20 ms·

I've never understood this either. I assume the genome is many megabytes of [ATCG]+. If we have that sequence, what does it tell us? Do we look at it and say "A

I've never understood this either. I assume the genome is many megabytes of [ATCG]+. If we have that sequence, what does it tell us? Do we look at it and say "Ah, yes, ...ATGCTACGACTACGACTAGCG... very interesting?"

jiggawatts 3y ago
Many genes are highly conserved or consistent enough. E.g.: if there's a 1% difference between two people, then it's a bit like two very unique sentences that have a couple of small typos. They're sill recognisable, and it's also still pretty obvious that they're the "same". A gene sequence allows researchers to determine the amino acids that are coded for, and from those, which proteins match which genes. This can be matched up with genetic diseases. If you know that damage to a certain location in a chromosome causes a problem with a certain biological process, then ergo, the associated protein is needed for that process! So: genetic illness -> gene sequence -> protein -> role in the body Without sequencing, that chain can't be built.
- dclowd9901 3y ago
  But you can only know that by having a large sample of very “stable” (have few genetic irregularities) gene samples compared to a large pool of samples from people with very narrow and pronounced gene irregularities, right? Is this why it’s so hard? This feels more like a healthcare records keeping people and less like an “actually reading the data problem”. I can’t help but feel like some form of single payer healthcare is truly the way out of this problem. One where all disease record keeping is uniform and complete.
  - benignslime 3y ago
    [dead]
  - Earw0rm 3y ago
    Single payer healthcare here (UK) is still subject to privacy controls in a way which would make it very difficult to do that. (Also our health system's IT is a hellscape, but one reason for that is that people would literally rather not have a working system at all, than one with less than impeccable privacy controls. Personally I'd gladly sacrifice a fair bit of medical privacy in return for giving scientists greater insight into disease processes, but the average citizen here wants advanced healthcare without giving their data to research scientists. /facepalm )
    - spookie 3y ago
      I trust the scientists, the problem isn't them. Look at the whole abortion data scandal in the U.S.
      - Earw0rm 3y ago
        The problem there is the US' insane theocrat-conservatives (or just misogynist assholes hiding behind a thin veneer of religious justification, as the case may be). I'm not saying a health IT system should have no privacy controls either. But the requirements for such controls need to be balanced against having a system that actually works, and that means having some people who actually understand the tech, and the workings of hospitals, having a role in requirements conversations. Instead it was dominated by MPs, "patient advocacy" groups and privacy campaigners, none of whom know or care anything about how to build a workable system.
  - hwillis 3y ago
    > But you can only know that by having a large sample of very “stable” (have few genetic irregularities) gene samples compared to a large pool of samples from people with very narrow and pronounced gene irregularities, right? No- A "gene" isn't an A/G/C/T- it's a sequence of 1000-1000000 base pairs. Each gene has a well-defined start/stop sequence called a start/stop codon. When people have genetic differences, one (an SNP- single nucleotide polymorph) of the tens of thousands of base pairs in that gene is different. Even for genes that are entirely "missing" in some people, they're really just different in a way that makes them nonfunctional. Does that make it obvious how sequencing all those genes is useful, even if everyone has different genes? It tells us 99.999% of how proteins are coded, even if individual variation is the other .001%.
throw3823423 3y ago
For the same reason Monsanto sequences basically anything: Because we can tell what proteins are encoded in there, and what is near them, and we can have good ideas of what proteins are expressed together. When dealing with genetic modification, we get to see whether our modification went in, and where it landed: Having a protein in a genome isn't enough. Its expression might be having an effect on other things, depending on where it is. When we have baselines, we can compare different individuals, and eventually make predictions of how they are going to be based solely on the genetic code. If I know that a certain polymorphism is tied to some trait I want, I might not have to even bother spending the time growing a plant: I know that it's not what I want, and discard it as a seed. With humans we are probably not going to see much modification soon, but just being able to detect genetic diseases, risk factors for other diseases that have genetic omponents, or allow for selection of embryos in cases of artificial insemination is already quite valuable. It's not source code that we are all that good at understanding just yet, but there's already some applications, and we have good reason to think there's a lot more to come
khazhoux 3y ago
It's just about 3 gigabytes (each byte a letter). Pretty mind-blowing, if you ask me.
- deleted 3y ago
  [deleted]
- cvoss 3y ago
  It's a slight exaggeration of the information content to report the data size using an ASCII encoding. Since there are 4 bases, each can be encoded using 2 bits, rather than 8. So we're really talking 750 megabytes. But still mind-blowing.
  - khazhoux 3y ago
    Yes, and if you gzip it it's even smaller. But the big takeaway is that the amount of info that fully defines a human, is what we consider "not much data," even in its plainest encoding.
    - astrange 3y ago
      We don't know that it fully defines a human until we can create one without the starting condition of being inside another human. It's prototype-based inheritance.
      - hotnfresh 3y ago
        Some of the research about being able to make simple animals grow structures from other animals in their evolutionary “tree” by changing chemical signaling—among other wild things like finding that memories may be stored outside the brain, at least in some animals—makes me think you need more than just the “code” to get the animal that would have been produced if that “code” were in its full context (of a reproductive cell doing all sorts of other stuff). Even if the dna contains the instructions for that reproductive cell, too, in some sense… which instructions do you “run”? There might be multiple possible variants, some of which don’t actually reproduce the animal you took the dna from.
bglazer 3y ago
It’s actually about 3 gigabases (ATCG). There are some recurrent features of the genome whose function we’ve worked out. For example the TATA box is a classic sequence that typically indicates the start of a part of the genome that codes for a protein. The vast majority of the genome doesn’t code for proteins. The function of these genome regions are much more murky. Some of these regions function like scaffolds for proteins to assemble into complexes. These protein complexes then start transcribing the genome into into mRNA. So the genome regulates its own expression, in a sense. Many of the sequences that function in this way are known. There are also just a bunch of parts of the genome that probably don’t do anything. There are also many regions of the genome that are basically self replicating sequences. They code for proteins that are capable of inserting their own genetic sequence back into the genome. These are transposons. In short, a lot of very painstaking genetics and molecular biology work has gone into characterizing the function of certain sequences.
- dopylitty 3y ago
  Also interesting are HERVs - human endogenous retroviruses which integrated into the human or our ancestor species’ genomes. They have degraded over time so none of the human hervs seem to be capable of activating but there are some in other mammals that can fully reactivate. In humans even though hervs don’t reactivate into infectious viruses they have been implicated in both harmful (senescence during aging[0]) and beneficial (protection from modern retroviruses)[1] activities in the body. They might be up to 8% of the human genome. 0: https://www.cell.com/cell/pdf/S0092-8674(22)01530-6.pdf https://www.cell.com/cell/pdf/S0092-8674(22)01530-6.pdf 1:https://www.microbe.tv/twiv/twiv-956/ https://www.microbe.tv/twiv/twiv-956/
dekhn 3y ago
If you think like an ML engineer, the genome is a feature vector 3B bases (or 6B binary bits) long that is highly redundant (many sections contain repeats and other regions that are correlated to other regions), and the mapping between that feature vector and an individual's specific properties (their "phenotype", which could be their height at full maturity, or their eye color, or hair properties, or propensity to diseases, etc) is highly nonlinear. If you had a list of all the genomes of all the people in the world, and all their phenotypes (height, eye color, hair type, etc), you could take all their genomes as input variables and treat all their phenotypes as output variables, and make embeddings or other models that mapped from genomes to phenotypes. The result would be a predictive model that could take a human genome, and spit out a prediction of what that person looks like and other details around them (up to the limits of heritability). A good example is height. If you take a very large diverse sample of people, and sequence them, you will find that about 50% of the variance in height can be traced to the genomic sequence of that individual (other things, such as socioeconomic status, access to health care, pollution, etc, which are non-genomic, contribute as well). originally many geneticists believed that a small number of genes- tiny parts of the feature vector- would be the important features in the genome that explained height. But it didn't turn out that way. Instead, height is a nonlinear function of thousands of different locations (either individual bases, entire genes, or other structures that vary between individuals) in the genome. This was less surprising to folks who are molecular biologists (mainly based on the mental models geneticists and MBers use to think about the mapping of genotype to phenotype), and we still don't have great mechanistic explanations of how each individual difference works in concert with all the others to lead to specific heights. When I started out studying this some 35 years ago the problem sounded fairly simple, I assumed it would be easy to find the place in my genome that led to my funny shaped (inherited) nose, but the more I learn about genomics and phenotypes, the more I appreciate that the problem is unbelievably complex, and really well suited to large datasets and machine learning. All the pharma have petabytes of genome sequences in the cloud that they try hard to analyze but the results are mixed. I spent my entire thesis working on ATGCAAAT, by the way. https://en.wikipedia.org/wiki/Octamer_transcription_factor https://en.wikipedia.org/wiki/Octamer_transcription_factor is a family of proteins that are incredibly important during growth and development. Your genome is sprinkled with locations that contain that sequence- or ones like it- that are used to regulate the expression of proteins to carry out the development plan.
globular-toast 3y ago
The genetic code maps nucleotide sequences (DNA) to amino acid sequences (proteins). Every three bases (say AGT) maps to one amino acid. So you can literally read a sequence of ACGTs and decode it into a protein. A sequence that encodes a protein is called a gene. Almost all variations that humans have in their genomes (compared to each other or a reference genome) are tiny, mostly one base differences called single nucleotide polymorphisms (SNPs). These tiny changes encode who you are. The rest of it just makes you carbon-based organism, a eukaryote, an animal, a mammal etc, just like a whole load of other organisms.
dwattttt 3y ago
You could say exactly the same of all data; it's just 1s and 0s, but when I look I just see blonde, brunette.
VeninVidiaVicii 3y ago
I always make this mistake too as a computational biologist; when talking about DNA it’s megabases not megabytes.
zbaxrl 3y ago
Kinda, https://youtu.be/1ThNnuSuZC0?t=4925 https://youtu.be/1ThNnuSuZC0?t=4925

jiggawatts 3y ago

Many genes are highly conserved or consistent enough. E.g.: if there's a 1% difference between two people, then it's a bit like two very unique sentences that have a couple of small typos. They're sill recognisable, and it's also still pretty obvious that they're the "same". A gene sequence allows researchers to determine the amino acids that are coded for, and from those, which proteins match which genes. This can be matched up with genetic diseases. If you know that damage to a certain location in a chromosome causes a problem with a certain biological process, then ergo, the associated protein is needed for that process! So: genetic illness -> gene sequence -> protein -> role in the body Without sequencing, that chain can't be built.

dclowd9901 3y ago
But you can only know that by having a large sample of very “stable” (have few genetic irregularities) gene samples compared to a large pool of samples from people with very narrow and pronounced gene irregularities, right? Is this why it’s so hard? This feels more like a healthcare records keeping people and less like an “actually reading the data problem”. I can’t help but feel like some form of single payer healthcare is truly the way out of this problem. One where all disease record keeping is uniform and complete.
- benignslime 3y ago
  [dead]
- Earw0rm 3y ago
  Single payer healthcare here (UK) is still subject to privacy controls in a way which would make it very difficult to do that. (Also our health system's IT is a hellscape, but one reason for that is that people would literally rather not have a working system at all, than one with less than impeccable privacy controls. Personally I'd gladly sacrifice a fair bit of medical privacy in return for giving scientists greater insight into disease processes, but the average citizen here wants advanced healthcare without giving their data to research scientists. /facepalm )
  - spookie 3y ago
    I trust the scientists, the problem isn't them. Look at the whole abortion data scandal in the U.S.
    - Earw0rm 3y ago
      The problem there is the US' insane theocrat-conservatives (or just misogynist assholes hiding behind a thin veneer of religious justification, as the case may be). I'm not saying a health IT system should have no privacy controls either. But the requirements for such controls need to be balanced against having a system that actually works, and that means having some people who actually understand the tech, and the workings of hospitals, having a role in requirements conversations. Instead it was dominated by MPs, "patient advocacy" groups and privacy campaigners, none of whom know or care anything about how to build a workable system.
- hwillis 3y ago
  > But you can only know that by having a large sample of very “stable” (have few genetic irregularities) gene samples compared to a large pool of samples from people with very narrow and pronounced gene irregularities, right? No- A "gene" isn't an A/G/C/T- it's a sequence of 1000-1000000 base pairs. Each gene has a well-defined start/stop sequence called a start/stop codon. When people have genetic differences, one (an SNP- single nucleotide polymorph) of the tens of thousands of base pairs in that gene is different. Even for genes that are entirely "missing" in some people, they're really just different in a way that makes them nonfunctional. Does that make it obvious how sequencing all those genes is useful, even if everyone has different genes? It tells us 99.999% of how proteins are coded, even if individual variation is the other .001%.

throw3823423 3y ago

For the same reason Monsanto sequences basically anything: Because we can tell what proteins are encoded in there, and what is near them, and we can have good ideas of what proteins are expressed together. When dealing with genetic modification, we get to see whether our modification went in, and where it landed: Having a protein in a genome isn't enough. Its expression might be having an effect on other things, depending on where it is. When we have baselines, we can compare different individuals, and eventually make predictions of how they are going to be based solely on the genetic code. If I know that a certain polymorphism is tied to some trait I want, I might not have to even bother spending the time growing a plant: I know that it's not what I want, and discard it as a seed. With humans we are probably not going to see much modification soon, but just being able to detect genetic diseases, risk factors for other diseases that have genetic omponents, or allow for selection of embryos in cases of artificial insemination is already quite valuable. It's not source code that we are all that good at understanding just yet, but there's already some applications, and we have good reason to think there's a lot more to come

khazhoux 3y ago

It's just about 3 gigabytes (each byte a letter). Pretty mind-blowing, if you ask me.

deleted 3y ago
[deleted]
cvoss 3y ago
It's a slight exaggeration of the information content to report the data size using an ASCII encoding. Since there are 4 bases, each can be encoded using 2 bits, rather than 8. So we're really talking 750 megabytes. But still mind-blowing.
- khazhoux 3y ago
  Yes, and if you gzip it it's even smaller. But the big takeaway is that the amount of info that fully defines a human, is what we consider "not much data," even in its plainest encoding.
  - astrange 3y ago
    We don't know that it fully defines a human until we can create one without the starting condition of being inside another human. It's prototype-based inheritance.
    - hotnfresh 3y ago
      Some of the research about being able to make simple animals grow structures from other animals in their evolutionary “tree” by changing chemical signaling—among other wild things like finding that memories may be stored outside the brain, at least in some animals—makes me think you need more than just the “code” to get the animal that would have been produced if that “code” were in its full context (of a reproductive cell doing all sorts of other stuff). Even if the dna contains the instructions for that reproductive cell, too, in some sense… which instructions do you “run”? There might be multiple possible variants, some of which don’t actually reproduce the animal you took the dna from.

bglazer 3y ago

It’s actually about 3 gigabases (ATCG). There are some recurrent features of the genome whose function we’ve worked out. For example the TATA box is a classic sequence that typically indicates the start of a part of the genome that codes for a protein. The vast majority of the genome doesn’t code for proteins. The function of these genome regions are much more murky. Some of these regions function like scaffolds for proteins to assemble into complexes. These protein complexes then start transcribing the genome into into mRNA. So the genome regulates its own expression, in a sense. Many of the sequences that function in this way are known. There are also just a bunch of parts of the genome that probably don’t do anything. There are also many regions of the genome that are basically self replicating sequences. They code for proteins that are capable of inserting their own genetic sequence back into the genome. These are transposons. In short, a lot of very painstaking genetics and molecular biology work has gone into characterizing the function of certain sequences.

dopylitty 3y ago
Also interesting are HERVs - human endogenous retroviruses which integrated into the human or our ancestor species’ genomes. They have degraded over time so none of the human hervs seem to be capable of activating but there are some in other mammals that can fully reactivate. In humans even though hervs don’t reactivate into infectious viruses they have been implicated in both harmful (senescence during aging[0]) and beneficial (protection from modern retroviruses)[1] activities in the body. They might be up to 8% of the human genome. 0: https://www.cell.com/cell/pdf/S0092-8674(22)01530-6.pdf https://www.cell.com/cell/pdf/S0092-8674(22)01530-6.pdf 1:https://www.microbe.tv/twiv/twiv-956/ https://www.microbe.tv/twiv/twiv-956/

dekhn 3y ago

If you think like an ML engineer, the genome is a feature vector 3B bases (or 6B binary bits) long that is highly redundant (many sections contain repeats and other regions that are correlated to other regions), and the mapping between that feature vector and an individual's specific properties (their "phenotype", which could be their height at full maturity, or their eye color, or hair properties, or propensity to diseases, etc) is highly nonlinear. If you had a list of all the genomes of all the people in the world, and all their phenotypes (height, eye color, hair type, etc), you could take all their genomes as input variables and treat all their phenotypes as output variables, and make embeddings or other models that mapped from genomes to phenotypes. The result would be a predictive model that could take a human genome, and spit out a prediction of what that person looks like and other details around them (up to the limits of heritability). A good example is height. If you take a very large diverse sample of people, and sequence them, you will find that about 50% of the variance in height can be traced to the genomic sequence of that individual (other things, such as socioeconomic status, access to health care, pollution, etc, which are non-genomic, contribute as well). originally many geneticists believed that a small number of genes- tiny parts of the feature vector- would be the important features in the genome that explained height. But it didn't turn out that way. Instead, height is a nonlinear function of thousands of different locations (either individual bases, entire genes, or other structures that vary between individuals) in the genome. This was less surprising to folks who are molecular biologists (mainly based on the mental models geneticists and MBers use to think about the mapping of genotype to phenotype), and we still don't have great mechanistic explanations of how each individual difference works in concert with all the others to lead to specific heights. When I started out studying this some 35 years ago the problem sounded fairly simple, I assumed it would be easy to find the place in my genome that led to my funny shaped (inherited) nose, but the more I learn about genomics and phenotypes, the more I appreciate that the problem is unbelievably complex, and really well suited to large datasets and machine learning. All the pharma have petabytes of genome sequences in the cloud that they try hard to analyze but the results are mixed. I spent my entire thesis working on ATGCAAAT, by the way. https://en.wikipedia.org/wiki/Octamer_transcription_factor https://en.wikipedia.org/wiki/Octamer_transcription_factor is a family of proteins that are incredibly important during growth and development. Your genome is sprinkled with locations that contain that sequence- or ones like it- that are used to regulate the expression of proteins to carry out the development plan.

globular-toast 3y ago

The genetic code maps nucleotide sequences (DNA) to amino acid sequences (proteins). Every three bases (say AGT) maps to one amino acid. So you can literally read a sequence of ACGTs and decode it into a protein. A sequence that encodes a protein is called a gene. Almost all variations that humans have in their genomes (compared to each other or a reference genome) are tiny, mostly one base differences called single nucleotide polymorphisms (SNPs). These tiny changes encode who you are. The rest of it just makes you carbon-based organism, a eukaryote, an animal, a mammal etc, just like a whole load of other organisms.

dwattttt 3y ago

You could say exactly the same of all data; it's just 1s and 0s, but when I look I just see blonde, brunette.

VeninVidiaVicii 3y ago

I always make this mistake too as a computational biologist; when talking about DNA it’s megabases not megabytes.

zbaxrl 3y ago

Kinda, https://youtu.be/1ThNnuSuZC0?t=4925 https://youtu.be/1ThNnuSuZC0?t=4925