
Theory Suggests That All Genes Affect Every Complex Trait - digital55
https://www.quantamagazine.org/omnigenic-model-suggests-that-all-genes-affect-every-complex-trait-20180620/
======
madhadron
There'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
Very 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

~~~
civilitty
I think it's easier to understand if you rephrase it as "evolution doesn't
encapsulate." Just because a bunch of smaller proteins fold into a bigger
quaternary protein structure doesn't mean that those smaller proteins become
"private" members of the new protein "class". Any chemical binding sites that
are still exposed on the surface of the complex protein will still be
chemically active and affected by evolutionary pressure. Even if you have a
protein A made up of B, C, and D that all evolved together to metabolize
fructose, an exposed binding site from protein C on A can still effect some
completely unrelated biochemistry. At the same time, protein C could also be a
critical component of a new protein E.

If the evolutionary pressures on E (or C individually) are greater than on A,
C could evolve completely out from under A to the point where A is no longer
functional or foldable. As such, evolution can't "rely" on abstractions like
"protein C" because their "source code" can be changed nonlocally and their
function is dependent on very local conditions like temperature, pH, and
surrounding molecules. Abstracting away g(h(i(x))) as f(x) in Mathematica is
pointless when your packet sniffer can arbitrarily change the meaning of
"h(x)" to "nop".

~~~
felipemnoa
>>evolution doesn't encapsulate.

I'm not a biologist or geneticists but from everything that I've read about
cellular biology and genetics I get the strong feeling that there is a lot of
encapsulation going on. Sure, it isn't 100% percent perfect but there is still
encapsulation going on. Evolution would probably be way harder without it.

One hint is the human body, there are lots of encapsulations: eyes, heart,
kidneys, digestive system, etc.

Evolution can repurpose an existing system for a completely different use with
just some tweaking.

~~~
telchar
I think that's a misleading observation though. It is squinting at the macro
structure of the body and saying "ah ha, encapsulation!". When you look closer
the apparent encapsulation seems less and less like an accurate notion. For
example the newer research showing how the gut affects cognition. [0]

This is a bit off-topic but I think paleo-ontologists fall into a similar
trap, at least based on popular writing about e.g. sharks. Claims that they
haven't evolved in 100M years because they're the same shape as they used to
be completely ignore all the other aspects of the shark that could change
without affecting the overall shape.

0\.
[https://www.ncbi.nlm.nih.gov/pubmed/24997042](https://www.ncbi.nlm.nih.gov/pubmed/24997042)

------
zfrenchee
The 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
You might want to check out the evo-devo community. They've been doing that
for some time.

------
sriku
There 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
What 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.

~~~
sriku
> 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.

------
ancorevard
Two 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
#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
Eh 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
I think the interesting discovery has been that epigenetic traits can be
inherited to some degree.

~~~
NegativeLatency
Neo-Neo-Lamarckism ;)

------
spruciefic399
This 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.

~~~
jjeaff
The 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."

------
woodandsteel
A 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
And 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.

------
api
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.

~~~
aphextron
>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".

~~~
perl4ever
Is it really magic or is the genetic code just defining something much more
like a CPU or OS than an application program?

If you took a bug report and did a statistical analysis of what transistors
contributed to the bug, in most cases it would tell you "pretty much all of
them". In _very_ rare cases, it would tell you there were specific broken
transistors. Similar for OS instructions. Because it's just the wrong level to
be analyzing problems with the ultimate behavior of a system that's mostly
functional. 99.9999% of the time, you don't have a compiler bug or an OS bug
or a hardware bug, because if you did, everything would be dead.

My kneejerk reaction* is that genes are like transistors or OS instructions
and not like application program instructions, and it really shouldn't be
surprising or mysterious if they don't correspond to specific behaviors. It's
just a different level of abstraction.

*having not studied biology and genetics, and just assuming living organisms have to be like computers.

~~~
saalweachter
The closest analogy in technology would be the Internet, IMO.

A CPU or a single computer is still a fairly homogeneous, consistent creation.
Sure, it has a lot of transistors, but it's just the same pattern over and
over.

Think about the Internet: many of the billions of things on the internet are
similar enough to be called the same, but many of them are ... a little not.
This computer is Intel, this is AMD. This one runs Microsoft, this one Ubuntu.
This one Ubuntu 15.07 with a 5.3.2.2 Linux kernel, that one with a 5.3.7.1
kernel. This part uses IPv4, that IPv6. This HTML on this site is a little
nonstandard, that one relies on an expired SSL certificate.

The body, and modifying it, is a lot like the Internet. You set up 1.1.1.1 as
a DNS server and accidentally partition the Internet.

------
themodelplumber
This 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
> "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
That'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
The 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.

------
dboreham
There'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
...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.

------
nonbel
Of 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
Don'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
Well 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
Intelligence at adulthood is determined by genes. The same organization can
predict height within one inch (again, based on genes).

------
orasis
If 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.

------
raincom
A 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
Then 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
Think 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.

------
reptation
One 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/S136759311...](https://www.sciencedirect.com/science/article/pii/S1367593114000647)

------
jcims
I was hoping CRISPR/Cas9 (or some similar system) was going to answer many
prayers. Maybe this means it's less likely?

~~~
meowface
I 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.

------
acchow
I think of DNA encoding as analogous to video encoding supporting multiple
reference frames with no keyframes (or 1 keyframe?)

------
hamilyon2
I would be surprised if some important macro trait such as height would be
encoded without some redundancy.

------
gwern
R.A. Fisher was right, as usual.

~~~
toasterlovin
Off 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
Not really, with the exception of genetics Twitter.

------
0x86DD_
hmm interesting stuff.

------
jk3232
Old 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
> 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
Yes. Since you know especially what toxins to look for. Not.

And you know exactly under what conditions the toxins are expressed. Not.

------
frgtpsswrdlame
These 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.

~~~
adjkant
That doesn't make it nondeterministic if the environment is also
deterministic. The nature/nurture debate is independent of determinism.

