you identify the conditions in which the general pattern does not hold and you formulate a less simple explanation.
- orasis 8y agoIf you look at how random projections work in machine learning or error correcting codes this makes perfect sense. The information is distributed across all bits.
- acchow 8y agoI think of DNA encoding as analogous to video encoding supporting multiple reference frames with no keyframes (or 1 keyframe?)
- raincom 8y agoA similar debate goes on in Cognitive Neuroscience and/or neuropsychology/neurophysiology: can cognitive phenomena--like emotion, learning, memory, affect, etc--be localized in the brain? can fMRI solve this localization-distribution issue? Whatever we have known so far, early phases of the input system (sensory) and later phases of the output system (motor) can be localized. Even there is an overlap between the input and the output system.
- simonh 8y agoThen there’s the problem that fMRI is hardly providing us with a complete view of everything going on in the brain. The same goes for the other instruments we have. Who knows what parts of the puzzle we’re not yet even seeing?
- raincom 8y agoThink of thermometer, which everyone of us uses. It doesn't tell much about what is going on inside, but it tells us that something is NOT normal esp out of normal body temp range. Does fMRI play the role of thermometer? Yes when there are injuries; but injury itself plays the role of the thermometer. fMRI is not useful in settling the disputes about how brain makes the mind--esp higher cognitive processes.
- themodelplumber 8y agoThis reminds me of systems theory; anyone else? It makes intuitive sense if I think of traits as one outcome of a system. Rather than converging to a single particle-like "cause," such as a gene, it seems that the wider system is the basis for the trait--the objective appearance of the trait is an expression of the system. It seems it should follow that you can continue tracing the trait from the individual level up though additional systems, like social group, atmosphere/environment, etc.
- chiefalchemist 8y ago> "It makes intuitive sense if I think of traits as one outcome of a system." Put another way, if you were building something and you wanted it to survive, would you want a flexible multifaceted system, and not a dogma-esque checklist of X, Y and Z.
- themodelplumber 8y agoThat's a great way to put it. You'd want a system that would instinctively re-implement patterns as a way of protecting itself, as well. I've noticed lately that if you take business process development, personal productivity, value-creation philosophy, socio-political framework-building (e.g. development of democracy) and combine that sort of thing with the traditional "software OR firmware OR hardware" definition of technology, the human system is always building "technology" toward what might be called survival+. In this human systems/outside-systems interaction there is a periodicity aspect where at times (e.g. giant meteor approaching) human "survival" is definitely the question, and other times we surge way past just putting meat on the table, so to speak. Also, a trait, e.g. a psychological trait, or a group of them ("values-centered, empathetic, philosophical" vs. "productivity-centered, logical, process-oriented") could be seen as a technology orientation that helps the system build technology of a specific kind.
- chiefalchemist 8y agoThe humans sub-systems compliment each other and at the same time feels like backups of each other. The hardware of genes get adjusted by the software of epigenetics. And who knows what we have yet to find. But it's making more and more sense in a why didn't we see this sooner sorta way.
- 0x86DD_ 8y agohmm interesting stuff.
- sriku 8y agoThere has been what I think is direct evidence of the possibility of this in the digital world. Adrian Thompson's work[1] in evolving an FPGA circuit to tell the difference between the spoken words "stop" and "go" (yes .. digital circuit design with an analogue task) threw many surprises. The evolved circuit was highly economical with gates and didn't use a clock. It had also started exploiting the specific physics of the FPGA chip and included transmitters and receivers. Digitally "useless" structures were critical to its performance. If this is true of a simple evolved circuit - i.e. the connection between the circuit specification and the behaviour being complex, with the circuit specification already encoding physics beyond the digital gates - then I'm not sure what hope we should actually place in statistical attempts to connect genes with organism behaviour. Pushing the link a bit more, just as the circuit representation went beyond the target domain of digital circuits, could what is encoded in our genes explicitly encode exploitations at quantum level? With this, the possibility of brain structures acquiring quantum error correction schemes doesn't seem too far fetched or crazy thought. [1] https://www.damninteresting.com/on-the-origin-of-circuits/ https://www.damninteresting.com/on-the-origin-of-circuits/
- adrianN 8y agoWhat do you mean with "quantum level"? All of biochemistry is best described by quantum mechanics. Do you mean large scale entanglement and coherence as would be required for quantum computation? That seems a bit unlikely in a warm soup like our bodies. We haven't been able to achieve it on a useful scale even in the controlled environments of physics labs.
- NegativeLatency 8y agoSounds like some measurement threshold of what degree a cellular process is reliant on quantum effects. (Maybe something like electron tunneling or photon wave/particle behavior?)
- sriku 8y ago> All of biochemistry is best described by quantum mechanics. .. much the same as all of what the FPGA does is captured by electromagnetism + material physics. Nevertheless, the encoding of the FPGA circuit, while it describes a digital process, can hack into the features of a level below. Similar to that, while gene sequences may encode protein production, I'm wondering whether the resultant system could similarly make explicit use of below-the-protein-level features. Our inability to achieve that yet is not an argument, much the same as a digital circuit designer will be at a loss to make a "stop" versus "go" detector and that too one without a clock.
- nonbel 8y agoOf course, to me this is obvious: "everything correlates with everything else". Wait until we start seeing the results of the hyped up "gene editing" studies where they follow up for a few years and look at more than one/few outcomes at a time...
- polski-g 8y agoDon't even need that. Later this year BGI will allow you to submit zygotes and they'll provide a 23andme compatible report. And you can plug that in to dnaland and find out which zygote you should select for the most intelligent offspring.
- nonbel 8y agoWell that is almost surely fake. This is like a list of companies whose stocks should be shorted in (at what age is intelligence determined? 5 years?) as the lawsuits come rolling in.
- polski-g 8y agoIntelligence at adulthood is determined by genes. The same organization can predict height within one inch (again, based on genes).
- dboreham 8y agoThere's an encoding scheme used (probably several) and we don't understand it. This is like showing someone the hex dump of an mpeg file and expecting them to know it makes a picture of a kitten.
- jccooper 8y ago...and a picture of the Grand Canyon, and a recording of Beethoven, and also somehow a couple of sonnets, depending on what the temperature is.
- hamilyon2 8y agoI would be surprised if some important macro trait such as height would be encoded without some redundancy.
- jk3232 8y agoOld news. Pleiotropy is an example for it. https://en.wikipedia.org/wiki/Pleiotropy https://en.wikipedia.org/wiki/Pleiotropy What is a bigger problem: Even an average idiot must now realize, that GM food may be riskier than you think.
- c4h8o3del 8y ago> Even an average idiot must now realize, that GM food may be riskier than you think. Yes and no. It may lead to dangerous expressions, but plain chemical testing and analysis prior to commercial release should ensure nothing toxic makes it into people's food. If your apples suddenly start producing magnitudes more cyanide after modifying something, just don't sell them.
- jk3232 8y agoYes. Since you know especially what toxins to look for. Not. And you know exactly under what conditions the toxins are expressed. Not.