[HN Gopher] The complete sequence of a human Y chromosome
___________________________________________________________________
The complete sequence of a human Y chromosome
Author : birriel
Score : 463 points
Date : 2023-08-25 01:36 UTC (21 hours ago)
(HTM) web link (www.nature.com)
(TXT) w3m dump (www.nature.com)
| mrazomor wrote:
| This is exciting!
|
| BTW. if you want to know the applications of this work, have a
| look at this ACM SIGPLAN Keynote:
| https://youtu.be/JTU3JYp3JYc?si=jOZz611ATQar3Gec (helped me
| understand DNA more than all biology classes at my high school)
| dramebaaz wrote:
| Thanks for that ACM SIGPLAN talk link, it was very fascinating
| and engaging.
| icoder wrote:
| 1) What we had was not complete because sequencing happened for
| (relatively) small chunks. Due to overlap the sequence could be
| reconstructed, but not for areas with a lot of repeats.
|
| 2) This incomplete sequence has nevertheless been VERY useful,
| because these repeats mostly are outside of protein encoding
| regions ('genes').
|
| 3) 'The' human genome is of course non existent because you and I
| have a different one. What is meant is that this has been done
| for a 'bunch' of individual humans.
|
| 4) Because we're much more alike than we are different in our
| genome, this is still very informative.
| hanniabu wrote:
| What are the implications of this? What's now possible with this
| feat completed?
| tomcam wrote:
| ...and mine has been found sorely wanting
| nvader wrote:
| [flagged]
| coldtea wrote:
| Is this like: "we have a working keyboard driver" or more like
| "we identified all 104 keys on a standard 104-key US QWERTY
| layout"?
| moffkalast wrote:
| Sounds more like they've been using the 87-key QWERTY so far,
| but now they also found the numpad.
| oldgradstudent wrote:
| They now have the raw data for the CAD files used for
| manufacturing the keyboard.
|
| We understand some CNC instructions, but there's no good
| understanding of the control mechanisms or sequencing.
|
| One day we'll identify the keys, but we are very far from the
| driver, and more importantly, from identifying what each key
| does.
|
| Oh, we did discover that changing specific bits in the raw data
| causes the keyboard to fail in interesting ways.
| gandalfgreybeer wrote:
| Not answering your question, but I have to say, this is one of
| the best analogies I've encountered in a while.
| quickthrower2 wrote:
| The keyboard driver means knowing what effect every key has?
| coldtea wrote:
| Wow, thanks!
| [deleted]
| msuvakov wrote:
| This news should be dated back in December, not now.
|
| The T2T team published a preprint [1] last December and released
| the data [2] in March. However, due to the peer review process,
| the findings have only just been formally published in Nature.
| The publication timeline can indeed be slow, and in cases like
| this one, the question is: what's the point when all scientists
| interested in the topic already know about it and working with
| this assembly?
|
| [1]
| https://www.biorxiv.org/content/10.1101/2022.12.01.518724v1....
| [2] https://github.com/marbl/CHM13
| goodcanadian wrote:
| _what 's the point when all scientists interested in the topic
| already know about it and working with this assembly?_
|
| In this context, I would say the point of a press release is
| getting the news out generally to non-scientists.
| madduci wrote:
| Why do they use a paywalled service to publish their research?
| space_fountain wrote:
| As I understand it this was hard because most mechanisms we have
| for sequencing genes work by first splitting large sequences of
| genes into random chunks and sequencing each chunk individually.
| These chunks then need arranged properly to form the entire
| genome. This is possible at all because we can get overlap
| between the chunks, but when a sequence has repeating sections
| overlap still isn't enough to stitch everything together
| correctly. There's also a newer technique involving nano pores.
| The dna is literally pulled through a little hole and the
| electrical properties change depending on which base pair is
| inside the pore, sadly it's liable to errors in a deterministic
| way depending on the sequence. I don't have access to the full
| paper so I'm not quite sure what was done here, but I have heard
| people talk about combining the two approaches above
| jakobnissen wrote:
| They relied mainly on PacBio HiFi reads (which I think is a
| truly understated revolutionary technology in genomics), then
| used Nanopore sequencing to link together the HiFi contigs to
| cover the truly gnarly regions of the chromosome.
|
| And yeah, you're right: All modern large-scale sequencing is
| shotgun sequencing where the DNA is randomly broken up, each
| fragment is sequenced, and then the individual segments (reads)
| are assembled using a genome assembler.
| robwwilliams wrote:
| And the PacBio system they used in this paper is already old
| news and has been replaced by PacBio Revio system. Higher
| throughput, cheaper per base and somewhat more accurate.
| ManuelKiessling wrote:
| So, did they find the reason why BMW drivers are always
| tailgating me on the Autobahn?
| hinkley wrote:
| Are you driving an Audi?
| jacquesm wrote:
| Because you stay in the left lane when you shouldn't?
| wallaBBB wrote:
| Yes, move out of the left lane.
| mikeyouse wrote:
| A good article about the achievement from UC Santa Cruz, where
| one of the lead scientists of the Telomere-to-Telomere project
| works:
|
| https://news.ucsc.edu/2023/08/t2t-y-chromosome.html
| catsarebetter wrote:
| omg and with the new tech around generative AI...
|
| This is shaping up to be a very interesting decade to be in tech.
|
| We might actually be able to generate new sequences and test them
| against all the diseases to remove them.
| muizelaar wrote:
| The preprint:
| https://www.biorxiv.org/content/10.1101/2022.12.01.518724v2....
| brayman30 wrote:
| This is actually kind of a huge deal since it means that all 24
| chromosomes have now been fully sequenced. As it says in the
| abstract, up until now the Y chromosome proved difficult to
| sequence due to its nature.
| p1mrx wrote:
| You can tell it's the Y chromosome because of the way it is.
| certifiedloud wrote:
| Thats pretty neat!
| AgentME wrote:
| I thought the human genome project finished in 2003, but now
| that I look it up again, apparently "finished" meant 92%. And
| then it was finished in 2022. And now it's finished again. Are
| there any remaining milestones left toward maybe finishing it
| again? Was the Y chromosome really just considered an exception
| until now?
| dclowd9901 wrote:
| human_genome_final_FINAL_3.txt
| tobinfricke wrote:
| What makes the Y chromosome more difficult?
| mnw21cam wrote:
| All of the chromosomes have difficult bits in them. The Y
| chromosome in particular has huge sections that are
| difficult.
|
| By difficult, imagine a jigsaw puzzle. Difficult bits in the
| jigsaw puzzle are where you have the same sub-image repeated
| over and over again, or where the same image section is
| repeatedly scattered over the wider image. Puzzle pieces from
| these bits are difficult because you can't tell which part of
| the image such a small puzzle piece comes from, because it
| matches multiple places. It's technically impossible to
| resolve repetitive features where the repeating unit is
| larger than the pieces you are trying to assemble together.
| Modern technology gives us long read sequencing, where
| sequenced sections of DNA may be up to 100kbp or larger
| (maybe up to a 1Mbp), where older sequencing methods (that
| are still heavily used because they are cheaper) give us
| sequenced sections of DNA between 100-300bp long. (bp stands
| for base-pairs - one of [ACGT].) These larger puzzle pieces
| allowed the whole picture to be assembled without ambiguity.
|
| However, this isn't why the Y chromosome was solved last. The
| reason for this is that the other chromosomes were analysed
| using a completely homozygous hydatidiform mole, which is
| where cells generate two copies of their entire genome from
| just one copy during conception, and therefore the two copies
| are identical. It makes the sequencing a lot easier if you
| don't have to deal with having two copies of the DNA that are
| slightly different. The side-effect of that is the
| hydatidiform mole doesn't have a Y chromosome, so they had to
| analyse a different sample later on to get a Y chromosome.
| tobinfricke wrote:
| What does "mole" mean in this context?
| mnw21cam wrote:
| https://en.wikipedia.org/wiki/Molar_pregnancy
| [deleted]
| BbzzbB wrote:
| Maybe someone can correct the details since it's been a few
| years I done this, but we sequence DNA by PCR. Roughly, (1)
| breaking it up in small pieces and split strands, (2) mixing
| it with an enzyme that completes each single strand, (3)
| repeat 1 and 2 a bunch to multiply the strands many times
| over to make the solution a sense DNA juice, (4) pass it
| through a machine that'll sequence thousands of these small
| strands and (5) align these short DNA sequences with a
| software that matches unique sequences.
|
| I did it with COI gene, which is just a short (1000ish base
| pairs with our snails IIRC) sequence of purely random ATGC
| base pairs. Lots of unique sequences make the short strands
| easy to match, just get a bunch of 10-15 BP bits and you can
| match the whole thing.
|
| Now if your gene is 62M BP of repeating palindrome sequences,
| you can imagine how hard it would be to align random pieces
| sequenced as it will be very hard to find unique sequences to
| match.
| inciampati wrote:
| We don't use PCR anymore! It's direct sequencing of the
| primary DNA. We can read single molecules. That's the quiet
| revolution in nanotechnology that's driving all these
| complete assemblies.
| bux93 wrote:
| It's on line 1 of the linked article: "The human Y chromosome
| has been notoriously difficult to sequence and assemble
| because of its complex repeat structure that includes long
| palindromes, tandem repeats and segmental duplications" and
| comes with 3 citations.
| bonestamp2 wrote:
| As others have asked in this thread, what does "fully
| sequenced" mean to the layman?
| yellowcake0 wrote:
| It looks like from the preprint that they sequenced the Y
| chromosome of HG002, which was one of the original 1000
| genomes samples from way back in the day, still held in deep
| freeze at a number of biobanks.
|
| Short-read sequencing data is a notoriously bad datatype for
| reconstructing the low-complexity / repetitive regions of
| genomes, so up until recently the most commonly used
| reference genomes have left many of these regions "dark".
| According to the preprint, the Y chromosome has the highest
| density of these low-complexity regions. It's also something
| of a bioinformatic nuisance when constructing a generic human
| reference genome, as it's only present in 50% of the
| population.
| scandum wrote:
| Isn't the problem the absence of random DNA?
|
| I wouldn't call random data 'complex', but it is easy to
| sequence when assembling short reads.
| icholy wrote:
| It provides a complete baseline/reference DNA "map". Common
| "problems" show up on specific parts of this map. So you can
| sequence small subsets of a patient's DNA and compare it to
| these "problem areas" to detect genetic diseases.
| Legend2440 wrote:
| TIL the human Y chromosome hadn't been completely sequenced until
| now.
| 10g1k wrote:
| For those who don't recall: Back in the Dark Ages, there was a
| race to decode the human genome. The leading competitiors
| (wealthiest) were Celera Genomics and the Human Genome Project.
| After some time, Celera (headed by Craig Venter), announced they
| had done the deed. However, what Celera had actually done was
| used what they called a "shotgun method", which meant they took
| small samples here and there, then built a model of the genome
| with various statistical shenanigans. About five years later,
| after all the hype, they admitted they had not sequenced the
| entire genome.
|
| Ref: https://www.technologyreview.com/2007/09/04/223919/craig-
| ven...
| comboy wrote:
| Anybody familiar with news sources which questioned Celera
| accomplishment before they admitted how they did it?
| cowsandmilk wrote:
| Parent is weird in claiming celera was hiding things. The
| second half of the 90s was a very vocal spat between Celera
| and the HGP about sequencing methods and Celera saying
| shotgun sequencing was superior. And the HGP was publishing
| updates to their genome every 24 hours while Celera published
| their sequence on completion of the initial draft, which
| showed their coverage. The fact that there wasn't 100%
| coverage wasn't hidden to anyone who read the published
| papers. (The abstract for the Celera paper even states
| "reduced the size and number of gaps", which plainly
| indicates there were still gaps...)
| comboy wrote:
| Huh, narration matters. Thanks.
| jhbadger wrote:
| As noted, the shotgun sequencing wasn't any worse than the
| traditional chromosome walking method used by the other human
| genome project, and neither created a truly complete sequence,
| which is only possible today with improvements in technology.
|
| And it is worth noting that despite all the critiques of
| shotgun sequencing at the time as "cheating", chromosome
| walking sequencing is dead, and shotgun is what we use today.
| If anything replaces that it will be long read technology like
| that done by Oxford Nanopore sequencing, although we aren't
| really there yet (you still need to assemble that data and
| don't really get end-to-end sequences yet).
| kazinator wrote:
| I feel a joke coming on.
|
| Mother: "Amy, dear, you hardly touched any of your
| vegetables. Most of them are still on your plate."
|
| Amy: "That's not true, Mom; I completely sequenced them into
| my tummy using the shotgun method."
| udkl wrote:
| Someone submit this to smbc comics !
| robwwilliams wrote:
| Not true now with PacBio Revio and new Oxford Nanopore
| chemistry and flow cells. We still use a bit of older
| Illumina data for polishing, but long read methods now as
| accurate. HiC and Bionano more important as supplements than
| 150 nucleotide pair-end reads.
|
| And the cost of a T2T using a combination of these
| technologies is already well under $10,000 in reagent costs.
| The assembly is still a complex art especially for a messy
| chromosome like Y.
| delecti wrote:
| I don't think this was a secret. I remember reading an article
| (IIRC in Readers Digest) nearly ~20 years ago which
| specifically referred to it as a "shotgun method". I wasn't
| (and still am not) enough of an expert to have known that was a
| less authentic/accurate method, but at least at the time the
| tone was not that they were doing anything illicit.
| ekianjo wrote:
| [flagged]
| tomrod wrote:
| I'm sorry, are you saying the media, whose job it is to
| report and not serve as experts, are useless ignorants, or
| Celera, which lied to the public, are useless idiots?
|
| If the first, time to let that dead dog lie. It's a tired
| trope.
| kaliqt wrote:
| Not a tired trope because that dog isn't dead. Until the
| media either 1. has no influence or 2. stops being
| dishonest then it needs to constantly be called out and
| berated.
| lemmsjid wrote:
| What if it is apparent that there are other groups
| pushing the narrative that the media is untrustworthy so
| that they themselves can own the narrative?
|
| Any given group of humans will have a mixture of
| deceptive and trustworthy participants. Singling one
| group out for constant castigation, held against an
| impossible standard, makes it easier for dishonest
| members of other groups to avoid the spotlight.
| kortilla wrote:
| It doesn't matter, because "the media" doesn't work as a
| concept. It's a bunch of amateurs trained on nothing more
| than hiding the fact that they are not an expert.
|
| How much of the reporting from the media revealed that
| Theranos was a fraud? Anything that wasn't was fucking
| useless because it's just a megaphone for corporate PR,
| despite what they think.
|
| The entire concept of a weekly news is risible, let alone
| daily news. A fully investigated story actually worthy of
| the term journalism requires probably 2 employee years
| worth of actual work.
|
| Look at how many articles the NYTimes publishes daily,
| multiply it by 700, and then compare that number with the
| actual number of journalists they have. It's a complete
| farce.
| lemmsjid wrote:
| Aren't we all a bunch of amateurs hiding our lack of true
| expertise? Each passing decade I feel that all the more.
| I think you've described the human condition.
| AnthonyMouse wrote:
| "The media" isn't a uniform entity, but when people refer
| to it in this context they typically mean the large
| consolidated media corporations that own major print and
| television outlets. And those entities have essentially
| eroded their own credibility to the point that trusting
| anything they say is foolish. If they say the sky is
| blue, go out and check.
|
| They _could_ do better, but until they _do_ , it makes
| sense to castigate them when they err, because avoiding
| that reputational harm is their incentive to do better.
| Or, if they fail to do better, the thing that should
| ultimately kill them so they can be replaced with
| something that can do better.
| lemmsjid wrote:
| The larger news outlets are some of the few remaining
| places that actually hold their news rooms to some kind
| of factual standard and facsimile of objective reality.
| If NYT or the Economist or the BBC tells me the sky is
| blue, I'm pretty sure it is. If they report on some
| scientific topic the reporter is not an expert on, I
| understand that there's probably some signal lost. If
| they publish something on a contested political topic, I
| understand there might be some slant in the direction of
| their overall political leaning. I also understand that
| they have an interest in the direction of their corporate
| ownership and host country. But there are plenty of other
| outlets trying (and succeeding) at capturing audiences
| who have all those same conflicts of interest, and more,
| but do not hold themselves to a factual standard.
|
| While media companies have indeed "eroded their own
| credibility", in that there's a steady stream of
| falseness alongside truth, I would add with equal measure
| that "their credibility has been undermined by others".
| The loudest voices that castigate the media, in America
| at least, tend to be the ones that profit the most from
| being the sole arbiter of truth for their own audiences.
|
| The business model of having an autonomous news room that
| holds itself to factual standards and is largely
| sequestered from advertising is shrinking and shrinking.
| I mourn its death, for I see no replacement coming along.
| AnthonyMouse wrote:
| > The business model of having an autonomous news room
| that holds itself to factual standards and is largely
| sequestered from advertising is shrinking and shrinking.
|
| In large corporations it's effectively already dead,
| because many of the "trusted" names have already
| abandoned it, and you can't even tell which ones they are
| without being inside the newsroom to know if stories
| there get spiked on behalf of advertisers.
|
| Where you can still get this is the likes of Substack,
| where you're paying a subscription to someone who doesn't
| _have_ advertisers.
|
| > The loudest voices that castigate the media, in America
| at least, tend to be the ones that profit the most from
| being the sole arbiter of truth for their own audiences.
|
| That's to be expected when it benefits them. But their
| criticisms would sure have a lot less weight if they
| weren't _accurate_.
| ekianjo wrote:
| > If NYT or the Economist or the BBC tells me the sky is
| blue
|
| Since these journalists are spending their time on
| Twitter and never put a foot outside on the real world,
| no, I dont trust anything they say.
| johnnyanmac wrote:
| I think Hanlon's razor applies here. ignorance is not
| dishonesty.
| 000ooo000 wrote:
| I'd rather these ideas spread to others, potentially
| younger readers, than never have to read a trope again. I'm
| not sure it will ever change if we just accept it and never
| discuss it again.
| dekhn wrote:
| In a sibling comment I give about 6 articles published over 3
| decades by a single outlet- the Old Grey Lady (NY Times)- and
| it the competition was widely covered at the time.
| mannykannot wrote:
| My recollection of the contentious issues at the time are that
| a) the Celera project needed the information being made public
| by the NIH/international Human Genome Project in order to
| assemble sequences, but was keeping secret its own results, and
| b) it was intent on acquiring IP rights before the information
| entered the public domain.
| jjtheblunt wrote:
| Shotgun sequencing could be better explained than "statistical
| shenanigans": imagine blasting a huge collection of identical
| long strings with a shotgun, each breaking into different
| fragments, and realizing overlaps in the fragments,
| collectively, can be enough to uniquely restore one copy of the
| original string.
| dekhn wrote:
| Yes, but the HGP didn't make a full sequence either, using
| their scaffold-based contig assembly. Both groups declared a
| truce and announced they were "finished with the first draft"
|
| 35 years ago: https://www.nytimes.com/1987/12/13/magazine/the-
| genome-proje...
|
| 33 years ago:
| https://www.nytimes.com/1990/06/05/science/great-15-year-pro...
|
| 29 years ago: the competition gets fierce
| https://www.nytimes.com/1994/02/22/science/scientist-at-work...
|
| 24 years ago: the race is alive!
| https://www.nytimes.com/1999/03/23/science/who-ll-sequence-h...
|
| 23 years ago: draft is complete
| https://archive.nytimes.com/www.nytimes.com/library/national...
|
| 20 years ago: https://www.nytimes.com/2003/04/15/science/once-
| again-scient...
|
| 2 years ago:
| https://archive.nytimes.com/www.nytimes.com/library/national...
|
| The celera approach using shotgun was tricky because assembling
| the bits required a great deal of computational finesse and
| horsepower; "The final assembly computations were run on
| Compaq's new AlphaServer GS160 because the algorithms and data
| required 64 gigabytes of shared memory to run successfully."
|
| At the time the GS160 was the monster machine, a classic big
| iron UNIX, which could be tightly clustered- unified
| IO/filesystem between all the machines. The primary author of
| the shotgun assembly was Gene Myers, who previously had written
| BLAST, and invented the Suffix Array with Udi Manber.
|
| The public project had its own issues, as many of the teams
| assigned to work on it still had the "cottage
| industry/artisinal/academic" approach, then Eric Lander came
| along and turned it into an industrial process, and parlayed
| that into running the Broad Institute, a privately funded
| MIT/Harvard research institute in Boston.
|
| These days petabytes of sequence data are generated every day
| and stored in clouds. The genome has been a fundamental tool
| for shaping our studies of humans, although its true potential
| for understanding complex phenotypes remains elusive.
| sublinear wrote:
| > The primary author of the shotgun assembly was Gene Myers,
| who previously had written BLAST...
|
| So... um... BLAST processing?
| heyoni wrote:
| I think blast is for mapping sequences on existing genomes,
| which uses similar algorithms but applied for a different
| purpose.
| jghn wrote:
| Lets not forget how Perl Saved The Human Genome Project [1],
| which I remember seeing in a print magazine at the time.
|
| As someone who is in the genomics world now as a software
| person, I find it amusing that I've gotten more into perl
| over the last year or so. It has its place, in the way that
| grep/sed/awk/etc does.
|
| [1] https://news.ycombinator.com/item?id=30327812
| dekhn wrote:
| Lincoln Stein is great, and perl was certainly critical to
| many processes, but it was and remains fairly niche in
| genomics, which used much more C++, Java, and later Python.
|
| IMHO the person who "saved the genome project" was WJ Kent,
| who developed the assembler, BLAT, that the public project
| needed. I strive to point out that he wasn't a sole hero,
| nor was Lincoln. What I really like about BLAT is that
| while Celera was using Big Iron UNIX (massive 64-bit 64GB
| machines with 10s of terabytes of central high performance
| storage), BLAT ran on a cluster of linux machines, right
| around the time that people were waking up to the fact that
| linux was becoming a useful tool for scientific data
| processing. BLAT's design allowed it to work on a cluster
| of cheaper/smaller machines, while celera's algorithm
| really needed a massive shared memory single machine. it
| was sort of a microcosm of the larger battle being fought
| between Big iron UNIX and little intel linux at the time.
| ryandv wrote:
| I had the privilege of working a co-op term at Stein's
| lab at the OICR. I encountered quite a bit of Perl during
| my short time there, and have yet to see it elsewhere in
| the modern enterprise tech world. BioPerl in particular
| stands out as a fairly substantial project in the
| bioinformatics space.
| jboy55 wrote:
| Amazon still has some Perl kicking around, mainly on the
| main website. I don't think there's any new development
| though, just maintenance and gradual replacement.
| jfoutz wrote:
| I know hn isn't the place for memes, but, I'm obligated.
| Imagine what they could do with a beowulf cluster of
| pentium pros?
| epistasis wrote:
| There was a NYTimes profile at the time of Kent's
| efforts, and they IIRC literally got the UC Santa Cruz
| administration to hand over desktop computers destined to
| go to various people for a few months to assemble into a
| cluster. So it was likely a bunch of pentium pros or
| similar. Not a Beowulf cluster, of course, but whatever
| clustering software Kent had hand rolled out of C for the
| purpose.
| jacquesm wrote:
| They weren't using pentium pros, they were using Alpha's
| because the memory interconnect between a beowulf cluster
| of pentium pros would be orders of magnitude slower. So
| likely 'the same, but much slower'.
| jfoutz wrote:
| oh, ha. yeah, that was sort of the root of the joke.
| companies like Celera, or whoever had the money would
| write a (large) check for big iron.
|
| smaller organizations were realizing they could get
| slower computers power pretty cheap, and they could get a
| whole lot of them. There was a little flurry of activity
| with flocking algorithms, objective-c had a little
| renaissance due to swarm computing. probably the most
| famous and lasting was map-reduce, from alphabet, but
| they were called google back then.
|
| there were a bunch of clever little tricks, like channel
| bonded network cards to make multiple cards look like one
| fast card, so you could double or triple bandwidth.
|
| The beowulf cluster joke was kind of the spirit of the
| scrappy, make something cool out of junk approach while
| calling companies like sun, hp, compaq dinosaurs. and it
| continued for a while with people building stuff like
| this - https://ncsa30.ncsa.illinois.edu/2003/05/ncsa-
| creates-sony-p... I think there was some weirdness with
| export controls of ps2's for this kind of stuff.
|
| I don't remember what pc chip was the new hotness back
| then, it was a good 20 years ago and my memory is dim.
|
| but that, I think, captures the gist of the meme.
| jacquesm wrote:
| www.clustercompute.com
| jghn wrote:
| I feel like this is the one domain where the beowfulf
| cluster meme is still funny
| jghn wrote:
| I agree from the human genome sequencing perspective and
| the superlatives of saving the HGP. But at the time I was
| a standard software dev who thought the topic was cool,
| as was this new fan dangled language named perl.
|
| However, I got into the genomics world in the early
| aughts, and the perl hung on and on and on. I remember
| starting a new job in the mid-teens, and one of the first
| tasks I had was to port over a legacy perl script. Such
| is the world of scientific software. 99% of the people I
| know who have touched perl since ~2003ish are in the
| bioinformatics space.
| iten wrote:
| Small correction: BLAT is a local alignment tool Jim Kent
| also wrote. I think his assembler you're referring to is
| GigAssembler
| (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC311095/).
| heyoni wrote:
| I also love that all of their genomic tools are released
| as a virtualbox virtual machine and their entire site can
| basically be run locally with personal genomic data. I
| think it's called genome in a box.
|
| And if I remember correctly BLAT was so useful because it
| could be run on machines with less cpu power by loading
| more data into memory...or was it the other way around?
| robwwilliams wrote:
| And Jim Kent!
| kapilkaisare wrote:
| Hi, I'm in software and looking to get into
| genomics/biotech. I'd like to learn more about how you made
| the move. Is there a way I could dm you? I saw no email in
| your profile.
| dotancohen wrote:
| > The primary author of the shotgun assembly was Gene Myers
|
| No conflict of interest there!
| checkyoursudo wrote:
| His wife, Chromosome, was an uncredited contributor.
| SubiculumCode wrote:
| This comment is needlessly negative. What they did had value
| and they did not hide what they did either, at least that
| wasn't my impression. The statistical "shenanigans" is better
| termed as an innovation.
| wslh wrote:
| TIL that. I was 100% sure the DNA was completely sequenced.
| Even have a friend with a sequencing company. It is incredible
| how ignorant one can be. Thank you 10g1k and HN.
| AlecSchueler wrote:
| Found out you were wrong on the day you became right!
| mnw21cam wrote:
| FWIW, the DNA was 100% sequenced. However, a proportion of
| that data that came back from the sequencing machine was too
| similar to each other, so it was impossible to assemble it
| into a coherent full set of contiguous chromosomes.
|
| Imagine it like putting together a jigsaw puzzle, except that
| the picture on the front of the puzzle has lots of repeating
| motifs, so you end up with multiple pieces that look
| identical. You won't be able to tell how the whole thing fits
| together, but you can assemble the bits that are well-behaved
| and unique.
|
| Modern technology gives us larger jigsaw pieces, which allows
| us to distinguish between almost-identical parts of the
| puzzle better. But I would note that the project linked did a
| _huge_ amount of sequencing using very expensive methods to
| be able to resolve the whole thing.
| nzach wrote:
| For anyone interested, the problem mostly boils down to the
| sequence lenght we can read.
|
| Modern sequencing techniques allow us o read 200 to 500
| bases at a time. So after hat we need do find a way o
| arrange these short sequences into a single sequence. And
| this can be prety hard, especially when you are doing 'de
| novo' assembly[0].
|
| Besides that, there is the fact that some regions of DNA
| are repeated[1].
|
| [0] - https://en.wikipedia.org/wiki/Third-
| generation_sequencing#De...
|
| [1] - https://en.wikipedia.org/wiki/Repeated_sequence_(DNA)
| nullfield wrote:
| So if one orders WGS at 30x or 100x from someplace like
| Nebula, what do you actually get?
| alexvitkov wrote:
| Thought so too, turns out we're right now
| mola wrote:
| Dumb question: what does it mean to sequence "the" X?
|
| I presume our DNA are not identical. So do they sequence a
| particular person's Y chromosome? Who's?
|
| How similar are two Y chromosomes from different persons?
| Tuna-Fish wrote:
| Very similar. The difference between you and a chimp is only
| 4%, the largest difference between two individual humans is
| about a tenth of that.
|
| The person they picked is pseudonymously HG002, who is an
| Ashkenazi man who took part in the project and consented to
| commercial distribution of his genome.
| subroutine wrote:
| Interesting they chose Ashkenazi, given this ancestry is
| fairly unique.
|
| https://gnomad.broadinstitute.org/news/images/2018/10/gnomad.
| ..
| kjkjadksj wrote:
| Geneticists like insular populations to reduce signal to
| noise ratio. Another favorite population is a utah
| population of mormons for similar reasons. African genetics
| for example are trickier to parse out cause and effect as
| there is a lot more genetic diversity (and therefore noise
| that makes it difficult to identify true signal), but they
| too are studies sometimes for this reason specifically. The
| Yoruba are pretty well sequenced. Among europeans, a good
| resource is the icelandic genome project, not only due to
| the sample size but the nature of the bottlenecked
| population.
| fwungy wrote:
| How can they sequence a thing that does not exist?
|
| It's the only way that 2023 Gender Science can be true, and all
| good community members know that it is true.
|
| All Glory to the Commune Leader!
|
| /s
| renewiltord wrote:
| So I have my whole genome sequenced by Nebula. What do I have to
| do to match it up?
| Metacelsus wrote:
| BWA-MEM is a good alignment tool. Then you can view the .bam
| file in IGV.
| mfld wrote:
| You could download the raw sequence reads (FASTQ files) and map
| them to the new T2T-Y. Probably it makes more sense to wait for
| a new release of the T2T human genome reference, as mapping to
| a subset of the genome increases false positives. It helps to
| have some genome bioinformatics knowledge to correctly handle
| those T2T references.
| readittwice wrote:
| Can someone explain how "I have my whole genome sequenced by
| Nebula" relates to the news just now that "The human Y
| chromosome has been completely sequenced"?
|
| How can someone have their whole (!) genome sequenced already
| when so far we weren't able to fully sequence the Y chromosome.
| And this person seems to have a Y chromosome.
| dekhn wrote:
| because commercial "whole" genome sequences aren't really
| whole. But, they normally deliver the raw reads to you in a
| 50+GB file so I suppose you could take the reads in that file
| that don't map to the previous reference and try to map them
| to the new one. Unless you are an expert it's unlikely you
| would get any actionable results.
| soligern wrote:
| Does this literally mean every single base pair with all the junk
| genome and everything else? Or is it some statistical
| model/extrapolated etc.
| dekhn wrote:
| It is a completely gapless assembly from the beginning of the
| start of each chromosome all the way to it's end ("telomere to
| telomere"). I haven't read in enough detail but I would imagine
| there are still some slightly fuzzy regions that are sort of a
| best-guess, although those would be quite small.
| dools wrote:
| Scary cowboy on Sesame Street: I WANNA KNOW Y!
|
| Scientists: here you go
| jshorty wrote:
| Could someone explain exactly what it means to be "completely
| sequence" the human genome when all humans have distinct genetic
| makeup (ie, different sequences of nucleobases in their DNA/RNA)?
| dekhn wrote:
| The public Human Genome Project used a group of people but most
| of the sequence library was derived from a single individual in
| Buffalo, NY. The celera project also used a group of people but
| it was mostly Venter's genome
|
| https://www.nytimes.com/2002/04/27/us/scientist-reveals-secr...
|
| I believe more recent sequencing projects have used a wider
| pool of individuals. I think some projects pool all the
| individuals and sequence them together, while others sequence
| each individual separately. This isn't really so much of a
| problem since the large-scale structure is highly similar
| across all humans and we have developed sophisticated
| approaches to model the variations in individuals, see
| https://www.biomedcentral.com/collections/graphgenomes for an
| explanation of the "graph structure" used to reprsent
| alternatives in the reference, which can include individual
| single nucleobase differences, as well as more complex ones
| such as large deletions in one individual, to rearrangements
| and even inversions.
| diekhans wrote:
| We really should say "a human genome". Reference genomes serve
| as a Rosetta Stone of genomics. So we can take DNA/RNA
| sequences from other individuals and align (pattern match) them
| to the reference as a way of understanding and comparing
| individuals.
|
| It is not perfect, as a references can be missing or have large
| variability in DNA regions. The goal of the Human Pangenome
| Reference Consortium (HPRC) https://humanpangenome.org/ is to
| sequence individuals from different populations to address this
| issue. We are also working to develop new computation models to
| support analysis of data across populations.
| jhbadger wrote:
| Traditional sequences of the Y chromosome (and other
| chromosomes) were missing parts, particularly the highly
| repetitive regions called "telomeres". This is different from
| the issue of individual variation (although the authors do
| provide a map of known variations as well).
| photochemsyn wrote:
| Good question. Practically they call their complete sequence a
| 'reference sequence' which can be thought of as a baseline for
| comparison to the complete spectrum of human Y chromosome
| genetic variation, so at least people have _something_ to use
| as a standard for comparison. The line in the abstract "mapped
| available population variation, clinical variants" is about the
| only mention of the issue.
|
| Ideally we'd have hundreds if not thousands of complete genomes
| which in total would reveal the population diversity of the
| human species as it currently exists, but this is a big ask.
| "Clincal variants" are of particular interest as those are
| regions of the genome associated with certain inherited
| diseases, although the promises of individual genomic knowledge
| leading to a medical revolution have turned out to be wildly
| overblown.
|
| Since the paper is paywalled, there's not much else to say than
| that they have a (fairly arbitrary in origin, i.e. it could
| have been from any one individual or possibly even a chimera of
| several individuals) reference sequence to which other specific
| human Y chromosomes can be compared, eventually leading to a
| larger dataset from many individuals which will reveal the
| highly conserved and highly variable regions of the chromosome,
| population-wise.
| wheelerof4te wrote:
| It means that they are trying to find a baseline from which
| they can eventually clone a human being.
|
| Let's not pretend that this is not an end goal. It always was.
| dclowd9901 wrote:
| Thank you for putting into words exactly the thing I wanted to
| understand but couldn't figure out how to ask.
| lopis wrote:
| While you are correct, the differences between different
| people's DNA is tiny, less 1% at best. So this information is
| still very valuable. This article is talking about the first
| time in finishing sequencing one person's Y chromosome's DNA.
| hk__2 wrote:
| > While you are correct, the differences between different
| people's DNA is tiny, less 1% at best
|
| How do we know this, if we have only sequenced the chromosome
| of one individual?
| lopis wrote:
| We have sequenced the genome using different sampling and
| statistical models for a long time.
| robwwilliams wrote:
| What you are getting at is now called a "pangenome assembly".
| Several high profile papers earlier this year, one by
| Guarracino and Garrison in Nature.
|
| A pangenome is a complex graph model that weaves together
| hundreds or more genomes/haplotypes--usually of one species,
| but the idea can extend across species too, or even cells
| within one individual (think cancer pangenomes).
|
| On the idealized human pangenome graph each human is
| represented by two threads along each autosome, plus threads
| through Chr X, Y, and the mitochondrial genome.
| gorjusborg wrote:
| I had the same question. Perhaps this will help you.
|
| https://en.m.wikipedia.org/wiki/DNA_sequencing
| mikepurvis wrote:
| That page describes the human genome as having been sequenced
| back in 2003. *confusion intensifies*
| dekhn wrote:
| the project started around 1990, they announced a draft
| completed in 2000, "completion" in 2003 (this was more a
| token announcement based on a threshold than a true
| milestone). Even then the scientists knew that major parts
| of the centromere, telomere, and highly repetitive regions
| were not fully resolved, and that was fully admitted. The
| work by Karen Miga at UCSC and others is more of a mop-up
| now that genome sequencing is a mature technology and we
| have much better ways at getting at those tricky regions.
|
| another "completion" happened 3 years ago, before this
| announcement. but this is the last one. I promise.
| chihuahua wrote:
| 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?"
| VeninVidiaVicii wrote:
| I always make this mistake too as a computational biologist;
| when talking about DNA it's megabases not megabytes.
| zbaxrl wrote:
| Kinda, https://youtu.be/1ThNnuSuZC0?t=4925
| throw3823423 wrote:
| 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
| dekhn wrote:
| 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 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.
| aastronaut wrote:
| > 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).
|
| Would such a predictive model really be possible? As far as
| I'm aware there is contradicting research whether a
| specific phenotype distinctly originates from a
| SNP/genotype.
| dekhn wrote:
| I can't technically say with 100% confidence that it
| would be possible. It does seem extremely likely based on
| all the evidence I've seen over the past 30 years.
|
| The model would be highly nonlinear and nonlocal, at the
| very least.
| alexchantavy wrote:
| Fascinating, are there lots of people looking at genetics
| with this ML kind of lens?
| dekhn wrote:
| Sure, although I'm not aware of anybody who is
| contemplating quite the level I believe is necessary to
| really nail the problem into the ground. When I worked at
| Google, I proposed that Google build a datacenter-sized
| sequencing center in Iowa or Nebraska near its data
| centers, buy thousands of sequencers, and run industrial-
| scale sequencing, push the data straight to the cloud
| over fat fiber, followed by machine learning, for health
| research. I don't think Google wants to get involved in
| the physical sequencing part but they did listen to my
| ideas and they have several teams working on applying ML
| to genomics as well as other health research problems,
| and my part of my job today (working at a biotech) is to
| manage the flows of petabytes of genomic data into the
| cloud and make it accessible to our machine learning
| engineers.
|
| The really interesting approaches these days, IMHO,
| combine genomics and microscopic imaging of organoids,
| and many folks are trying to set up a "lab in the loop",
| in which large-scale experiments run autonomously by
| sophisticated ML systems could accelerate discovery. It's
| a fractally complex and challenging problem.
|
| Statistics has been key to understanding genetics from
| the beginning (see Mendel, Fisher) and so at a big pharma
| you will see everything from Bayesian bootstrappers using
| R to deep learners using pytorch.
| 2dvisio wrote:
| Guys at Verily are working on Terra.bio with the Broad
| institute and others. Genomics England in the UK is also
| experiencing with multimodal and machine learning applied
| to whole genome sequences [1].
|
| [1] https://www.genomicsengland.co.uk/blog/data-
| representations-...
| krab wrote:
| But why Google? This is what big pharma are doing. Also
| you can outsource the data collection part. See for
| example UK Biobank. Their data are available to multiple
| companies after some period so it makes it more cost
| efficient.
| dekhn wrote:
| Why Google? Because this is a big data problem and Google
| mastered big data and ML on big data a long time ago.
| Most big pharma hasn't completely internalized the
| mindset required to do truly large-scale data analysis.
| panosfilianos wrote:
| I have spent the better part of the past year looking
| obsessively over genomics papers for cancer and I've
| grown very fond of the field.
|
| Are there any positions at Google/ companies you wold
| suggest me to look into? I'm coming from algortrading/ ML
| research with ML MSc.
| asielen wrote:
| You could try Calico. They are an Alphabet company that
| specifically studies aging. There how a good amount of
| machine learning roles. However biotech typically pays
| less than finance or software.
|
| https://calicolabs.com/careers/
| panosfilianos wrote:
| Thanks!
| krab wrote:
| Yes. For example when word2vec came out, immediately
| there were people trying similar approaches to protein
| sequences. Transformers work better.
| khazhoux wrote:
| It's just about 3 gigabytes (each byte a letter). Pretty
| mind-blowing, if you ask me.
| [deleted]
| [deleted]
| cvoss wrote:
| 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.
| borissk wrote:
| I'm curious if these 750MB + the DNA of mitochondria +
| the protein metagenomics contain all the information
| needed to build a human, or if there's extra info stored
| in the machinery of the first cell.
|
| That is if we transfer the DNA to an advanced alien
| civilization - would they be able to make a human.
| mfld wrote:
| Yes, there is extra information in the first cells, in
| particular regulatory elements such as miRNAs. The
| headline here is epigenetics.
| cvoss wrote:
| There's also some interesting work on understanding the
| roll of loops in the physical structure of the DNA
| storage on gene expression. [0] The base sequence of the
| DNA isn't everything; it may also matter how the DNA gets
| laid out in space---a feature which can be inherited.
|
| [0] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2638769/
| singularity2001 wrote:
| Our DNA does not contain the mitochondria nor the gut
| bacteria so the raw data would most certainly not be
| enough to build a working copy
| mjan22640 wrote:
| Imagine a machine shop that has blueprints of components
| of the machines they use in the shop, and processes to
| assemble machines from the components. When a machine
| shop grows large and splits in two, each inherits a half
| of shop with the ongoing processes and a copy of the
| blueprints.
| https://m.youtube.com/watch?v=B7PMf7bBczQ&pp=QAFIAQ%3D%3D
|
| DNA is the blueprints. There are infinite possibilities
| what to do with them. The advanced civilization would
| need additional information, like that they are supposed
| create a cell from the components to begin with, and a
| lot of detailed information how exactly to do that.
|
| Edit: improved clarity
| ejstronge wrote:
| > That is if we transfer the DNA to an advanced alien
| civilization - would they be able to make a human.
|
| You'd need a cell to start the process, with the various
| nucleic acids distributed correctly and proteins/energy
| with which to create further proteins using the
| information encoded by the DNA. Thus the civilization
| would need information about cells and a set of building
| blocks before being able to use the DNA.
| borissk wrote:
| The DNA contains all the code that creates and regulates
| the proteins.
| penteract wrote:
| Including code for the proteins that read DNA to produce
| proteins. You might hit similar problems trying to
| understand C given the source code for a C compiler - a
| non-standard environment could reproduce itself given the
| source code, meaning the code alone doesn't strictly
| determine the output.
| kibibyte wrote:
| I'll torture this DNA and C source code analogy a bit.
|
| Epigenetics is missing in this discussion about
| reproducing a human from just the DNA. These are
| superficial modifications (e.g. methylation, histone
| modification, repressor factors) to a strand of DNA that
| can drastically alter how specific regions get expressed
| into proteins. These mechanisms essentially work by
| either hiding or unhiding DNA from RNA polymerases and
| other parts of the transcription complex. These
| mechanisms can change throughout your lifetime because of
| environmental factors and can be inherited.
|
| So it's like reading C source code, except there so many
| of these inscrutable C preprocessor directives strewn all
| throughout. You won't get a successful compilation by
| turning on or off all the directives. Instead, you need
| to get this similarly inscrutable configuration blob that
| tells you how to set each directive.
|
| I guess in a way, it's like the weights for an ML model.
| It just works, you can't explain why it works, and
| changing this weight here produces a program that crashes
| prematurely, and changing a weight there produces a
| program with allergic reactions to everything.
| pfdietz wrote:
| There's also postprocessing: varying modification of the
| RNA, RNA interference, glycosylation and other post
| transcriptional modifications.
| khazhoux wrote:
| And how will you decode it?
| pmoriarty wrote:
| _" if we transfer the DNA to an advanced alien
| civilization - would they be able to make a human."_
|
| I'm really surprised that in all these responses to your
| question no one's mentioned the womb or the mother, who
| (at least with current technology) is still necessary for
| making a human.
|
| That's not to mention the necessity of the egg.
|
| We're not just DNA.
| borissk wrote:
| Instructions on how to make a womb and an "egg" are
| contained within the human DNA.
| wizofaus wrote:
| But maybe you needed a pre-human womb to bootstrap the
| first human, and we no longer have the blueprint for
| that...
| crdrost wrote:
| It is known that that is not true, due to the distinct
| genetic code of mitochondria and known epigenetic
| influences of mothers on their children in utero.
|
| You could say "well that's the last 10% of the details,
| maybe 90% is in the DNA," but I think I would be
| suspicious that it's that high, because one of the things
| we know about humans is that we are born with all of the
| ova that we will ever have, rather than deferring the
| process until puberty. I should think that if it could be
| deferred it would have been, "you will spend the energy
| to make these 15 years before you need to for no real
| reason" seems very unlike evolution whereas "my body is
| going to teach you how to make these eggs, just the same
| as my mother's body taught me," sounds quite
| evolutionarily reasonable.
| dchftcs wrote:
| This is a question about theoretical possibilities and
| what you're saying seems to be a rigid belief in an
| answer "no". But you provided no evidence or
| justification, except for "with current technology",
| which answers nothing about the theoretical question.
| dekhn wrote:
| Artificial wombs have come quite a long way! It is not
| inconcievable to imagine that you could bring a zygote to
| term in an artificial womb.
| kovacs_x wrote:
| it's bit like- if i have source code of Linux (think
| DNA), can I build a machine running Linux? (think cell).
| no- you cant, you need to have machine that can run the
| code.
|
| ie. "software" without "machine" to run it on, is kind of
| a useless.
| senkora wrote:
| I can't wait until we can bootstrap a human from a stage
| 3 tarball.
| dekhn wrote:
| This is a complex question. The cocktail soup in a gamete
| (sperm or egg) and the resulting zygote contains an awful
| lot of stuff that would be extremely hard to replace. I
| could imagine that if the receiving civilization was
| sufficiently advanced _and_ had a model of what those
| cells contained (beyond the genomic information) they
| could build some sort of artificial cell that could
| bootstrap the genome to the point of being able to start
| the development process. it would be quite an
| accomplishment.
|
| If they just received the DNA without some information
| about the zygote, I don't think it would be practical for
| even advanced alien civilization (LR5 or LR6) but
| probably an LR7 and definitely an LR8 could.
| namanyayg wrote:
| What do you mean by "LR"? I queried an LLM but no results
| there either.
| dekhn wrote:
| oops i've said too much
| namanyayg wrote:
| Or you've said too little?
| benignslime wrote:
| [dead]
| Angostura wrote:
| I'm just pondering this, and it's not clear to me that
| there is anything intrinsic in the genome itself that
| explicitly'says' "this sequence of DNA bases encodes a
| protein" or even "these three base-pairs equate to this
| amino acid".
|
| I wonder if that information could ever really be
| untangled by a civilisation starting entirely from
| scratch without access to a cell
| hwillis wrote:
| If you knew what DNA was and had seen a protein you could
| easily figure out start/stop codons. If you had only seen
| something similar it would be harder. If you had nothing
| similar, I don't know.
|
| Coding DNA and non-coding DNA looks very different.
| Proteins are full of short repetitive sequences that form
| structural elements like alpha helixes:
| https://en.wikipedia.org/wiki/Alpha_helix
|
| Once you've identified roughly where the protein-coding
| genes are it would be trivial to identify 3'/5' as being
| common to all those regions. You could pretty easily
| imagine a much more complicated system with different
| transcription mechanisms and codon categories, but earth
| genomes are super simple in that respect. Once you have
| those you just have the (incredibly complex) problem of
| creating a polymerase and bam, you'll be able to print
| every single gene in the body.
|
| Without the right balance of promoters/factors/polymerase
| you probably won't get anything close to a human cell,
| but you'd be able to at least work closer to what the
| natural balance _should_ be, and once you get closer to
| building a correct ribosome etc the cell would start to
| self-correct.
| brookst wrote:
| It's an interesting question. Naively, I would expect it
| to be about like reverse engineering a CPU from a binary
| program. Which sounds daunting but maybe not impossible
| if you understand the fundamentals of registers, memory,
| opcodes, etc.
|
| But... doing so from first principles without a mental
| model of how all (human) CPUs work? I guess it comes down
| to whether the recipients had enough context to know what
| they're looking at.
| dekhn wrote:
| Yes, it's intrinsic in the genome but implemented through
| such a complicated mechanism that attempting to
| understand these things from first principles is
| impractical, not impossible.
|
| In genomic science we nearly always use more cheaply
| available information rather than attempt to solve the
| hard problem directly. For example, for decades, a lot of
| sequencing only focused on the transcribed parts of the
| genome (which typically encode for protein), letting
| biology do the work for determining which parts are
| protein.
|
| If you look at the process biophysically, you will see
| there are actual proteins that bind to the regions just
| before a protein, because the DNA sequences there match
| some pattern the protein recognizes. If you move that
| signal in front of a non-coding region, the apparatus
| will happily transcribe and even attempt to translate the
| non-coding region, making a garbage protein.
| borissk wrote:
| The code how to build a sperm and an egg is inside the
| human DNA, isn't it?
| dekhn wrote:
| Yes, but it currently requires developmentally mature
| individuals to build the gametes, and the "code" is so
| complex you couldn't really decipher it from first
| principles.
| klyrs wrote:
| Given code written for unknown hardware... can you
| execute it?
| borissk wrote:
| Given that the code contains the instructions how to make
| the hardware - if one is very smart than yes.
| bbrx wrote:
| It would not necessary be possible, because it's
| incremental instructions on how to make the hardware, but
| based on already existing, unspecified and very complex,
| hardware. So the first instruction would be something
| like "take the stuff you have on your left and fuse it
| with the stuff you have on your right", both stuff being
| unspecified very complex protein assumed to be present.
| tobinfricke wrote:
| The code to build mitochondria is not.
| dekhn wrote:
| And since the data is highly redundant the 750MB can be
| compressed down even further using standard approaches
| (DEFLATE works well, it uses both huffman coding and
| dictionary backreferences).
|
| Or, you could build an embedding with far fewer
| parameters that could explain the vast majority of
| phenotypic differences. the genome is a hierarchical
| palimpsest of low entropy.
|
| My standard interview question- because I hate leetcode-
| walks the interviewee through compressing DNA using bit
| encoding, then using that to implement a rolling hash to
| do fast frequency counting. Some folks get stuck at "how
| many bits in a byte", others at "if you have 4 symbols,
| how many bits are required to encode a symbol?", and
| other candidates jump straight to bloom filters and other
| probabilistic approaches (https://github.com/bcgsc/ntHash
| and https://github.com/dib-lab/khmer are good places to
| start if you are interested).
| [deleted]
| khazhoux wrote:
| 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 wrote:
| 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 wrote:
| 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.
| astrange wrote:
| My favorite trivia here is that flamingos aren't actually
| "genetically" pink but "environmentally" pink because
| they pick up the color from eating algae.
|
| Except of course "genetics" and "environment" aren't
| actually separate things; sure, people's skin color isn't
| usually affected by their food, but only because most
| people don't eat colloidal silver.
|
| https://en.wikipedia.org/wiki/Paul_Karason
| hotnfresh wrote:
| AFAIK most poisonous frogs also aren't "naturally"
| poisonous--they get it from diet. Ones raised in
| captivity aren't poisonous unless you go out of your way
| to feed them the things they need to become poisonous.
| dekhn wrote:
| bzip2 is marginally better, and then genome-specific
| compressors were developed, and then finally, people
| started storing individual genomes as diffs from a single
| reference,
| https://en.wikipedia.org/wiki/CRAM_(file_format)
|
| Since genome files contain more data than just ATGC
| (typically a comment line, then a DNA line, then a
| quality score line), and each of those draws from a
| different distribution, DEFLATE on a FASTA file doesn't
| reach the full potential of the compressor because the
| huffman table ends up having to hold all three
| distributions, and the dictionary backlookups aren't as
| efficient either. It turns out you _can_ split the file
| into multiple streams, one per line type, and then
| compress those independently, with slightly better
| compression ratios, but it 's still not great.
| bglazer wrote:
| 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 wrote:
| 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
|
| 1:https://www.microbe.tv/twiv/twiv-956/
| globular-toast wrote:
| 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 wrote:
| You could say exactly the same of all data; it's just 1s and
| 0s, but when I look I just see blonde, brunette.
| jiggawatts wrote:
| 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 wrote:
| 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.
| hwillis wrote:
| > 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%.
| benignslime wrote:
| [dead]
| Earw0rm wrote:
| 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 wrote:
| I trust the scientists, the problem isn't them. Look at
| the whole abortion data scandal in the U.S.
| Earw0rm wrote:
| 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.
| pdonis wrote:
| They mean they have obtained the complete sequence for a
| particular Y chromosome that is considered to be a "reference"
| chromosome. This is similar to what was done for all the other
| chromosomes.
| BurningFrog wrote:
| Here is the "dumb question" I've always had about recording the
| human genome.
|
| We all have different DNA. So is "the human genome" some kind of
| "average" DNA, or is it the DNA of whoever they sampled, or is it
| maybe an overview of what is common for all of us?
| banjo_milkman wrote:
| They are talking about one 'reference genome'. The variation
| from human-to-human is relatively small (a few million bases
| out of 3 billion). The reference genome has historically been
| some kind of average/mosaic of several individuals (this has
| obvious disadvantages), good enough to put reads in the right
| place (mostly), and call 'variants' - the differences that make
| the test genome unique.
|
| The latest/greatest end-to-end T2T reference is entirely based
| on 'HG002' an individual from Utah, due partly to new
| information derived from long read technologies.
| inciampati wrote:
| Actually the level of variation per genome relative to a
| reference is still not completely known because we do not
| have more than a handful of truly complete assemblies. It is
| clear though that it is much higher than a few million base
| pairs, perhaps as high as tens of millions, depending on your
| alignment parameters. Most of the differences are in regions
| we have not been able to sequence and assemble until the past
| few years. This paper being a key example. If two males have
| different versions of large repetitive arrays on the Y then
| they will already be much more than "a few million" base
| pairs different
| ncr100 wrote:
| I assume it's one person's DNA. The last time there was talk
| about this in popular media was the DNA of one person.
| hwillis wrote:
| Kinda. The Human Genome Project's reference genome is from 4
| people. 70% of it is from one person, because that sample
| happened to be very good.
| fsckboy wrote:
| what would make a sample good? from the point of view of
| what quantity a sample would entail, there must be no
| shortage of cadavers or even discarded body parts?
| inciampati wrote:
| In this case it's one haplotype of one cell line.
|
| If you want a population model of genomes you need a pangenome.
|
| See "pangenome graph", "variation graph", and the human
| pangenome project.
| [deleted]
| xwdv wrote:
| Could we in theory just build up any kind of creature from
| scratch if we write out its genome? How would we compile it into
| organic matter?
| globular-toast wrote:
| There's a bootstrapping problem. You need something to run the
| code. An egg cell and sperm cell contain loads of other stuff
| in addition to the genome and the only way to get that stuff is
| from the genome...
|
| It's like if you had a program to 3D print a 3D printer but you
| don't have a 3D printer that can read that program.
|
| It's all ridiculously complicated. To get an idea about it you
| could learn about how simple RNA viruses like influenza or HIV
| replicate. It's easy enough for anyone to understand. But no
| single person can fully understand humans (or other mammals,
| plants etc, we're not special in that respect).
| jakobnissen wrote:
| No, this is not technically possible. Cells are simply to
| complex to just build using humanity's current level of
| technology. The closest thing we have done is to fully
| synthesize a bacterium's genome, remove the genome from a
| bacterial cell, then transplant the synthetic genome into the
| cell and have the cell survive:
| https://en.wikipedia.org/wiki/Mycoplasma_laboratorium
|
| That's insanely cool, but very far from what you are asking. An
| analogy: We have re-installed the operating system of an
| existing computer, when you are asking whether we can
| manufacture a computer.
| UI_at_80x24 wrote:
| For a very entertaining and educational book that tangentially
| related; I can highly recommend: Y - The Descent of Man by Steve
| Jones [0]
|
| I am thrilled to see more chromosomes being mapped/sequenced.
| Please excuse my high-school level of biology knowledge here, but
| have we definitively progressed beyond correlation when it comes
| to genes, gene expression, and how they all interact?
|
| Take "Blue eyes" as an example, we know that [1] OCA2 is
| responsible for brown/blue eye colour. BUT are we sure that none
| of the 20,000 others are involved/needed?
|
| In laymans terms I would guess that to get 'blue eyes' would
| require several genes to ALL be on/active/present as well. More
| like a recipe, then a simple on/off it's located in 1 position.
|
| [0] https://www.goodreads.com/work/editions/436071-y-the-
| descent... [1] https://www.nature.com/articles/s41433-021-01749-x
| largbae wrote:
| I would imagine all sorts of genes are necessary to have blue
| eyes depending on how you look at it. After all, you need eyes
| in order to have blue eyes, and a whole bunch of other
| machinery to open them to check the color...
| dekhn wrote:
| Eye color is subtle. How do you define blue eyes? It's not just
| one phenotype; there are a range of blue eyes, whose
| differences correspond to fairly subtle variations between
| people. The article you linked [1], is quite good but requires
| quite some time to absorb completely.
| brayman30 wrote:
| First I would like to state that human genetics are very, very
| complex and we still do not have a complete understanding of
| them. For example, only relatively recently has the field of
| epigenetics made major advancementa, which (broadly speaking)
| studies how a cell's behavior can be changed WITHOUT it's DNA
| being changed.[1] This brings into question the age-old
| questions about environmental impact vs genetic impact in even
| greater detail. Anyways, sidebar over.
|
| No, we are not completely sure how many chromosomes play a role
| in determining eye color. However, we do have a pretty good
| guess. Most recent estimates I found out the number at 16. OCA2
| and HERC2 have the largest impact on eye color, but, there are
| many OTHER genes that also have smaller impacts on eye color.
| [2] That article I cited is actually amazing. But, it does
| touch on some more advanced subjects that are more introductory
| college-level biology or AP Biology than standard high school
| bio e.g. Gene Regulation, introns and extrons, etc.
|
| To answer your more general question, in my (admittedly only
| mildly less basic, introductory college-level biology) opinion,
| it is unlikely that we will, anytime soon, reach a point where
| anything in genetics can be completly, 100% definitive. This is
| not to say that we haven't made amazing advancements in the
| field of genetics and biology more broadly. BUT, it would be a
| mistake to take for granted the complexity of the human genome.
| There is most definitely things we still do not understand
| about the genome, and will not for some time.
|
| But, practically speaking, while other genes may have impact on
| some simple phenotypic traits, such as eye color, we can
| generally make an accurate guess based on only a few genes. In
| eye color, for example, one study was able to predict eye color
| with only 6 genes with about ~75% accuracy. [3]
|
| The crazy part is, sometimes the genes that effect the
| phenotypic trait, don't actually store genetic material that
| determines the trait. In other words, they don't DIRECTLY
| determine the trait at all. Rather, the only effect ORHER genes
| which then effect the expression of the trait more directly.
| You can imagine that this could become very complex very very
| quickly when you have multiple genes effecting other genes
| which effect other genes, not to mention accoubting for
| environmental and demographic baises when doing these studies
| and you begin to see why this genetics is such a difficult
| field of study.
|
| Apologies for the long post and rambling. Hopefully I was still
| able to provide you with some mediocre introductory-collage-
| level biology
|
| [1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2791696/ [2]
| https://www.nature.com/articles/jhg2010126 [3]
| https://doi.org/10.1016/j.cub.2009.01.027
| moelf wrote:
| I guess nih will update this soon:
| https://www.ncbi.nlm.nih.gov/assembly/GCF_009914755.1/ since it
| was gap-less except for Y chromosome
| RajT88 wrote:
| [flagged]
| farhanhubble wrote:
| Does it make it any easier to snapshot Chromosomes and see them
| evolve with age and perhaps better correlate that with the onset
| of diseases? The correlation is still possible but will having
| multiple snapshots enable better association?
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