9 ms·

No human genome has ever been completely sequenced

241 points by shpx 9y ago

hprotagonist 9y ago
what do you mean, "the" human genome?
- sp332 9y ago
  No individual human's genome has ever been completely sequenced. In addition, there are some parts of human DNA that have never been unambiguously integrated into a larger map of humans' DNA.
- slavik81 9y ago
  The was flag killed. I vouched for this because I had the same question. What does it mean to have sequenced the human genome? If different individuals have a different genome, what is the human genome?
  - chrisamiller 9y ago
    You're right, and the next frontier in genome assembly and mapping algorithms is using graph-based genomes, where differences between individuals or populations can represented as different paths through a sequence graph. (There are lots of better explanations with pretty pictures out there with a little searching)
    - throwanem 9y ago
      That's more of a representation problem, isn't it? I'm not seeing where it would require any new development to produce such a graph - just a lot of CPU time to assemble one from a collection of FASTA files, or whatever linear representation. (And a lot of wall-clock time, to convince people to use it...)
      - chrisamiller 9y ago
        Right - It's not so much algorithmic development as development of the toolchains that will enable such representations to be actually useful for downstream analyses.
  - grzm 9y ago
    The article acknowledges this, though perhaps obliquely: > “As a matter of truth in advertising, the ‘finished’ sequence isn’t finished,” said Eric Lander, who led the lab at the Whitehead Institute that deciphered more of the genome for the government-funded Human Genome Project than any other. “I always say ‘finished’ is a term of art.” The phrasing of your parent is arguably dismissive and does little to further substantive discussion. Can one meaningfully discuss "the human genome"? As you point out, each human (with the exception of identical twins) has a unique genome. I think it's reasonable and useful to be able to say "the human genome" as opposed to "the chimpanzee genome" or "the drosophila genome". If one would rather insist on using the indefinite article, i.e., "a human genome", one can present it without resorting to a rhetorical question replete with scare quotes.
  - nonbel 9y ago
    Not only do different individuals have different genomes, each cell from the same person will have different genomes. It is more like an "average" human genome, one that no actual cell has ever contained.
    - deleted 9y ago
      [deleted]
    - viewtransform 9y ago
      "each cell from the same person will have different genomes" Did you mean each cell will have different gene expression ? I thought all the cells have the same nucleotide sequences barring maybe occasional mutations (like in cancer)
      - nonbel 9y ago
        Mutation rates are high enough that we should expect at least a few every division. There are supposedly n~6e9 base pairs[1] and mutation rate is said to be p~1e-8 per bp per division[2]. Assuming each mutation is independent, etc, etc we get a back of the napkin via the binomial distribution with mean = n*p ~ 60 mutations per division. [1] https://en.wikipedia.org/wiki/Human_genome https://en.wikipedia.org/wiki/Human_genome [2] https://en.wikipedia.org/wiki/Mutation_rate https://en.wikipedia.org/wiki/Mutation_rate
        chrisamiller 9y ago
        Most estimates I'm familiar with are substantially lower than that - between 0.1 and 3 errors per cell division.
        nonbel 9y ago
        Thanks, actually the wikipedia link was "per generation" and they assume ~ 100 divisions/mitoses per human generation. So it should be 1e-10 mutations/bp/division. However, that is for germline, somatic mutation rates are apparently 10-100x more more common: https://www.nature.com/articles/ncomms15183 https://www.nature.com/articles/ncomms15183 These rates no doubt vary by cell type, environment, etc. I was actually thinking something like 1e-6 to 1e-10 mutations/bp/division.
  - khedoros1 9y ago
    From Wikipedia: "The "genome" of any given individual is unique; mapping the "human genome" involved sequencing a small number of individuals and then assembling these together to get a complete sequence for each chromosome. Therefore, the finished human genome is thus a mosaic, not representing any one individual." Members of a species share most of their genetic material with each other, but there are known areas of high variability between individuals. So to build a specific individual's sequence, it seems like they take the baseline "human genome" data, and overlay the areas that are known to change.
iskander 9y ago
It's strange that this article ends as an advertisement for PacBio sequencing (which can ~50k-60k base reads) but makes no mention of Oxford Nanopore (which has gotten megabase reads and keeps improving). Single molecule nanopore sequencing is on track to sequence across the centromeres of human chromosomes in the next few years.
- IBM 9y ago
  As someone who's only casually interested in this field, what are the prospects of any of these upstarts actually unseating Illumina from the throne?
  - jcvhaarst 9y ago
    PacBio and ONT are far from upstarts, they have both already invested millions and millions into their respective technologies. Pacific Biosciences has a Market Cap of 532.88M Oxford Nanopore is at least as big.
  - eggie 9y ago
    I expect us to use the long reads from ONT and PacBio to discover that structural variation is even more important and common than previously appreciated. If that's the case, you'd be silly to use the Illumina technology for anything more complex than population genetics, and this will probably trickle into many parts of the market as the medically-relevant parts of the field realize what the basic science is demonstrating.
    - jashephe 9y ago
      The fact is, unfortunately, that Nanopore sequencing (and also, from what I’ve read, PacBio) has a dramatically higher error rate than Illumina sequencing-by-synthesis. In the near future, anyway, I would expect to see inaccurate PacBio/Nanopore long reads being used as scaffolds for accurate Illumina short reads (in fact, this is already happening). Illumina won’t be going anywhere any time soon.
      - 9y ago
coldtea 9y ago
In other words they don't know what they're doing and they're making it up as they go along -- "yeah, that part there is probably unused", "oh, wait, it's important after all".
- xj9 9y ago
  yes, that's kind of the idea of doing research. you know, to learn things that we don't know yet. or did you think science was a book of unambiguous answers that only the godly scientist may read?
  - sctb 9y ago
    Please leave the name-calling out of comments, like the guidelines ask. https://news.ycombinator.com/newsguidelines.html https://news.ycombinator.com/newsguidelines.html
- phyzome 9y ago
  As the article says, we know there's important stuff in those repetitive regions, it's just really hard to read.
  - coldtea 9y ago
    Well: "“A lot of people in the 1980s and 1990s [when the Human Genome Project was getting started] thought of these regions as nonfunctional,” said Karen Miga, a molecular biologist at the University of California, Santa Cruz. “But that’s no longer the case.” " And: "“I’m between agnostic and a little skeptical that these bits will be important for disease, but maybe I’m saying that because we can’t read them,” Lander said.".
    - throwanem 9y ago
      The "no such thing as junk DNA" claim comes from a paper which is, to say the least, controversial in the field. I would hesitate to take it as prima facie reliable, and in general would recommend looking with extensive skepticism upon popular reporting in this realm of scientific endeavor. After all, this very thread originates in a piece of popular reporting that only seems novel because all of the previous popular reporting has been wrong...
jessriedel 9y ago
As usual, the journalist spends many paragraphs painting a picture of human conflict before actually getting on to the interesting claim. > The reason for these gaps is that DNA sequencing machines don’t read genomes like humans read books, from the first word to the last. Instead, they first randomly chop up copies of the 23 pairs of chromosomes, which total some 3 billion “letters,” so the machines aren’t overwhelmed. The resulting chunks contain from 1,000 letters (during the Human Genome Project) to a few hundred (in today’s more advanced sequencing machines). The chunks overlap. Computers match up the overlaps, assembling the chunks into the correct sequence. > That’s between difficult and impossible to do if the chunks contain lots of repetitive segments, such as TTAATATTAATATTAATA, or TTAATA three times. “The problem is, when you have the same exact words, it’s hard to assemble,” said Lander, just as if jigsaw puzzle pieces show the same exact blue sky. > In 2004, the genome project reported that there were 341 gaps in the sequence. Most of the gaps — 250 — are in the main part of each chromosome, where genes make the proteins that life runs on. These gaps are tiny. Only a few gaps — 33 at last count — lie in or near each chromosome’s centromere (where the two parts of a chromosome connect) and telomeres (the caps at the end of chromosomes), but these 33 are 10 times as long in total as the 250 gaps. I recommend reading HN user eggie's comments on this from last week. https://news.ycombinator.com/item?id=15482439 https://news.ycombinator.com/item?id=15482439 https://news.ycombinator.com/item?id=15483462 https://news.ycombinator.com/item?id=15483462
- shpx 9y ago
  https://youtu.be/fCd6B5HRaZ8 https://youtu.be/fCd6B5HRaZ8 is the best visualization of how the most popular type of DNA sequencer works (that I've found). Imagine you have a string of length 3 billion made by randomly choosing from 4 characters. Like this dna = ''.join(random.choices('atgc', weights=[30.9, 29.4, 19.9, 19.8], k=3_234_830_000)) you get to randomly sample 1 billion[3, page 7] overlapping substrings of length 200[3, page 7] with .1% of the characters randomly changed[3, page 8]. Trying to find the original string from this is technically an undecidable problem. If there's a sequence 400 characters long that repeats multiple times, how could you know if it repeats 5 times or 50 times? (this would be unlikely to happen with random.choices() but DNA isn't random). This is called sequence alignment and it's one of the hard problems in bioinformatics[4]. [0] https://docs.python.org/3/library/random.html https://docs.python.org/3/library/random.html random.choices() was added in Python 3.6 [1] http://www.biology-pages.info/B/BasePairing.html http://www.biology-pages.info/B/BasePairing.html source for `weights` [2] https://en.wikipedia.org/wiki/Human_genome https://en.wikipedia.org/wiki/Human_genome source for 3_234_830_000 (python ignores underscores in numbers) [3] http://sci-hub.io/10.1111/j.1755-0998.2011.03024.x http://sci-hub.io/10.1111/j.1755-0998.2011.03024.x illumina is the most popular producer of genome sequencers [4] https://news.ycombinator.com/item?id=5123377 https://news.ycombinator.com/item?id=5123377
grabcocque 9y ago
One of the things the HGP revealed is that we have way fewer genes than anyone expected. Given that the amount of data encoded in genes appears to be far too small to account for the sophistication and variability in humans, it strongly implied that large areas of DNA that were previously considered marker/filler DNA were of great epigenetic importance.
- toufka 9y ago
  There are also a lot more steps between 'genomic dna' -> 'protein' than was previously appreciated or thought to be of importance. There are a lot of ways to regulate and produce new protiens and variation that is not itself a genomic change. Alternative splicing, readthrough regulaton, multiple kinds of ribosomes, post-translational regulation, etc. all produce significant variation outside of the dna itself.
- ArchReaper 9y ago
  It always seemed insanely stupid to me every time I read something about people claiming certain genes being "non-important" or "non-functional" We have about a 0.0001% comprehension of this whole system, how can you possibly be so arrogant as to think you KNOW that certain parts of the sequence are not important or used in _any_ way? Then again, I'm definitely not qualified to comment on the topic.
joering2 9y ago
Slightly off-topic, but this semi-animation of DNA replication machine that is working right now in your body (in amounts of trillions of devices) blew my mind few months ago. from TED: https://youtu.be/WFCvkkDSfIU?t=3m39s https://youtu.be/WFCvkkDSfIU?t=3m39s
mxwsn 9y ago
> “The problem is, when you have the same exact words, it’s hard to assemble,” said Lander, just as if jigsaw puzzle pieces show the same exact blue sky. This is inaccurate, though the fault is with the author, not Lander. When you have genomic repeats, the appropriate analogy is if you had multiple puzzle pieces that had the exact same edges on all sides. Puzzle pieces that show the same blue sky but with different edges can still be uniquely assembled. But puzzle pieces with identical edges create non-unique but equally satisfactory assembly solutions, and this is the case with the problem of genomic assembly.
Bartweiss 9y ago
> * A gene called ARHGAP11B, which was created by one such duplication, causes the cortex to develop the myriad folds that support complex thought; SRGAP2C, also a duplication, triggers brain development.* A question I've never seen addressed: is one justification for junk DNA to create space for beneficial mutations? Obviously some mutations are actively harmful, but the reason most mutations are destructive is that they break something already-useful into something inert. That's not a risk with non-coding (or irrelevantly-coding) DNA, which means that in return for spending energy on copying junk DNA, we get space where even barely-useful changes will be net positive. Is this obvious to experts? Completely stupid for reasons I don't know? Even a possibility worth discussing?
- deleted 9y ago
  [deleted]
- pjschlic 9y ago
  If I recall correctly from my bioinformatcs classes (years ago) - the non-coding DNA still serve many functions - a protective role by containing sequences which stabilize the structure of the DNA, or providing binding sites used in promoting or suppress gene expression. The non-coding are recognizable by different characteristics from the coding sections. Not to mention the fact that by definition, at least half the sequences are just the complement of a coding sequence - so putting in stop codons before and after on the complement would be useful to make sure it's not expressed. Add in structural sequences to create preferences of where it's safe to swap genes with the sister chromosome DNA during meiosis, and all sorts of other things, and you end up with quite a but of non-coding DNA still serving a purpose.
- nkrumm 9y ago
  Perhaps not exactly "junk dna" but you are right in your thinking about gene duplications... duplications are thought to promote "neofunctionalization" (a new function) or "subfunctionalization" (specialization). See wikipedia [1] for an overview. [1] https://en.wikipedia.org/wiki/Gene_duplication#As_an_evolutionary_event https://en.wikipedia.org/wiki/Gene_duplication#As_an_evoluti...
- searine 9y ago
AaronFriel 9y ago
A question and a story for any intrepid biologists and geneticists. I'm seeing in other comments that this is fundamentally a problem with how genome sequencing works today. When I was a movie theatre projectionist, I had a similar problem. Movies have to be assembled onto platters, from a handful of reels which contain 10-20 minute lengths of film. There's about a mile of film per hour, and to assemble it quickly you have a motorized platter and a table with its own motor with dials to control the speed of one or the other. How it should work is you take a center ring - a circle with a gap to wind film through and metal spokes that sit in the platter - and you spin the film on. You put the reels one by one onto this, stopping with each one to cut the footer of one and the header of the next to splice them together with tape. Well, that's how it's supposed to work. Sometimes, the film tightens up, when moving the film from one platter to another. The center ring spokes might not fit, or might create additional stress. Well, I went full speed ahead anyway, and when a tiny bit of slack resulted in a sudden jerk on the platter, the center ring popped off, and about an hour of film flew over my hand and into the wall behind me. What happened next is almost impossible to describe. A circular disk of film and metal hitting a solid wall briefly became a vertical column as the tension-less film was forced to go any direction except forward, and the result then splayed itself out on the floor in front of me in a tangled mess a mile long. Perhaps like an early sequencing machine, my first attempt at recovering this was to look at a piece of the film and determine what part of the movie it was from, and to begin throwing away the parts I thought were from trailers. They weren't. It was the wrong movie. I despaired, the film was a mile long and tangled into unbelievable knots. I had to cut it to untangle it. But how? And it hit me, I knew where a handful of colored markers were, and I began randomly pulling segments of film out from the mess, placing masking tape across a frame, and making 3 lines in 3 different colors. I made dozens of these little loops, and that was how I put it together. The process: cutting, labeling, and placing the segments into new reels made my shift from that night run into the next day's matinee. This process was painstaking, and that's where my question leads: can we label the ends when we cut up the DNA, like I did with my film? Are we stuck watching chromosomes splash against the wall and shatter into indecipherable pieces?
- bsmrea 9y ago
  This is a nice analogy to genome assembly and there are some technologies that try to label DNA before sequencing to aid reconstruction. The one that comes to mind when reading your post is the 10X Genomics system, which acts as a preprocessor before Illumina sequencing. The idea is that you can introduce nucleotide tags into the DNA molecule(s) before sequencing, then use the tags to figure out what short reads came from the same DNA fragment later on. There is a nice video on 10X's website explaining how this works and how it helps: https://www.10xgenomics.com/technology/ https://www.10xgenomics.com/technology/
pishpash 9y ago
Haven't paid attention to this area in a while but back in the day I've wondered about the garbage-in garbage-out problem in genome databases. A lot of subsequent sequence assemblies were made on the basis of approximate matching to certain results in the database that have no quality information, and conclusions made on the basis of further approximate matching across datasets. Has anyone seriously worked out how reliable some of these conclusions are? At least physicists spend a lot of time worrying about p-values.
- et2o 9y ago
  I don't think anyone knows.
kusmi 9y ago
“I’d be the last one to give you a quote saying that we don’t need to bother with these [unsequenced] regions.” I wonder if he said this with a straight face.

241 points by shpx 9y ago

hprotagonist 9y ago

what do you mean, "the" human genome?

sp332 9y ago
No individual human's genome has ever been completely sequenced. In addition, there are some parts of human DNA that have never been unambiguously integrated into a larger map of humans' DNA.
slavik81 9y ago
The was flag killed. I vouched for this because I had the same question. What does it mean to have sequenced the human genome? If different individuals have a different genome, what is the human genome?
- chrisamiller 9y ago
  You're right, and the next frontier in genome assembly and mapping algorithms is using graph-based genomes, where differences between individuals or populations can represented as different paths through a sequence graph. (There are lots of better explanations with pretty pictures out there with a little searching)
  - throwanem 9y ago
    That's more of a representation problem, isn't it? I'm not seeing where it would require any new development to produce such a graph - just a lot of CPU time to assemble one from a collection of FASTA files, or whatever linear representation. (And a lot of wall-clock time, to convince people to use it...)
    - chrisamiller 9y ago
      Right - It's not so much algorithmic development as development of the toolchains that will enable such representations to be actually useful for downstream analyses.
- grzm 9y ago
  The article acknowledges this, though perhaps obliquely: > “As a matter of truth in advertising, the ‘finished’ sequence isn’t finished,” said Eric Lander, who led the lab at the Whitehead Institute that deciphered more of the genome for the government-funded Human Genome Project than any other. “I always say ‘finished’ is a term of art.” The phrasing of your parent is arguably dismissive and does little to further substantive discussion. Can one meaningfully discuss "the human genome"? As you point out, each human (with the exception of identical twins) has a unique genome. I think it's reasonable and useful to be able to say "the human genome" as opposed to "the chimpanzee genome" or "the drosophila genome". If one would rather insist on using the indefinite article, i.e., "a human genome", one can present it without resorting to a rhetorical question replete with scare quotes.
- nonbel 9y ago
  Not only do different individuals have different genomes, each cell from the same person will have different genomes. It is more like an "average" human genome, one that no actual cell has ever contained.
  - deleted 9y ago
    [deleted]
  - viewtransform 9y ago
    "each cell from the same person will have different genomes" Did you mean each cell will have different gene expression ? I thought all the cells have the same nucleotide sequences barring maybe occasional mutations (like in cancer)
    - nonbel 9y ago
      Mutation rates are high enough that we should expect at least a few every division. There are supposedly n~6e9 base pairs[1] and mutation rate is said to be p~1e-8 per bp per division[2]. Assuming each mutation is independent, etc, etc we get a back of the napkin via the binomial distribution with mean = n*p ~ 60 mutations per division. [1] https://en.wikipedia.org/wiki/Human_genome https://en.wikipedia.org/wiki/Human_genome [2] https://en.wikipedia.org/wiki/Mutation_rate https://en.wikipedia.org/wiki/Mutation_rate
      - chrisamiller 9y ago
        Most estimates I'm familiar with are substantially lower than that - between 0.1 and 3 errors per cell division.
        nonbel 9y ago
        Thanks, actually the wikipedia link was "per generation" and they assume ~ 100 divisions/mitoses per human generation. So it should be 1e-10 mutations/bp/division. However, that is for germline, somatic mutation rates are apparently 10-100x more more common: https://www.nature.com/articles/ncomms15183 https://www.nature.com/articles/ncomms15183 These rates no doubt vary by cell type, environment, etc. I was actually thinking something like 1e-6 to 1e-10 mutations/bp/division.
- khedoros1 9y ago
  From Wikipedia: "The "genome" of any given individual is unique; mapping the "human genome" involved sequencing a small number of individuals and then assembling these together to get a complete sequence for each chromosome. Therefore, the finished human genome is thus a mosaic, not representing any one individual." Members of a species share most of their genetic material with each other, but there are known areas of high variability between individuals. So to build a specific individual's sequence, it seems like they take the baseline "human genome" data, and overlay the areas that are known to change.

iskander 9y ago

It's strange that this article ends as an advertisement for PacBio sequencing (which can ~50k-60k base reads) but makes no mention of Oxford Nanopore (which has gotten megabase reads and keeps improving). Single molecule nanopore sequencing is on track to sequence across the centromeres of human chromosomes in the next few years.

IBM 9y ago
As someone who's only casually interested in this field, what are the prospects of any of these upstarts actually unseating Illumina from the throne?
- jcvhaarst 9y ago
  PacBio and ONT are far from upstarts, they have both already invested millions and millions into their respective technologies. Pacific Biosciences has a Market Cap of 532.88M Oxford Nanopore is at least as big.
- eggie 9y ago
  I expect us to use the long reads from ONT and PacBio to discover that structural variation is even more important and common than previously appreciated. If that's the case, you'd be silly to use the Illumina technology for anything more complex than population genetics, and this will probably trickle into many parts of the market as the medically-relevant parts of the field realize what the basic science is demonstrating.
  - jashephe 9y ago
    The fact is, unfortunately, that Nanopore sequencing (and also, from what I’ve read, PacBio) has a dramatically higher error rate than Illumina sequencing-by-synthesis. In the near future, anyway, I would expect to see inaccurate PacBio/Nanopore long reads being used as scaffolds for accurate Illumina short reads (in fact, this is already happening). Illumina won’t be going anywhere any time soon.
    - 9y ago

coldtea 9y ago

In other words they don't know what they're doing and they're making it up as they go along -- "yeah, that part there is probably unused", "oh, wait, it's important after all".

xj9 9y ago
yes, that's kind of the idea of doing research. you know, to learn things that we don't know yet. or did you think science was a book of unambiguous answers that only the godly scientist may read?
- sctb 9y ago
  Please leave the name-calling out of comments, like the guidelines ask. https://news.ycombinator.com/newsguidelines.html https://news.ycombinator.com/newsguidelines.html
phyzome 9y ago
As the article says, we know there's important stuff in those repetitive regions, it's just really hard to read.
- coldtea 9y ago
  Well: "“A lot of people in the 1980s and 1990s [when the Human Genome Project was getting started] thought of these regions as nonfunctional,” said Karen Miga, a molecular biologist at the University of California, Santa Cruz. “But that’s no longer the case.” " And: "“I’m between agnostic and a little skeptical that these bits will be important for disease, but maybe I’m saying that because we can’t read them,” Lander said.".
  - throwanem 9y ago
    The "no such thing as junk DNA" claim comes from a paper which is, to say the least, controversial in the field. I would hesitate to take it as prima facie reliable, and in general would recommend looking with extensive skepticism upon popular reporting in this realm of scientific endeavor. After all, this very thread originates in a piece of popular reporting that only seems novel because all of the previous popular reporting has been wrong...

jessriedel 9y ago

As usual, the journalist spends many paragraphs painting a picture of human conflict before actually getting on to the interesting claim. > The reason for these gaps is that DNA sequencing machines don’t read genomes like humans read books, from the first word to the last. Instead, they first randomly chop up copies of the 23 pairs of chromosomes, which total some 3 billion “letters,” so the machines aren’t overwhelmed. The resulting chunks contain from 1,000 letters (during the Human Genome Project) to a few hundred (in today’s more advanced sequencing machines). The chunks overlap. Computers match up the overlaps, assembling the chunks into the correct sequence. > That’s between difficult and impossible to do if the chunks contain lots of repetitive segments, such as TTAATATTAATATTAATA, or TTAATA three times. “The problem is, when you have the same exact words, it’s hard to assemble,” said Lander, just as if jigsaw puzzle pieces show the same exact blue sky. > In 2004, the genome project reported that there were 341 gaps in the sequence. Most of the gaps — 250 — are in the main part of each chromosome, where genes make the proteins that life runs on. These gaps are tiny. Only a few gaps — 33 at last count — lie in or near each chromosome’s centromere (where the two parts of a chromosome connect) and telomeres (the caps at the end of chromosomes), but these 33 are 10 times as long in total as the 250 gaps. I recommend reading HN user eggie's comments on this from last week. https://news.ycombinator.com/item?id=15482439 https://news.ycombinator.com/item?id=15482439 https://news.ycombinator.com/item?id=15483462 https://news.ycombinator.com/item?id=15483462

shpx 9y ago
https://youtu.be/fCd6B5HRaZ8 https://youtu.be/fCd6B5HRaZ8 is the best visualization of how the most popular type of DNA sequencer works (that I've found). Imagine you have a string of length 3 billion made by randomly choosing from 4 characters. Like this dna = ''.join(random.choices('atgc', weights=[30.9, 29.4, 19.9, 19.8], k=3_234_830_000)) you get to randomly sample 1 billion[3, page 7] overlapping substrings of length 200[3, page 7] with .1% of the characters randomly changed[3, page 8]. Trying to find the original string from this is technically an undecidable problem. If there's a sequence 400 characters long that repeats multiple times, how could you know if it repeats 5 times or 50 times? (this would be unlikely to happen with random.choices() but DNA isn't random). This is called sequence alignment and it's one of the hard problems in bioinformatics[4]. [0] https://docs.python.org/3/library/random.html https://docs.python.org/3/library/random.html random.choices() was added in Python 3.6 [1] http://www.biology-pages.info/B/BasePairing.html http://www.biology-pages.info/B/BasePairing.html source for `weights` [2] https://en.wikipedia.org/wiki/Human_genome https://en.wikipedia.org/wiki/Human_genome source for 3_234_830_000 (python ignores underscores in numbers) [3] http://sci-hub.io/10.1111/j.1755-0998.2011.03024.x http://sci-hub.io/10.1111/j.1755-0998.2011.03024.x illumina is the most popular producer of genome sequencers [4] https://news.ycombinator.com/item?id=5123377 https://news.ycombinator.com/item?id=5123377

grabcocque 9y ago

One of the things the HGP revealed is that we have way fewer genes than anyone expected. Given that the amount of data encoded in genes appears to be far too small to account for the sophistication and variability in humans, it strongly implied that large areas of DNA that were previously considered marker/filler DNA were of great epigenetic importance.

toufka 9y ago
There are also a lot more steps between 'genomic dna' -> 'protein' than was previously appreciated or thought to be of importance. There are a lot of ways to regulate and produce new protiens and variation that is not itself a genomic change. Alternative splicing, readthrough regulaton, multiple kinds of ribosomes, post-translational regulation, etc. all produce significant variation outside of the dna itself.
ArchReaper 9y ago
It always seemed insanely stupid to me every time I read something about people claiming certain genes being "non-important" or "non-functional" We have about a 0.0001% comprehension of this whole system, how can you possibly be so arrogant as to think you KNOW that certain parts of the sequence are not important or used in _any_ way? Then again, I'm definitely not qualified to comment on the topic.

joering2 9y ago

Slightly off-topic, but this semi-animation of DNA replication machine that is working right now in your body (in amounts of trillions of devices) blew my mind few months ago. from TED: https://youtu.be/WFCvkkDSfIU?t=3m39s https://youtu.be/WFCvkkDSfIU?t=3m39s

mxwsn 9y ago

> “The problem is, when you have the same exact words, it’s hard to assemble,” said Lander, just as if jigsaw puzzle pieces show the same exact blue sky. This is inaccurate, though the fault is with the author, not Lander. When you have genomic repeats, the appropriate analogy is if you had multiple puzzle pieces that had the exact same edges on all sides. Puzzle pieces that show the same blue sky but with different edges can still be uniquely assembled. But puzzle pieces with identical edges create non-unique but equally satisfactory assembly solutions, and this is the case with the problem of genomic assembly.

Bartweiss 9y ago

> * A gene called ARHGAP11B, which was created by one such duplication, causes the cortex to develop the myriad folds that support complex thought; SRGAP2C, also a duplication, triggers brain development.* A question I've never seen addressed: is one justification for junk DNA to create space for beneficial mutations? Obviously some mutations are actively harmful, but the reason most mutations are destructive is that they break something already-useful into something inert. That's not a risk with non-coding (or irrelevantly-coding) DNA, which means that in return for spending energy on copying junk DNA, we get space where even barely-useful changes will be net positive. Is this obvious to experts? Completely stupid for reasons I don't know? Even a possibility worth discussing?

deleted 9y ago
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pjschlic 9y ago
If I recall correctly from my bioinformatcs classes (years ago) - the non-coding DNA still serve many functions - a protective role by containing sequences which stabilize the structure of the DNA, or providing binding sites used in promoting or suppress gene expression. The non-coding are recognizable by different characteristics from the coding sections. Not to mention the fact that by definition, at least half the sequences are just the complement of a coding sequence - so putting in stop codons before and after on the complement would be useful to make sure it's not expressed. Add in structural sequences to create preferences of where it's safe to swap genes with the sister chromosome DNA during meiosis, and all sorts of other things, and you end up with quite a but of non-coding DNA still serving a purpose.
nkrumm 9y ago
Perhaps not exactly "junk dna" but you are right in your thinking about gene duplications... duplications are thought to promote "neofunctionalization" (a new function) or "subfunctionalization" (specialization). See wikipedia [1] for an overview. [1] https://en.wikipedia.org/wiki/Gene_duplication#As_an_evolutionary_event https://en.wikipedia.org/wiki/Gene_duplication#As_an_evoluti...
searine 9y ago

AaronFriel 9y ago

A question and a story for any intrepid biologists and geneticists. I'm seeing in other comments that this is fundamentally a problem with how genome sequencing works today. When I was a movie theatre projectionist, I had a similar problem. Movies have to be assembled onto platters, from a handful of reels which contain 10-20 minute lengths of film. There's about a mile of film per hour, and to assemble it quickly you have a motorized platter and a table with its own motor with dials to control the speed of one or the other. How it should work is you take a center ring - a circle with a gap to wind film through and metal spokes that sit in the platter - and you spin the film on. You put the reels one by one onto this, stopping with each one to cut the footer of one and the header of the next to splice them together with tape. Well, that's how it's supposed to work. Sometimes, the film tightens up, when moving the film from one platter to another. The center ring spokes might not fit, or might create additional stress. Well, I went full speed ahead anyway, and when a tiny bit of slack resulted in a sudden jerk on the platter, the center ring popped off, and about an hour of film flew over my hand and into the wall behind me. What happened next is almost impossible to describe. A circular disk of film and metal hitting a solid wall briefly became a vertical column as the tension-less film was forced to go any direction except forward, and the result then splayed itself out on the floor in front of me in a tangled mess a mile long. Perhaps like an early sequencing machine, my first attempt at recovering this was to look at a piece of the film and determine what part of the movie it was from, and to begin throwing away the parts I thought were from trailers. They weren't. It was the wrong movie. I despaired, the film was a mile long and tangled into unbelievable knots. I had to cut it to untangle it. But how? And it hit me, I knew where a handful of colored markers were, and I began randomly pulling segments of film out from the mess, placing masking tape across a frame, and making 3 lines in 3 different colors. I made dozens of these little loops, and that was how I put it together. The process: cutting, labeling, and placing the segments into new reels made my shift from that night run into the next day's matinee. This process was painstaking, and that's where my question leads: can we label the ends when we cut up the DNA, like I did with my film? Are we stuck watching chromosomes splash against the wall and shatter into indecipherable pieces?

bsmrea 9y ago
This is a nice analogy to genome assembly and there are some technologies that try to label DNA before sequencing to aid reconstruction. The one that comes to mind when reading your post is the 10X Genomics system, which acts as a preprocessor before Illumina sequencing. The idea is that you can introduce nucleotide tags into the DNA molecule(s) before sequencing, then use the tags to figure out what short reads came from the same DNA fragment later on. There is a nice video on 10X's website explaining how this works and how it helps: https://www.10xgenomics.com/technology/ https://www.10xgenomics.com/technology/

pishpash 9y ago

Haven't paid attention to this area in a while but back in the day I've wondered about the garbage-in garbage-out problem in genome databases. A lot of subsequent sequence assemblies were made on the basis of approximate matching to certain results in the database that have no quality information, and conclusions made on the basis of further approximate matching across datasets. Has anyone seriously worked out how reliable some of these conclusions are? At least physicists spend a lot of time worrying about p-values.

et2o 9y ago
I don't think anyone knows.

kusmi 9y ago

“I’d be the last one to give you a quote saying that we don’t need to bother with these [unsequenced] regions.” I wonder if he said this with a straight face.