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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 chromo

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.

bonestamp2 3y ago
As others have asked in this thread, what does "fully sequenced" mean to the layman?
- yellowcake0 3y ago
  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 3y ago
    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 3y ago
  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.
p1mrx 3y ago
You can tell it's the Y chromosome because of the way it is.
- certifiedloud 3y ago
  Thats pretty neat!
tobinfricke 3y ago
What makes the Y chromosome more difficult?
- bux93 3y ago
  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.
- deleted 3y ago
  [deleted]
- BbzzbB 3y ago
  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 3y ago
    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.
- mnw21cam 3y ago
  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.
AgentME 3y ago
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 3y ago
  human_genome_final_FINAL_3.txt

bonestamp2 3y ago

As others have asked in this thread, what does "fully sequenced" mean to the layman?

yellowcake0 3y ago
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 3y ago
  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 3y ago
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.

p1mrx 3y ago

You can tell it's the Y chromosome because of the way it is.

certifiedloud 3y ago
Thats pretty neat!

tobinfricke 3y ago

What makes the Y chromosome more difficult?

bux93 3y ago
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.
deleted 3y ago
[deleted]
BbzzbB 3y ago
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 3y ago
  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.
mnw21cam 3y ago
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.

AgentME 3y ago

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 3y ago
human_genome_final_FINAL_3.txt