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As DNA reveals its secrets, scientists are assembling a new picture of humanity

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Re: As DNA reveals its secrets, scientists are assembling a new picture of humanity

#11

Post by volodia »

apathy wrote: post #10
niels_olson wrote: post #5

Earlier quoted context omitted.

Hi, I'm a pathology resident and I would like to present a journal club on this. My undergrad is in physics and I have taught myself some bioinformatics, like Durbin's use of Markov models, Ukkonen's suffix tree, BWT, BLAST, but clearly I'm no informatics expert. Two questions: 1) in the absence of a reference genome, does Burrows-Wheeler not apply? 2) Could you recommend any good articles to start from?

There's probably, in spirit, a graph version of the BWT, but I'm not familiar enough to know it. The approach is less straightforward because you're not just modifying BWT to allow for indels/errors, but rather a graph compression algorithm to allow for fragment searching along vertices of a sequence graph. That said, it has to happen eventually. It's been a while since I took comp bio (sequences & graphs) but what y…

Here is a paper that presents a graph version of the BWT:

http://bioinformatics.oxfordjournals.org/content/29/13/i361....

Re: As DNA reveals its secrets, scientists are assembling a new picture of humanity

#13

Post by a_bonobo »

veli_joza wrote: post #12

Is there an open source project that tries to replicate the Seven Bridges proprietary graphing technology? It seems like a logical next step.

There are many people working on various aspects of DNA graphs - for example, there's now the FASTG format, a replacement for the FASTA format which is essentially a graph in text form: http://fastg.sourceforge.net/

Some assemblers (SPAdes?) have started to support this format, but most downstream software only uses the FASTA format (the non-graph version from a single genome/representation).

Heng Li (somewhat now the godfather of bioinformatics) wrote a blog post about various implementations here: https://lh3.github.io/2014/07/25/on-the-graphical-representa...

Re: As DNA reveals its secrets, scientists are assembling a new picture of humanity

#14

Post by a_bonobo »

a_bonobo wrote: post #13
veli_joza wrote: post #12

Is there an open source project that tries to replicate the Seven Bridges proprietary graphing technology? It seems like a logical next step.

There are many people working on various aspects of DNA graphs - for example, there's now the FASTG format, a replacement for the FASTA format which is essentially a graph in text form: http://fastg.sourceforge.net/ Some assemblers (SPAdes?) have started to support this format, but most downstream software only uses the FASTA format (the non-graph version from a single genome/representation). Heng Li (somewhat now th…

Just realised that most of the above is from 2014 - here are some recent works:

A novel data structure to store the whole graph: https://almob.biomedcentral.com/articles/10.1186/s13015-016-... Software is here: https://www.uni-ulm.de/in/theo/research/seqana.html

This one maps the whole DNA space using markers: http://www.nature.com/articles/ncomms7914

Here's a paper that looks at the total genetic space of several individuals, but with read mapping alone, no graphs: http://genomebiology.biomedcentral.com/articles/10.1186/s130...

Most of this is based on open source or openly available software. A big company that's closed source is NRGene from Israel, I've read good things about their DeNovoMAGIC/PanMAGIC but I'm unsure how that stuff works exactly (apart from massive short read coverage).

Re: As DNA reveals its secrets, scientists are assembling a new picture of humanity

#16

Post by roye »

veli_joza wrote: post #12

Is there an open source project that tries to replicate the Seven Bridges proprietary graphing technology? It seems like a logical next step.

The main one is vg, which I think Benedict Paten is actively supervising, along with Richard Durbin. The main developer is Erik Garrison. I'm pretty surprised it wasn't mentioned by name: https://github.com/vgteam/vg

Re: As DNA reveals its secrets, scientists are assembling a new picture of humanity

#17

Post by roye »

a_bonobo wrote: post #13
veli_joza wrote: post #12

Is there an open source project that tries to replicate the Seven Bridges proprietary graphing technology? It seems like a logical next step.

There are many people working on various aspects of DNA graphs - for example, there's now the FASTG format, a replacement for the FASTA format which is essentially a graph in text form: http://fastg.sourceforge.net/ Some assemblers (SPAdes?) have started to support this format, but most downstream software only uses the FASTA format (the non-graph version from a single genome/representation). Heng Li (somewhat now th…

The more relevant continuation of Heng Li's posts is Pall Melsted et al's work on GFA: https://github.com/GFA-spec/GFA-spec

This is pretty close to my area...

Re: As DNA reveals its secrets, scientists are assembling a new picture of humanity

#18

Post by toufka »

nonbel wrote: post #15

Genetics question: How many cells do you need in a population so that there is at least one variant at each position (ie a SNP)? This can be for any species or cell line for which the info is available.

Humans have two copies of ~3 Billion base pairs. A reasonable error rate of DNA replication (not under stress) is about 1 write error in 1 billion reads. Many of those errors are actually immediately corrected by post-replication error correction mechanisms. Also, as cells divide, errors that happen early will be propagated more times than errors that happen late in development. Further, mutations are not uniformly distributed though the genome. A human has > 10^14 cells, so any given human might have a few thousand different variants among its cells. The error rates of human polymerase is way less than a bacterial polymerase. And a human genome is way larger than a bacterial (or viral) genome. Viruses actually have mechanisms to increase the error rate of DNA replication.

For a human, you would need a LOT more than a single human to have a variant at each position. Something like HIV can actually have a small enough genome, a high enough error rate, and a large enough population in an infected patient, that it can realistically have a unique variant at each position in its genome within a single human host.

Re: As DNA reveals its secrets, scientists are assembling a new picture of humanity

#19

Post by amelius »

nonbel wrote: post #15

Genetics question: How many cells do you need in a population so that there is at least one variant at each position (ie a SNP)? This can be for any species or cell line for which the info is available.

NCBI has dbSNP, a database of important SNPs, with statistics on the variation of alleles among different populations. See e.g. [1]. From there you could compute the answer to your question.

[1] https://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=rs6564851

Re: As DNA reveals its secrets, scientists are assembling a new picture of humanity

#20

Post by jhbadger »

WhitneyLand wrote: post #3

There's got to be a lot more to the story that I don't understand. Why wouldn't it have been obvious 16 years ago that a thoughtfully designed data model was necessary, possibly using graphs, to account for variability and other attributes of the genome? Surely it was foreseeable that tooling would be crucial and that a solid software foundation would be invaluable to enable efficient and flexible processing for year…

There has always been a fight in genomics between bench-types and computational biologists. Traditionally molecular biology yielded very binary yes/no answers requiring little mathematical analysis -- even when I was in grad school in the 1990s, I had a professor say in all seriousness "If you need statistics to understand the results of your experiment, you did the wrong experiment". Things are changing and many of the current generation of grad students are becoming hybrid bench/computational biologists, which is a good thing.
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