The OpenHelix Blog

The last tip of the week I did was Genome Variation Tour I where we started our journey following one SNP in an individual’s genome through various databases to see what we can find out about that variation. In that tip we started out by looking at a SNP in the CYP4F2 gene in the UCSC Genome Browser and followed it to dbSNP. Today’s tip will continue our journey to OMIM to see what information we can find there. We’ll find this variation is clinically associated with Warfarin dosage effects and specifically this individual’s C/T heterozygosity indicates an intermediate dosage for effectiveness if indeed he ever needed this drug.  In some ways, your guess is as good as mine as to what we will find and what avenues we will be taking in the next few tips I’ll be doing. I’m am discovering information as I go along too. I can tell you though that the next installment of the genome variation tour will take us to PubMed, and a few not particularly well known but gem databases perhaps and probably back to the UCSC Genome Browser to expand our look at the interactions of several variations in this individuals genome.

Yesterday Mary found this twitter post from NCBI that they’ve updated the look of OMIM reports and shortened its URL. I’ve been at OMIM this morning to check out the changes, and I like what I see. We actually saw the URL change (from http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim to http://www.ncbi.nlm.nih.gov/omim) back in July, when we updated our introductory tutorial on OMIM, but now the new address is official.  The old URL still works, and I’m not sure they will every discontinue it, but you probably want to update your bookmarks to the new one. And hey, what’s not to love about shorter URLs?

On the individual disease reports, NCBI announces a table of contents for the report. This isn’t so much new – we featured the table of contents in our v4 OMIM tutorial back in 2006 – but the table has shifted from the left-side blue navigation area that you see on many NCBI pages over to the right in a clean looking navigation area similar to the new navigation style that you will now see when using PubMed. As you might know, OMIM reports can be huge, with all sorts of information, so the table of contents is great. It makes navigating to exactly the category of information that you are interested in a simple click, rather than scroll & scan. Since July They’ve also added all the internal and external resource links to the right-side navigation areas. I think that’s a GREAT idea – those links provide so much additional information and connections. They used to be somewhat buried under a few clicks of navigation. We always really featured these links in our tutorials, to be sure people were aware and using this valuable feature, but having the links front and center will make them all the more prominent, and hopefully utilized! Below I show the old and new views for you to compare.
This is how OMIM reports used to look:

And here’s their new style:

Note how the links area has expanded – this is a really nice usability feature!

The Lancet paper, Clinical assessment incorporating a personal genome, has held my fascination this weekend (yes, I read it at the beach). Mary posted Friday and again Saturday on the paper and related NPR segment. It feels to me to be a seminal paper, though I do agree with Daniel at Genetic Future, there are a lot there we still don’t know. A large portion of the variation is in non-coding regions, and thus predictions and propensities are hard to come by with the available analysis. In fact, as he pointed out, many of the coding region variations have little information as to their effect on disease. I would add also that even if we get to that holy grail of $1,000 to sequence a personal genome, this kind of extensive analysis would still be time and cost-prohibitive for the vast majority of sequenced genomes.

Yet, as with all early steps in science and medicine, there’s missing pieces, large gaps and huge efforts (think “space travel,” “computers,” “microwave ovens,” “internet,”) that over time become inexpensive and commonplace (ok, so the former isn’t necessarily “inexpensive”). Sequencing genomes will become inexpensive before the analysis does, but both will come. And I think this paper is pointing to that future.

The other hurdle to large scale personal genomics I see (of course) is the understanding and use of the genomics and data resources. The authors use a large (and excellent, in my opinion) suite of genomics resources to do obtain data and do their analysis. I’ll list them here with links in alphabetical order:

dbSNP (T)
GVS (T)
HapMap (T)
HGMD
OMIM (T)
PharmGKB
PolyPhen
PubMed (T)
SIFT
UniProt (T)

All of these resources have a wealth of data, but even then, that is a lot of analysis and familiarization that is needed with each tool. Each tool does have documentation and tutorials, and of course OpenHelix has tutorials on many of the ones mentioned (those with linked “T”s after the name). Still, this one analysis took a large number of tools and familiarization.

The paper does have a pretty good figure (figure 1) outlining the analysis process. For example, they SIFTed the genome to find gene-associated, non-synonymous, rare and novel and disease associated variations and then analyzed those using dbSNP, HGMD, OMIM and PubMed to analyze something like HFE2 which might have an association with Haemochromotosis. One of my quibbles with the paper, as often is with these papers, is that there isn’t a good methods ‘walk-through’ of the paper using something like Galaxy or Taverna in a history or workflow that would help reproduce the analysis.

We also have a tutorial I’d like to point you to, one that walks through a similar process and teaches users the basics of walking through that process. You can find this tutorial here, it’s free and publicly available. The tutorial walks the user through the analysis of a gene variation, in this case in the CYPC9 that effects an individual’s response to Warfarin. There is a similar variation (different gene, affects same drug response) in the paper. The tutorial uses the NIEHS SNPs site to get an overview of the variation including SIFT and PolyPhen predictions, then to the UCSC Genome Browser to find an overview of the region, walks through the dbSNP information and does a quick tag SNP analysis using GVS. That tutorial is only one very small step in what will have to be a immense education into genomics and genomics resources.

That is all to point out that the paper is an fascinating first step, and as a first step suggests the gaping holes we will have in bringing personal genomics to medicine.

Ashley, E., Butte, A., Wheeler, M., Chen, R., Klein, T., Dewey, F., Dudley, J., Ormond, K., Pavlovic, A., & Morgan, A. (2010). Clinical assessment incorporating a personal genome The Lancet, 375 (9725), 1525-1535 DOI: 10.1016/S0140-6736(10)60452-7

(click either graphic to see the tip of the week movie) It’s not Halloween yet, but thought I’d get us started in the mood by introducing you to a database that has some obvious references to the movie “The Fly” (the 1958 version is the only really worth watching . Ok, so the database doesn’t actually help you turn humans into flies, that’s a few years away (that’s a joke of course). No, this is one of those resources that does one thing and does it well. It’s very straightforward and simple… it takes human disease genes and sequences found in OMIM and finds the homologs in the Drosophila melanogaster genome. The name of the database is Homophila. From the results you can find the links to the data and go from there. Simple function that can be very useful. Give it a try.

We go through the thousands of resources and databases available online in our search to do tutorials we found many that are great resources but for one or more reasons we don’t or can’t do a tutorial for. Yet they are great resources. So, we occasionally do “Tip of the Week” on some, but even those are not enough to at least touch on all the great resources out there, so occasionally I we are going to give a quick “shout out” to some of these resources occasionally.

So today it’s F-SNP.

From the Genetic Alliance announcement list–I am reprinting in full because although I had met him, I certainly couldn’t write a tribute of this nature:

Dear Colleagues,

It is with great sadness that I inform you that Victor Almon McKusick,
M.D., University Professor of Medical Genetics since 1985, namesake of
the McKusick-Nathans Institute of Genetic Medicine at the Johns Hopkins
University School of Medicine, and a towering international figure in
genetics research, diagnosis and treatment, died Tuesday, July 22, at
home. He was 86.

To the world genetics community, Victor has been rightfully honored as
the founding father of medical genetics as a specialty, as well as a
strong mentor by generations of students, trainees and faculty.

Throughout his energetic and long professional career, spent entirely
at Johns Hopkins beginning with medical school, class of 1946, he served
as Osler Professor and chairman of the Department of Medicine and
physician in chief of The Johns Hopkins Hospital from 1973 to 1985. He
was a distinguished cardiologist and executive chief of the
cardiovascular unit at Baltimore Marine Hospital while progressing
rapidly through the ranks in the Johns Hopkins Department of Medicine.

He completed his internship and residency in internal medicine and
training in cardiology here, held joint professorships in epidemiology
in the Johns Hopkins University School of Public Health and in biology
at The Johns Hopkins University. In 1957, Victor founded the Division of
Medical Genetics and became a full professor in the Department of
Medicine in 1960.

An early proponent of the complete mapping of the human genome, in 1966
Victor created the first edition of his now classic reference Mendelian
Inheritance in Man, an ever-enlarging compilation of inherited disease
genes, which now exists as OMIM, Online Mendelian Inheritance in Man, a
continuously updated version on the Internet, providing a searchable
database of disease genes’ locations and characteristics.

Victor was the recipient of scores of national and international
prizes, honorary doctorates and accolades, including the 1997 Albert
Lasker Award for Special Achievement in Medical Science, the 2001
National Medal of Science, and the 2008 Japan Price in Medical Genetics
and Genomics. He was the founding president of the Human Genome
Organization and a member of the National Academy of Sciences.

Visitation is scheduled for Friday, Aug. 1 from 3 p.m. to 5 p.m., and
from 7 p.m. to 9 p.m. at the Ruck Towson Funeral Home, in Towson,
Maryland. A memorial service will be held Saturday, Aug. 2 at 2 p.m. at
the Second Presbyterian Church of Baltimore. Interment will be Friday,
Aug. 8 at 11 a.m. at Pingree Cemetery in Parkman, Maine.

I know that the whole of the Johns Hopkins family joins me in extending
our deepest condolences to his wife, Anne, a retired member of our
faculty; and their children and families.

Edward D. Miller, M.D.
Dean/CEO
Johns Hopkins Medicine

To read more about the life and work of Victor A. McKusick, M.D., go
to:

European Genetics Foundation:
http://www.ronzano.org/index.php?l=it&p=mcks

Lasker Award 1997:
http://www.the-scientist.com/article/display/17766/
http://www.jhu.edu/news_info/news/univ97/sep97/lasker2.html

National Academies of the Sciences
http://www.nasonline.org/site/PageServer?pagename=AWARDS_scirev

Oral History of Human Genetics Project
http://www.socgen.ucla.edu/hgp/mckusick.html

University of New England
CHP and CAS Honorary Degree Recipients 2008
http://www.une.edu/studentlife/graduation/honorary.asp

Memorial University of Newfoundland
World’s best known geneticist visits Memorial
http://www.med.mun.ca/munmed/104/genetics.htm

The New York Academy of Medicine 2006
http://www.nyam.org/news/2663.html

Other Links:
http://astro4.ast.vill.edu/mendel/mckusick.htm

Alas. A giant has left us. But what a great legacy. I remember him describing the original version of OMIM on index cards. From index cards to major impact. A tremendous life.

Link to the Johns Hopkins press release: http://www.hopkinsmedicine.org/Press_releases/2008/07_23_08.html

UPDATES: links to obituaries in the press

NYT: Victor McKusick, 86, Dies; Medical Genetics Pioneer

LA Times:  Victor A. McKusick, 86; Johns Hopkins physician pioneered genetics research

Washington Post:  Victor McKusick; Genetics Pioneer

I shudder each time I read a new ‘ome’ coined. “Omes” have proliferated to the point of meaninglessness I believe sometimes. Though, I have to say my favorite to date is the “Unome” (the network of genes of unknown function). Seems very Zen.

Ok, that mini rant over.. the diseasome. The NY Times had an interesting article about some research done on the genetic interconnections of diseases. It was an interesting read on a purely personal level, and they have a fun little interactive graphic (I’m a sucker for fun little interactive graphics). The article is about this research published in PNAS last year. The research is actually a fascinating read. Using OMIM to find interconnected disease genes, the authors seek to:

” improve the single gene–single disorder approach by developing a conceptual framework to link systematically all genetic disorders (the human “disease phenome”) with the complete list of disease genes (the “disease genome”), resulting in a global view of the “diseasome,” the combined set of all known disorder/disease gene associations”

I’ve yet to delve more deeply into the article, but I will. The list of articles that cite this paper (scroll to the bottom of that PNAS link) is also very fascinating and I think I’ve got a few weeks of reading ahead of me. A recent paper in Nature used a ‘network’ approach to identify three genes previously unidentified in association with obesity.

I tried to see if there is a database yet of the “diseasome,” but have come up empty-handed. There was a ‘diseasome.net’ site, but it looked more like a google-ad honeypot than a real site (even the ‘about’ page had nothing on it yet). But you know and I both know the database is coming if it isn’t already here, it’s only a matter of time. I’ll be keeping a look out.

For funding reasons, NCBI (home of PubMed, BLAST, dbSNP, OMIM and more) has cut their outreach staff, canceled all onsite training seminars and this has to mean decreased support for online help, documentation and tutorials.

When we wrote our NIH grant, one of the models of success in the bioinformatics training area that we highlighted was the NCBI Field Guide program. For those who may be unfamiliar with it, it is a set of training modules delivered by the outreach team at NCBI. They would come to your site, cover many NCBI tools and do hands-on workshops. Another course (Enhanced Field Guide) drew science librarians and other trainers together to train them, and those folks could go back to their institutions and offer more-and-better searches and training for their constituents. We thought the Guides are a terrific group of people who were interested in people getting their hands on the myriad tools at NCBI and using them effectively. It wasn’t really a competitive situation—their remit was only for NCBI tools, and there were plenty of others out there for us to do. In fact, many people who contacted us for training did so because their local users enjoyed the NCBI training and they wanted similar engagements for other tools.

Recently, though, the calls changed. We found we were getting calls from people who said they weren’t going to be able to get any more Field Guide trainings. NCBI is discontinuing the outreach program. Quite frankly, we were surprised. A sample of the notifications people were getting: http://www.library.uiuc.edu/blog/bicnews/archives/2008/02/ncbi_field_cour.html

Unfortunately, that tremendous training opportunity will NOT occur. Yesterday NCBI Field Guide coordinator, Peter Cooper, sent the following email:

Because of budgetary constraints, NCBI has made reductions in some of its programs, and the education programs are affected. In fact, all outreach education programs (Field Guide, Mini-courses, Structures, PubChem) are terminated effective immediately. At this point we cannot reschedule this course or accept requests for future courses of any kind. This was as much a surprise to me as it is to you. Feel free to contact me if you have questions.

The Field Course, as well as the Mini-Courses and the Structure course, has been tremendously popular and useful (see list of sites where the Field Course has been offered recently), but the NCBI budget situation will not allow NCBI to continue to travel and offer these courses for the foreseeable future.

(emphasis mine)

Here’s a link to a similar letter at another location: http://www.twu.edu/as/bio/NCBI/FieldGuide/

We’ve confirmed this with a number of people directly involved; they have laid off nearly all of the outreach team. Some got reassigned. There can hardly be anyone there to even answer emails to the helpdesk anymore—and they get lots of emails every day.

I’ve been through layoffs before, a few times. It actually feels like a punch to the gut when I hear about it anywhere else—especially among people I know. I expect layoffs at companies, though. But if there was any group that was solidly in place, going to be around for a long time, I would have thought it was the NCBI outreach team. I’m quite sorry to hear that it has been dissolved.

In this time of so many resources & so much need for increased understanding, outreach has become an intregal part of a resource’s success – fewer instructional resources is an unfortunate consequence of decreased funding for science.

The bloggers here at OpenHelix and some of our family and friends decided to do the taste tests. You know the ones. You probably did them in your genetics class. I used them in my introductory biology class at CCSF years ago and had hundreds of the test strips left. So, we thought we’d distribute them to the bloggers and families here and see what the results were. The test strips are for sodium benzoate, PTC and thiourea. There is also a control strip of no taste (but paper). I numbered the strips and sent them to the bloggers and families (so they wouldn’t know what they were tasting, control or otherwise). And here are the results (and some database links to more about the genetics of taste):

Bioinformatics and Genomics sometimes (always?) brings together two very different groups: biologists and computer scientists. They are often biologists who know something about computers and computer scientists who know something about biology and sometimes they are computational biologists who do both. We (OpenHelix scientists) train biologists who want to use genomics tools that computational biologists (or a team of computer scientists and biologists) have developed. Sometimes those biologists want to do more and sometimes computer scientists need to learn a bit of biology. So, in that vein…