The human genome is, at long last, complete
rockefeller.edu
rockefeller.edu
And the scientist quote seems so wrong. if missing almost 10% of something when that ~10% is not like the other 90% then it seems like a very bad assumption to assume that it doesn’t show a lot of important features.
The quote: “ You would think that, with 92 percent of the genome completed long ago, another eight percent wouldn’t contribute much“
And I also agree with the bad assumption on the remaining 8% not being significant when we knew that it was structurally different. Less than 8% of an ELF is the header, but boy howdy will that thing not run well if you cut it off.
Instead, we are learning the "unknown" DNA performs biological functions due to its physical nature, such as physically blocking things from binding.
Imagine if a small section of a hard drive was so strongly magnetized that it repulsed the read head - if you were trying to translate it into binary it would appear to be nonsense.
Of course you are accurate as well: if we subtract the protein coding and the known non-coding but useful bits the rest is almost certainly absolute junk... duplications, bits of retroviruses, etc. But it would be inappropriate to claim we are absolutely certain none of it is useful. Will we find out 50% is useful? Obviously not. But I would rather say "current evidence suggests at least 97% is true junk; we are not likely to find large sequences with hidden uses at this point".
My rough read of biology is that it could use the same mechanism to lock down both.
Why is a viral insertion any different? Why is a recombination error any different?
Looking at the hex dump of RAM, some repetition is garbage, some is lookup tables with multiple entries into the same routine, some is initialized scratch memory for distant functions. It'd be premature to assume it's worthless.
Software code analogies to biological encoding break down, of course, because code is built intentionally and biological systems aren't. On the flip side, that very lack of intentionality in biological systems means it's risky to assume something is junk without a really holistic understanding of the context.
I did _some_ research on epigenetics during my MS degree. Spacing between sites was an important factor in our modeling of gene expression.
This makes it sound like it represents control flow rather than data. If its presence does / can make a material difference on the output encoding, it strikes my non-expert ears as actively perilous to label such DNA 'junk'
We still don't know how hard bootstrapping it would be :)
Disclaimer: not a biologist, and would be interested in hearing from someone more knowledgeble than I, both about the Ptashne book and about recommended reading.
Also disclaimer: My only knowledge of this is from Nessa Carey's The Epigenetics Revolution and some additional online reading.
Basically it's like using a "buggy filesystem" (like ext2) that only shows the first ~16000 files in a directory. So having too much junk can hide stuff, having too little of it can uncover files that evolution carefully hid, and so on.
If you prefer think of it as “spandrel” DNA in the sense used by SJ Gould.
There are clearly parts of DNA that are not essential, this is clear if you compare genome sizes between different organism. They can vary enormously, and not in a way correlated with any complexity of the organism. There are also parts of DNA that are remnants of viruses inserting many copies of their DNA, which are the parts that could be considered junk. Even those might have an effect simply due to their presence, but essentially everything in the cell has some effects if you look closely enough.
That's not true. Over millenia leftover chunks of DNA can accumulate for no good reason. Duplication mistakes, viral infections etc. The term junk dna originated from the initial assumption that all noncoding dna was useless. Evolutionary theory has nothing to do with this.
IIRC, much of these non-coding sequences (so-called "junk DNA") are preserved in a way that shows they are being relied upon for something.
If you do not know what “effective population size” means then you should watch from the side lines.
I think I am a respectable quantitative geneticist. I do not use the term myself but I have no fundamental distaste for the idea of junk DNA.
It is inevitable given our constant war with viruses that want to highjack our genomes.
Undoubtedly much of it could be pruned out with no undesirable result, but there does not seem to be any ongoing process to do that, so stuff piles up. As it will.
Such hubris as this is what led us to:
- define DNA we didn't and still don't understand as useless "junk"
- call the appendix a useless vestigial organ
- declared "silenced" b-cells useless
The list goes on and on and on... When will somebody compile a list of how often science is wrong just to slap the arrogance out of people before they cost more time and lives with such reckless and impatient reasoning?
You should think of science as the “least wrong” set of beliefs we have at any point in time. It will never be perfectly right, and every day it’s less and less wrong. The reason it’s so reliable is because it embraces (and doesn’t dismiss) this uncertainty.
That was a terrible idea, but one that was supported by science at the time. There are practical reasons to be skeptical about scientific assumptions.
Science becomes less wrong faster if we allow history to remind us that a lot of what we believe will likely turn out to be wrong.
Appendices are still removed, to this day, and people lacking them make do without. A thymus gland is harder to dispense with.
Terribly often, science grinds to a dead halt on some range of subject matter until certain scientists retire or die. It is easy to list remarkably recent cases where they did finally die and work could proceed, and many others where they have not died yet and the field is still stuck fast.
Science will always be incomplete. It has nothing to say yet about most possible questions. What it does pronounce upon should be reliably correct, but that is often not true, traceably to those individuals who maintain falsehoods. Sometimes the falsehoods become doctrine and hang on even after the offenders have obliged by dying.
There is so very much of it that even were the actually-junk just 5% of that, it would still qualify as "much of".
Now you might claim humans are more complex than pufferfish but that is mainly human hubris at work and would be exceedingly hard to prove in a court of law.
Fish genomes range “in size from 342 Mb of Tetraodon nigroviridis to 2967 Mb of Salmo salar” (from https://bmcgenomics.biomedcentral.com/articles/10.1186/s1286...).
Do you think all of that difference between two teleosts is functional?
Show me 100 million lines of human computer code.
Promotors, enhancers, insulators, CpG regions, 5’ and 3’ UTRs, splice junctions in introns, transposons, retrotransposons, LTRs, …
You would be astonished at how much of reality falls into that category.
also, do you consider introns to be junk DNA? those didn't evolve from viral insertion (probably?) so though they might end up hosting "junk", presumably they're not all "junk."
https://en.wikipedia.org/wiki/Bacterial_genome#Deletional_bi...
The label “junk DNA” was one of the biggest mistakes in the history of genetics. A lot of high school textbooks still reference this term and it’s worse than misleading.
In many ways, non-coding DNA is just as important as the parts of the genome that code for proteins. Non-coding DNA determines expression levels, genome confirmation (shape), and replication efficiency among other things.
The term junk DNA misleads students into thinking that these sections of DNA play little part in how a cell functions. Quite the opposite, the “junk DNA” is responsible for orchestrating the “non-junk” bits.
Statistically, the average human has ~1 base variant (SNP) in a protein coding region somewhere in their genome. In almost all people the effect of that SNP is no more apparent than the effect of SNPs in “junk DNA”.
So much charming and well intentioned misinformation on this thread; as much as if I were to weigh in on the pros and cons of MariaBD versus PostgreSL.
Coding sequence is under significantly higher levels of active “purifying” selection than regulatory DNA, and much higher than de novo mutations in repetitive mobile elements that only rare perturb phenotypes.
the redundancy of codons - several codons code for most amino acids, and one-base-pair changes are often synonymous or will code for similarly-charged residues - provides some protection.
on the other hand, if you have a mutation in, say, a non-coding intronic splice site, that can really fuck a protein up. I got unlucky there.
We can compare each base vs ancestor bases, eg primates and other vertebrates - called conservation scores.
Some areas are highly conserved, so changing those will probably have worse outcomes than less conserved regions.
But another part is the term is poorly defined, this article seems to use junk DNA to mean the until-recently unsequenced portions of our genome (and I think that's an unconventional usage), some comments here take it to mean non-protein coding, and another common use is for the term to mean non-functional.
If it helps, a defensible recent accounting is probably something like 1% of our genome being protein coding, perhaps 10% being functional in some way but not protein coding (e.g. regulatory, or transcribed to RNA that is functional etc), and the remaining 90% being without known function and likely non-functional.
After further years and much great painstaking work we'll perhaps learn that to a bit more is functional, though it may end up being say 11% vs 89% non-functional. And that's ok! I wouldn't worry progress being stunted by assumptions of too much of the genome being non-functional, rather the opposite, continuing to believe there is function where there is little evidence to warrant it.
disclaimer: not a geneticist, but sometimes write tools they might use.
Same with AC power transfer - the imaginary power doesn't drive the load, but it's quite real because I^2*R turns the term into a real power for resistive losses.
This sounds wrong for three reasons:
1. You can multiply any vector of qubits representing a quantum state by any complex number and it's the same state.
2. Measurement is always with respect to a basis. A result can be measured with 0% probability in one basis, 50% in another, 100% in another.
3. It doesn't take into account interference, so it's missing the whole point of how quantum differs from regular probabilities.
Read Michael Lynch: The Origins of Genome Architecture.
I suspect you have not had a recent course in population genetics.
Read Michael Lynch’s “The Origins of Genome Architecture” before you make dubious pronouncements. The human genome is a jungle of code and under rather weak selection due to small effective population size. There is a tremendous amount of cruft in all human genomes due to mobile element insertions and spread.
Are you saying this is wrong and so-called junk DNA is indeed worthless?
Why you say to disregard ENCODE claims and are the functions mentioned in parent even related to them?
Can you make a synopsis of what the book you're recommending talks about?
Also note the book predates ENCODE project results and being 15 year old it doesn't consider any newer developments either.
1. Junk DNA is irrelevant from the perspective of the cell but in some way selected for by the fitness function of likely DNA transcription errors.
2. Junk DNA is formerly-coding legacy DNA that was "turned off" by natural selection but never fully deleted.
3. Junk DNA is in some way error-correction / check-sums for the coding part of DNA.
4. Junk DNA is physically protecting the coding parts of DNA by letting most stray radiation act inconsequentially.
Non-coding DNA is much more difficult to understand in terms of function. It can act to regulate gene expression both through the local sequence (promoters, enhancers) and through long distance effects. For example, very distant promoters can be brought together within the nucleus and hence interact with each. These interactions are a result of both the local sequence and the sequence of the very distant interacting region. The interactions are also dependent on the concentrations of proteins/transcription factors that also interact with these sequences. We have no good way of modelling that kind of complexity.
I suppose they could also survive selection pressure by hurting the organism if they're not expressed. for instance, by capturing a vital protein-coding gene from the host, and arranging things so the transposon must stay active for the gene to be transcribed.
Eukaryotic genome are the worst noodle code you have ever seen—but miraculously they help to make humans and other creatures, bugs, and plants with some consistency. That is a miracle to even the most hardened atheist!
The human genome is littered with cruft and dumb code comments just like you would expect for very very old code.
Investing in organizations such as H3Africa will be important.
Note that this has nothing to do with collecting variations in individual genes - that’s easy and widely available. But about collecting variations in the actual content and structure of the genome. e.g. Some populations have a bunch of extra DNA that most other humans lack, amazing.
What does complete mean?
"However, limitations of BAC cloning led to an underrepresentation of repetitive sequences, and the opportunistic assembly of BACs derived from multiple individuals resulted in a mosaic of haplotypes. As a result, several GRC assembly gaps are unsolvable because of incompatible structural polymorphisms on their flanks, and many other repetitive and polymorphic regions were left unfinished or incorrectly assembled (5)."
Looks like there were "gaps" in the sequence due to technical limitations associated with the original sequencing methods and the authors have filled in those gaps. I haven't read the full paper, though.
Every human has unique de novo germline mutations (estimated to be in the range of 100 to 200).
In addition every cell (other than RBCs) will have a small number of its own unique somatic mutations.
And then there is radiation!
With new techniques you generate much longer pieces, so there is much less confusion.
One common analogy is to consider the genome sequence (a.k.a. assembly) as a map. Since the initial publication of the human genome in the early 2000s, most regions of human DNA has been known in full resolution. Other portions, most prominently the repetitive centromeres that lie at the middle of chromosomes, have remained unmapped. It was known that they exist, approximately how big they were, and which types of sequences lay inside, but the full order of the sequence had never been determined for any human genome until this work.
You could consider the genome like the earth and the centromeres like a dense rainforest. Previously we had detailed maps of most of the earth, and we had mapped the boundaries of the rainforest and had satellite-level images (i.e. we knew they were full of plants). Now we have on-the-ground pictures with full detail.
Having a map of these sequences makes the accessible to study. One of the most valuable uses of the human genome is as a shared coordinate system used by scientists to compare different individuals and identify and name genetic variants that explain human traits. We lacked that coordinate system for a big chunk of the genome until now.
As you say, this paper reports the sequence of a single human cell line named CHM13. Each of us has a slightly different genome sequence (really two of them, one from each parent). Now when scientists sequence the genomes of more individuals, they can look at these regions that were previously ignored. Certainly understanding those regions will improve our understanding of human biology. Exactly how much will remain to be seen.
* Telomerase is a reverse transcriptase that allows to achieve replicative immortality (https://academic.oup.com/hmg/article/9/3/403/715108).
Mitochondria have their own DNA, which is also sequenced.
So, this complete genome is a full set of 23 sequences without any "not sure" positions or "gaps" in the sequence.
The problem is endless. Life on earth is huge.
Pangenomes allow us to discard the kludge of a “reference” genome.
And can be applied to cancers too.
(from the paper itself)
It is a respectable achievement. But the Y chromosome is too important to be left out in order to call this the complete human genome.
https://www.science.org/content/article/most-complete-human-...
The genome’s Y chromosome came from Peshkin, and the rest of the DNA sequenced by the Telomere-to-Telomere (T2T) Consortium comes from a so-called molar pregnancy, a uterine growth that results on rare occasions when a sperm enters an egg that has no chromosomes. The fertilized cell can copy the sperm’s 23 chromosomes, creating two identical sets, and begin to replicate.
The question remains open of whether the owner of CHM13’s genome could be identified using public DNA sequences in genealogy databases. Phillippy thinks not because CHM13’s genome only represents one-half of that person’s DNA. Even if it were possible, NHGRI officials argue it would be unethical to reveal him for any reason, including to get consent.
Because CHM13 has an X chromosome but no Y, the T2T Consortium added Peshkin’s DNA
https://www.washingtonpost.com/science/2022/03/31/human-geno...
Second part is doubtful.
Individualized medicine needs a much more robust computational framework than it current has.
Each of us has a unique genome, a unique developmental history, and has lived in a unique environment.
We are n=1 experiments. Organ culture and IPSCs are a pipe dream.
Here is our approach to addressing this barrier:
If somebody completes a version of software, are they not allowed to announce future versions? Is scientific understanding not allowed to advance and change? Such views of science, as fixed and unchanging, with rigid definitions of inherently fuzzy concepts, are inherently anti-science.
We all need to be able to live with the notion of levels of completeness. This is biology—not engineering.
What is the precise definition of a filled glass of water?
Is it gonna be GRCh39 or will they change the naming scheme again?
https://www.ncbi.nlm.nih.gov/grc
The complete Y chromosome from HG002 was added with v2 (after the paper was written). Probably a patched form of GRCh38 will be made using T2T sequence, but IMO it makes more sense to use T2T-CHM13 as a reference with its single origin instead of a weird chimera, at least until pan-genome graph methods mature.
The cool stuff people imagine about in response to the title won't happen until researchers finish figuring out regulatory regions in the DNA; and, how DNA interacts with itself and environment, both spatially and temporally. Regulatory regions are promoters, enhancers, silencers, and insulators, and impact gene expression and regulation.
No.
> The title is on the sensationalistic side when you consider how most lay people will interpret it.
The title refers to a large scientific collaboration that has succeeded in utilizing single-molecule sequencing technology that only matured in the last 3-5 years to sequence regions of the human genome that were previously unmapped, bringing the completeness of the mapping to 100%. That doesn't seem sensationalistic.
1. Two cool long-read sequencing technologies (PacbBio HiFi and Oxford Nanopore)
2. Hydatiform moles carrying human chromosomes for easier sequencing
3. Excellent code for assembly through complex regions of the human genome (e.g., code for assembling pangenomes by Garrison and Li).
As a programmer, I find the code segments the most interesting.
how useful is it? not very at the moment. most analysis is still around specific variants that are understood. most function is not understood.
Cost would be under $25,000 for great depth (about 20X for both platforms=overkill).
The hard part is the de novo assembly. At least a few weeks in cottage industry mode. A few days if in full factory mode.
For instance it says I'm "99th percentile genetic predisposition" for melanoma - yes, thanks, I know I'm Scottish - and left-handedness, which I'm not.
> Jarvis and Formenti hope that their contribution will not only help tie a bow on the Human Genome Project, but also inform research into diseases linked to the heterochromatic genome—chief among them cancer
So the TL;DR or ELI5 version of this is this completion can help fight cancer. Had to wade through this article to get as to why we would want a complete sequencing. Any other non-obvious things we can do after this? Like perhaps life extension or other diseases we can cure?
This work has sequenced the “glue” so we know what’s supposed to be there and can better understand what’s different about cancerous cells beyond the usual gene mutations.
But it's science. Nobody knows what might come out, which is really the point.
What can you do with a road or a bridge?
v2, now with a Y chromosome
We need to stop using proprietary genomes. Free genomes, free society.
See https://github.com/marbl/CHM13 and https://www.science.org/doi/10.1126/science.abj6987.
https://www.discovermagazine.com/planet-earth/race-is-real-b...
https://en.m.wikipedia.org/wiki/Race_and_genetics#Race_and_h...
https://www.independent.co.uk/news/science/iq-tests-are-fund...
Information about the benefits of genomic research are trivially easy to find. To get you started in general, checkout [1] below. For one of the most prominent examples-- the way it fundamentally transformed cancer research, checkout [2].
[1] https://www.google.com/search?q=genomic+research+application...
[2] https://www.icr.ac.uk/news-features/latest-features/how-the-...
The first part of your sentence doesn't follow from the second despite the second part being true. (well… the "99.9%" part is pop science bullshit.)
Genomes do run in families, that being the whole point of them. And they certainly do have health effects whether they're shared with everyone or unique to you.