What I’m not clear on is how those two numbers (20,000 genes and a few thousand neuron types) specifically relate to each other in your model of brain functioning.
Start with 25,000 genes, but then reduce it a bunch because they also have to build hair follicles and the Golgi apparatus and on and on. But then increase it a bit too because each gene has more than one design degree of freedom, e.g. a protein can have multiple active sites, and there’s some ability to tweak which molecules can and cannot reach those active sites and how fast etc. Stuff like that.
Putting those two factors together, I dunno, I figure it’s reasonable to guess that the genome can have a recipe for a low-thousands of distinct neuron types each with its own evolutionarily-designed properties and each playing a specific evolutionarily-designed role in the brain algorithm.
And that “low thousands” number is ballpark consistent with the slide-seq thing, and also ballpark consistent with what you get by counting the number of neuron types in a random hypothalamus nucleus and extrapolating. High hundreds, low thousands, I dunno, I’m treating it as a pretty rough estimate.
Hmm, I guess when I think about it, the slide-seq number and the extrapolation number are probably more informative than the genome number. Like, can I really rule out “tens of thousands” just based on the genome size? Umm, not with extreme confidence, I’d have to think about it. But the genome size is at least a good “sanity check” on the other two methods.
Is the idea that each neuron type roughly corresponds to the expression of one or two specific genes, and thus you’d expect <20,000 neuron types?
No, I wouldn’t necessarily expect something so 1-to-1. Just the general information theory argument. If you have N “design degree of freedom” and you’re trying to build >>N specific machines that each does a specific thing, then you get stuck on the issue of crosstalk.
For example, suppose that some SNP changes which molecules can get to the active site of some protein. It makes Purkinje cells more active, but also increases the ratio of striatal matrix cells to striosomes, and also makes auditory cortex neurons more sensitive to oxytocin. Now suppose there’s very strong evolutionary pressure for Purkinje cells to be more active. Then maybe that SNP is going to spread through the population. But it’s going to have detrimental side-effects on the striatum and auditory cortex. Ah, but that’s OK, because there’s a different mutation to a different gene which fixes the now-suboptimal striatum, and yet a third mutation that fixes the auditory cortex. Oops, but those two mutations have yet other side-effects on the medulla and … Etc. etc.
…Anyway, if that’s what’s going on, that can be fine! Evolution can sort out this whole system over time, even with crazy side-effects everywhere. But only as long as there are enough “design degrees of freedom” to actually fix all these problems simultaneously. There do have to be more “design degrees of freedom” in the biology / genome than there are constraints / features in the engineering specification, if you want to build a machine that actually works. There doesn’t have to be a 1-to-1 match between design-degrees-of-freedom and items on your engineering blueprint, but you do need that inequality to hold. See what I mean?
Interestingly, the genome does do this! Protocadherins in vertebrates and DSCAM1 are expressed in exactly this way, and it’s thought to help neurons to distinguish themselves from other neurons…
Of course in an emulation you could probably just tell the neurons to not interact with themselves
Cool example, thanks! Yeah, that last part is what I would have said. :)
Interesting...I think I vaguely understand what you’re talking about, but I’m doubtful that these concepts really apply to biology. Especially since your example is about constraints on evolvability rather than functioning. In practice that is pretty much how everything tends to work, with absolutely wild amounts of pleiotropy and epistasis, but that’s not a problem unless you want to evolve a new function. Which is probably why the strong strong evolutionary default is towards stasis, not change.
I guess my priors are pretty different because my background is in virology, where our expectation (after decades of painful lessons) is that the default is for proteins to be wildly multifunctional, with many many many “design degrees of freedom.” Granted viruses are a bit of a special case, but I do think they can provide a helpful stress test/simpler model for information theoretic models of genome function.
Start with 25,000 genes, but then reduce it a bunch because they also have to build hair follicles and the Golgi apparatus and on and on. But then increase it a bit too because each gene has more than one design degree of freedom, e.g. a protein can have multiple active sites, and there’s some ability to tweak which molecules can and cannot reach those active sites and how fast etc. Stuff like that.
Putting those two factors together, I dunno, I figure it’s reasonable to guess that the genome can have a recipe for a low-thousands of distinct neuron types each with its own evolutionarily-designed properties and each playing a specific evolutionarily-designed role in the brain algorithm.
And that “low thousands” number is ballpark consistent with the slide-seq thing, and also ballpark consistent with what you get by counting the number of neuron types in a random hypothalamus nucleus and extrapolating. High hundreds, low thousands, I dunno, I’m treating it as a pretty rough estimate.
Hmm, I guess when I think about it, the slide-seq number and the extrapolation number are probably more informative than the genome number. Like, can I really rule out “tens of thousands” just based on the genome size? Umm, not with extreme confidence, I’d have to think about it. But the genome size is at least a good “sanity check” on the other two methods.
No, I wouldn’t necessarily expect something so 1-to-1. Just the general information theory argument. If you have N “design degree of freedom” and you’re trying to build >>N specific machines that each does a specific thing, then you get stuck on the issue of crosstalk.
For example, suppose that some SNP changes which molecules can get to the active site of some protein. It makes Purkinje cells more active, but also increases the ratio of striatal matrix cells to striosomes, and also makes auditory cortex neurons more sensitive to oxytocin. Now suppose there’s very strong evolutionary pressure for Purkinje cells to be more active. Then maybe that SNP is going to spread through the population. But it’s going to have detrimental side-effects on the striatum and auditory cortex. Ah, but that’s OK, because there’s a different mutation to a different gene which fixes the now-suboptimal striatum, and yet a third mutation that fixes the auditory cortex. Oops, but those two mutations have yet other side-effects on the medulla and … Etc. etc.
…Anyway, if that’s what’s going on, that can be fine! Evolution can sort out this whole system over time, even with crazy side-effects everywhere. But only as long as there are enough “design degrees of freedom” to actually fix all these problems simultaneously. There do have to be more “design degrees of freedom” in the biology / genome than there are constraints / features in the engineering specification, if you want to build a machine that actually works. There doesn’t have to be a 1-to-1 match between design-degrees-of-freedom and items on your engineering blueprint, but you do need that inequality to hold. See what I mean?
Cool example, thanks! Yeah, that last part is what I would have said. :)
Interesting...I think I vaguely understand what you’re talking about, but I’m doubtful that these concepts really apply to biology. Especially since your example is about constraints on evolvability rather than functioning. In practice that is pretty much how everything tends to work, with absolutely wild amounts of pleiotropy and epistasis, but that’s not a problem unless you want to evolve a new function. Which is probably why the strong strong evolutionary default is towards stasis, not change.
I guess my priors are pretty different because my background is in virology, where our expectation (after decades of painful lessons) is that the default is for proteins to be wildly multifunctional, with many many many “design degrees of freedom.” Granted viruses are a bit of a special case, but I do think they can provide a helpful stress test/simpler model for information theoretic models of genome function.