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The complete sequence of a human Y chromosome
- muizelaar 3y agoThe preprint: https://www.biorxiv.org/content/10.1101/2022.12.01.518724v2.full.pdf https://www.biorxiv.org/content/10.1101/2022.12.01.518724v2....
- brayman30 3y agoThis 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.
- bonestamp2 3y agoAs others have asked in this thread, what does "fully sequenced" mean to the layman?
- yellowcake0 3y agoIt 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 3y agoIsn'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 3y agoIt 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.
- p1mrx 3y agoYou can tell it's the Y chromosome because of the way it is.
- certifiedloud 3y agoThats pretty neat!
- tobinfricke 3y agoWhat makes the Y chromosome more difficult?
- bux93 3y agoIt'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.
- deleted 3y ago[deleted]
- BbzzbB 3y agoMaybe 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 3y agoWe 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.
- mnw21cam 3y agoAll 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.
- AgentME 3y agoI 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 3y agohuman_genome_final_FINAL_3.txt
- Legend2440 3y agoTIL the human Y chromosome hadn't been completely sequenced until now.
- 10g1k 3y agoFor 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-venters-genome/ https://www.technologyreview.com/2007/09/04/223919/craig-ven...
- ekianjo 3y ago[flagged]
- tomrod 3y agoI'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 3y agoNot 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 3y agoWhat 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.
- jshorty 3y agoCould 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)?
- gorjusborg 3y agoI had the same question. Perhaps this will help you. https://en.m.wikipedia.org/wiki/DNA_sequencing https://en.m.wikipedia.org/wiki/DNA_sequencing
- mikepurvis 3y agoThat page describes the human genome as having been sequenced back in 2003. *confusion intensifies*
- dekhn 3y agothe 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 3y agoI've never understood this either. I assume the genome is many megabytes of [ATCG]+. If we have that sequence, what does it tell us? Do we look at it and say "Ah, yes, ...ATGCTACGACTACGACTAGCG... very interesting?"
- jiggawatts 3y agoMany 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.
- UI_at_80x24 3y agoFor 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-of-men https://www.goodreads.com/work/editions/436071-y-the-descent... [1] https://www.nature.com/articles/s41433-021-01749-x https://www.nature.com/articles/s41433-021-01749-x
- largbae 3y agoI 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...
- brayman30 3y agoFirst 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/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2791696/ [2] https://www.nature.com/articles/jhg2010126 https://www.nature.com/articles/jhg2010126 [3] https://doi.org/10.1016/j.cub.2009.01.027 https://doi.org/10.1016/j.cub.2009.01.027
- RajT88 3y ago[flagged]
- nvader 3y ago[flagged]
- space_fountain 3y agoAs 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 3y agoThey 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 3y agoAnd 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.
- mikeyouse 3y agoA 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 https://news.ucsc.edu/2023/08/t2t-y-chromosome.html
- soligern 3y agoDoes this literally mean every single base pair with all the junk genome and everything else? Or is it some statistical model/extrapolated etc.
- dekhn 3y agoIt 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.
- mrazomor 3y agoThis 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 https://youtu.be/JTU3JYp3JYc?si=jOZz611ATQar3Gec (helped me understand DNA more than all biology classes at my high school)
- dramebaaz 3y agoThanks for that ACM SIGPLAN talk link, it was very fascinating and engaging.
- xwdv 3y agoCould 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?
- jakobnissen 3y agoNo, 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 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.
- globular-toast 3y agoThere'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).
- moelf 3y agoI guess nih will update this soon: https://www.ncbi.nlm.nih.gov/assembly/GCF_009914755.1/ https://www.ncbi.nlm.nih.gov/assembly/GCF_009914755.1/ since it was gap-less except for Y chromosome
- hanniabu 3y agoWhat are the implications of this? What's now possible with this feat completed?
- coldtea 3y agoIs this like: "we have a working keyboard driver" or more like "we identified all 104 keys on a standard 104-key US QWERTY layout"?
- gandalfgreybeer 3y agoNot answering your question, but I have to say, this is one of the best analogies I've encountered in a while.
- coldtea 3y agoWow, thanks!
- quickthrower2 3y agoThe keyboard driver means knowing what effect every key has?
- moffkalast 3y agoSounds more like they've been using the 87-key QWERTY so far, but now they also found the numpad.
- oldgradstudent 3y agoThey 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.
- deleted 3y ago[deleted]
- msuvakov 3y agoThis 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.full https://www.biorxiv.org/content/10.1101/2022.12.01.518724v1.... [2] https://github.com/marbl/CHM13 https://github.com/marbl/CHM13
- goodcanadian 3y agowhat'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.
- farhanhubble 3y agoDoes 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?
- ManuelKiessling 3y agoSo, did they find the reason why BMW drivers are always tailgating me on the Autobahn?
- renewiltord 3y agoSo I have my whole genome sequenced by Nebula. What do I have to do to match it up?
- mfld 3y agoYou 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.
- Metacelsus 3y agoBWA-MEM is a good alignment tool. Then you can view the .bam file in IGV.
- readittwice 3y agoCan 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 3y agobecause 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.
- dools 3y agoScary cowboy on Sesame Street: I WANNA KNOW Y! Scientists: here you go
- catsarebetter 3y agoomg 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.
- mola 3y agoDumb 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 3y agoVery 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 3y agoInteresting they chose Ashkenazi, given this ancestry is fairly unique. https://gnomad.broadinstitute.org/news/images/2018/10/gnomad-v2-1/pca-umap2.jpg https://gnomad.broadinstitute.org/news/images/2018/10/gnomad...
- kjkjadksj 3y agoGeneticists 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.
- icoder 3y ago1) 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.
- tomcam 3y ago…and mine has been found sorely wanting
- BurningFrog 3y agoHere 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?
- deleted 3y ago[deleted]
- ncr100 3y agoI 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 3y agoKinda. 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 3y agowhat 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 3y agoIn 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.
- banjo_milkman 3y agoThey 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.
- madduci 3y agoWhy do they use a paywalled service to publish their research?
- fwungy 3y agoHow 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