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No human genome has ever been completely sequenced

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Re: No human genome has ever been completely sequenced

#81

Post by quotemstr »

Obi_Juan_Kenobi wrote: post #60
Bartweiss wrote: post #31

> * A gene called ARHGAP11B, which was created by one such duplication, causes the cortex to develop the myriad folds that support complex thought; SRGAP2C, also a duplication, triggers brain development.* A question I've never seen addressed: is one justification for junk DNA to create space for beneficial mutations? Obviously some mutations are actively harmful, but the reason most mutations are destructive is that…

Not stupid at all. If you're interested in that, I'd look up "Whole Genome Duplications". For instance, corn underwent a WGD about 7 million years ago (IIRC, the number might be off), and we can identify an 'a' and 'b' genome. After these events, most of the duplicated genes will be lost, either through purging selection or drift. However, some will stick around and take on new subset functions (see nkrumm reply). If…

Why is it that plants are so much better than animals at tolerating chromosomal shenanigans? Plants can be highly polyploid, get chromes swapped out, randomly get duplicates, etc., and not seem to suffer massive problems. In a human, you duplicate one chromosome, and you get a very buggy phenotype.

Re: No human genome has ever been completely sequenced

#82

Post by a_bonobo »

quotemstr wrote: post #81
Obi_Juan_Kenobi wrote: post #60

Earlier quoted context omitted.

Not stupid at all. If you're interested in that, I'd look up "Whole Genome Duplications". For instance, corn underwent a WGD about 7 million years ago (IIRC, the number might be off), and we can identify an 'a' and 'b' genome. After these events, most of the duplicated genes will be lost, either through purging selection or drift. However, some will stick around and take on new subset functions (see nkrumm reply). If…

Why is it that plants are so much better than animals at tolerating chromosomal shenanigans? Plants can be highly polyploid, get chromes swapped out, randomly get duplicates, etc., and not seem to suffer massive problems. In a human, you duplicate one chromosome, and you get a very buggy phenotype.

This has, as usual, several reasons :)

One reason is the absence of sex chromosomes in plants. If humans get a duplicated sex chromosomes things go completely haywire. Another reason is that due to so many WGDs, plants have ample gene copies, so the copies can freely mutate around or even break, there's always a backup.

Not all of these shenanigans work out, in plants this has the wonderful name 'genomic shock'. In wheat there's a candidate gene (Ph-1) which seems to somehow stabilise these instabilities between chromosome copies. In other species people have been trying for a few years to make polyploids but have been failing because there is no stability mechanism - for example, there are only few papers where people managed to make a Brassica hexaploid, these hexaploids are usually very unstable and have problems generating offspring (see for example http://www.cropj.com/malek_7_9_2013_1375_1382.pdf )

Re: No human genome has ever been completely sequenced

#83

Post by lolreally1 »

nether wrote: post #80
labster wrote: post #52

Earlier quoted context omitted.

Seriously. I can't go a week in HN without reading someone's complaint about not being able to read a quote, probably on mobile. If users keep complaining regularly, it's a problem with the software interface, not the users.

I emailed dang about it a while (years) ago. He said he's added it to the fix list, after initially saying that having a quote tag would mess up the site's "character." You may want to email him too.

I fail to see how a quote tag would drive away the throngs of Silicon Valley elites, people who begin sentences with “I’m not an expert, but...”, hardcore Randians, and Paul Graham sycophants.

Re: No human genome has ever been completely sequenced

#84

Post by chrisamiller »

throwanem wrote: post #29
chrisamiller wrote: post #15

Earlier quoted context omitted.

You're right, and the next frontier in genome assembly and mapping algorithms is using graph-based genomes, where differences between individuals or populations can represented as different paths through a sequence graph. (There are lots of better explanations with pretty pictures out there with a little searching)

That's more of a representation problem, isn't it? I'm not seeing where it would require any new development to produce such a graph - just a lot of CPU time to assemble one from a collection of FASTA files, or whatever linear representation. (And a lot of wall-clock time, to convince people to use it...)

Right - It's not so much algorithmic development as development of the toolchains that will enable such representations to be actually useful for downstream analyses.

Re: No human genome has ever been completely sequenced

#85

Post by chrisamiller »

nonbel wrote: post #61
viewtransform wrote: post #45

Earlier quoted context omitted.

"each cell from the same person will have different genomes" Did you mean each cell will have different gene expression ? I thought all the cells have the same nucleotide sequences barring maybe occasional mutations (like in cancer)

Mutation rates are high enough that we should expect at least a few every division. There are supposedly n~6e9 base pairs[1] and mutation rate is said to be p~1e-8 per bp per division[2]. Assuming each mutation is independent, etc, etc we get a back of the napkin via the binomial distribution with mean = n*p ~ 60 mutations per division. [1] https://en.wikipedia.org/wiki/Human_genome [2] https://en.wikipedia.org/wiki/…

Most estimates I'm familiar with are substantially lower than that - between 0.1 and 3 errors per cell division.

Re: No human genome has ever been completely sequenced

#86

Post by sspiff »

lolreally1 wrote: post #83
nether wrote: post #80

Earlier quoted context omitted.

I emailed dang about it a while (years) ago. He said he's added it to the fix list, after initially saying that having a quote tag would mess up the site's "character." You may want to email him too.

I fail to see how a quote tag would drive away the throngs of Silicon Valley elites, people who begin sentences with “I’m not an expert, but...”, hardcore Randians, and Paul Graham sycophants.

And yet here you are, on the site whose users you are attacking, commenting on an off-topic comment thread. Perhaps you should rethink your life choices?

Re: No human genome has ever been completely sequenced

#87

Post by teekert »

shpx wrote: post #12
jessriedel wrote: post #6

As usual, the journalist spends many paragraphs painting a picture of human conflict before actually getting on to the interesting claim. > The reason for these gaps is that DNA sequencing machines don’t read genomes like humans read books, from the first word to the last. Instead, they first randomly chop up copies of the 23 pairs of chromosomes, which total some 3 billion “letters,” so the machines aren’t overwhelm…

https://youtu.be/fCd6B5HRaZ8 is the best visualization of how the most popular type of DNA sequencer works (that I've found). Imagine you have a string of length 3 billion made by randomly choosing from 4 characters. Like this dna = ''.join(random.choices('atgc', weights=[30.9, 29.4, 19.9, 19.8], k=3_234_830_000)) you get to randomly sample 1 billion[3, page 7] overlapping substrings of length 200[3, page 7] with .1%…

Very nice movie indeed. This Sequencing by Synthesis is indeed the most popular method, the words in this type of DNA sequencing are usually 150 base bairs long, but by using fragments that can be much longer (say 2500 base pairs) and sequencing from both ends (as the movie explains) one can derived information on the position of 2 150 base pair long "words" relative to each other.

The alternative technologies, sometimes called third generation sequencing are nanopore based (PacBio and Oxford Nanopore technologies), they work by pulling long DNA molecules through tiny holes and read the sequence directly, more specifically, they read a couple of base pairs at a time and infer the sequence from the current between the sides of the pores. This is very error prone and the (around 1 in 10?) random errors are corrected by sequencing every part of the genomic area of interest multiple times.

To be clear, most sequencing experiments (in research and in the hospital) are designed to look at variations we can understand and thus the "words" (we call them reads) are aligned against "the" reference genome (as opposed to assembling de novo), which is the genome for as far as we understand it (the last official version is from 2013 but is updated regularly with new parts). Typically, a significant portion of the reads a sequencer produces cannot be mapped to the reference, probably as a results of unmapped regions indeed or perhaps deviations between the patient and the reference genome, this is of course even worse in patients with tumors with unstable genomes. This field still has a lot of challenges to tackle.

Re: No human genome has ever been completely sequenced

#88

Post by technofiend »

lolreally1 wrote: post #83
nether wrote: post #80

Earlier quoted context omitted.

I emailed dang about it a while (years) ago. He said he's added it to the fix list, after initially saying that having a quote tag would mess up the site's "character." You may want to email him too.

I fail to see how a quote tag would drive away the throngs of Silicon Valley elites, people who begin sentences with “I’m not an expert, but...”, hardcore Randians, and Paul Graham sycophants.

You forgot the folks who turn every article on the latest Google phone into a discussion on Apple products. See the latest posting about the Pixel 2 as an example.

Re: No human genome has ever been completely sequenced

#89

Post by danieltillett »

epistasis wrote: post #79
x0x0 wrote: post #77

Earlier quoted context omitted.

I think the entire tech that I worked on has been superseded by better technologies. However, I (think?) the limitations are still of interest because they influenced the original sequencing and probably a lot of the early data. The other takeaway I had, as someone who came to this with a CS and stats background, is that chemistry sucks. None of it is deterministic, and when people say some chemistry does X, what the…

Older tech stays around quite a while! No sequencing technology is perfect, so even Sanger sequencing is still used quite a bit for various tasks from clinical sequencing to validation studies to anywhere you just want to phase something that's longer than 300bp, etc. And yes, the chemistry that biology takes advantage of means embracing uncertainty in the world. It's all thermodynamic chances, with lots of non-linea…

Sanger sequencing is still about 1/3rd of the market by dollar value. There is more Sanger sequencing being done today than 10 years ago.

Re: No human genome has ever been completely sequenced

#90

Post by nonbel »

chrisamiller wrote: post #85
nonbel wrote: post #61

Earlier quoted context omitted.

Mutation rates are high enough that we should expect at least a few every division. There are supposedly n~6e9 base pairs[1] and mutation rate is said to be p~1e-8 per bp per division[2]. Assuming each mutation is independent, etc, etc we get a back of the napkin via the binomial distribution with mean = n*p ~ 60 mutations per division. [1] https://en.wikipedia.org/wiki/Human_genome [2] https://en.wikipedia.org/wiki/…

Most estimates I'm familiar with are substantially lower than that - between 0.1 and 3 errors per cell division.

Thanks, actually the wikipedia link was "per generation" and they assume ~ 100 divisions/mitoses per human generation. So it should be 1e-10 mutations/bp/division.

However, that is for germline, somatic mutation rates are apparently 10-100x more more common: https://www.nature.com/articles/ncomms15183

These rates no doubt vary by cell type, environment, etc. I was actually thinking something like 1e-6 to 1e-10 mutations/bp/division.

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