I’ve just been visiting CNIO in madrid – a great, fancy new(ish) institute in Madrid focusing on cancer – it was a great visit if you ignore the 2 hour delay (thanks Iberia) coming out and currently 1 hour delay (thanks BA…) coming back. They are doing all the things one expects from a high-end molecular biology institute. There are a chip-chip guys, moving to chip-seq. There are some classic cell biologists moving into more genome wide assays (in this case, replication). They have a great prospective sample collection in two cancers, and are about to get into a Genome Wide Association Study (GWAS).

David – the head of bioinformatics service – already is leveraging Ensembl alot. They script against our databases (Perl API mainly) and have a local mirror set up. They ran courses, bringing over Ensembl people for both an API course and a Browser course (contact helpdesk if you’d like this to happen at your institute…). But even then, discussions with David made us realise that they could use us even more – for the functional genomics schema and the variation schema in particular.

This is what Ensembl is all about. We make it easier for people who want to work genomically to do the sometimes painful data manipulation and plumbing. In particular, Ensembl provides public domain information in a large scale, well organised and ready to be browsed on the web, scripting against in Perl and accessible to clients like bioconductor. And more than any other group, we help group’s like David’s do more for his institute and have to worry less about the infrastructure. David was very interested in the “geek for a week” program when someone comes to work at Ensembl to help accelerate a project.

Returning to the airline theme, some of the biologists admitted using the UCSC browser in a little embarrassed way. I responded that it was fine – UCSC is a great browser, with some great tools. Like airlines, we know people have a choice browsers, and we hope people come “fly ensembl” and enjoy it, but we know the competition is good (and really friendly as well – we like working with those crazy californians, and have a number of joint projects). If you are a biologist, you should use the best tool for the job at hand. Of course, we know where we’re lacking, in particular in comparison to UCSC, and we are working on getting better. Keep an eye open on changes in Ensembl this year – and do come fly with us even if your “regular browser” is US based.

Finally my plane I think is ready to depart.

(Madrid airport is so big I think I’m half way to the UK already)

Today the 1000 Genomes projects was announced. By any measure this is a big deal.
The goal is simple: to create the most comprehensive and medically useful collection of human variation ever assembled by producing approximately 6 terabases of sequence. To put this amount of data in prospective, 6 terabases is more than 60 times the amount of data that is currently available in the DDBJ/GenBank/EMBL Archive and that took more than 25 years to collect. At the peak production of the 1000 Genomes project more that 8 billion basepairs per day will be sequenced. It’s data output of the the entire human genome project every week. All made publicly available.
The data generation rate and the short read length mean that the bioinformatics requires for the project are equally ambitious (or terrifying depending on your point of view). The EBI and NCBI, working together, are creating a joint DCC (data coordination centre) to collect, organise and provide the data to the world. Steve Sherry at the NCBI and I are eager to take this on.
At Ensembl we’ve been expecting this development and built support for re-sequencing data into our variation database a couple of years ago. So far, we have data for about 6 humans, 5 mouse strains, and a smattering of rat data. Small stuff compared to six months from now, but large enough that we have both experience and confidence dealing with the large-scale resequencing data. We are probably going to need both.
Check out more at http://www.1000genomes.org

Richard posted the next release intentions here:

ensembl-dev archive

Lots of good stuff – orangutan, horse being released, the usual tweaks about contamination (viral genes) into the gene sets being removed, little details.

But one thing is quite a change. It is from Javier’s Compara team, and it is simply stated as

“Generate the 7-way alignments using the new enredo-pecan-ortheus pipline”

Unpacking this statement, it is a big change in how we’re thinking about comparative genomics alignments. Enredo is a method to produce a set of co-linear regions, sometimes called a “synteny map” though this term is a dreadful term. The key thing is that it handles duplications in the genome, allowing (say) two regions of human to be co-linear with one region of mouse. This is hard to handle on a genome-wide scale in a scaleable manner. Pecan is the multiple aligner written by the brilliant Ben Paten (used to be my student, and wrote Pecan whilst at the EBI; he is now at UCSC with Jim and David and co). Pecan is the best aligner – by both simulation testing and testing via ancient repeat alignability criteria – it has the highest sensitivity of alignment with the same specificity as the next best aligner. Finally Ortheus, also from Ben, provides (potentially) realignment whilst simultaneously sampling correctly from a probabilistic model of sequence evolution, critically including insertion and deletions, and thus as a side effect, producing likely ancestral sequences. This also has been stringently tested using a hold-one-out criteria, basically can we “predict” the marmoset sequence only using other extant species (answer – not completely correctly, but better than any other method, eg taking the nearest sequence).

So – what does this all mean. Basically there are two key things:

  1. Handling lineage specific duplications. This is a headache, and we have a good solution, providing the alignment of therefore the paralogous and orthologous regions (the paralogy is limited to relatively recent paralogy, ie, within mammals) simultaneously
  2. We can reliably predict ancestoral sequences

One headache is that some of the things we display, in particular the GERP continuous conservation score, needs to be adapted to work on the basis now of regions with paralogy. There is a fascinating piece of theory to work through here – what is the concept of the “neutral tree” when there has been a lineage specific duplication? How should one treat paralogs? Currently this is ignored by virtue of the fact that the alignments don’t allow this. Now the alignments do allow this, and we need to do something sensible, as well as stimulate evolution theory people to look at the data and work out new methods.

The next headache is what do we do with the ancestral sequences? Dump them? Display them? Gene predict on them? If so, how?

The end result is that release 49, even the comparative genomics, wont look very different, but it will have these new alignments, and over 2008 we will be working out how to present, analyse and leverage them more – so if you are interested, please do take them for a spin!

(Release 49 is due to be out sometime in mid-Feb)

We’re going to be experimenting with broader content generated by the Ensembl team in the Ensembl blog – at the very least by myself, Ewan Birney. So you can expect to read more about what we’re doing, the things which are coming up in the pipeline and our thoughts on how genomic infrastructure is going to evolve over time. Ensembl is a big team, with alot of components, so it is often hard to track what we’re doing and why we’ve made some decisions. This blog hopefully will keep you up to date with our progress in an informal manner.