Hotel Dieu

The Hotel Dieu in Paris has been one of the first pediatric hospital in the world (see my photo of the hospital entrance). I recall from the detailed history of allergic diseases by Schadewaldt that at the beginning of the last century it was difficult to presen the students a case of the Bostock hayfever.
The disease was so rare that it took more than one week to find a child with the typical symptoms. Yea, yea.


Science is about recognizing errors

-moblog- I was already willing to accept that age related macular degeneration presents the first good case for a common variant responsible for a common disease (Y402H in CFH). Although the gene may be correct according to a new report from the Chakravarty! group Y402H seems to be largely irrelevant. A haplotype indicating a CFHR3 deletion was seen LESS in AMD (and replicated in a second sample). As the authors say

Much work is required to unravel the complexity of the transcripts and proteins arising from this highly duplicated gene cluster.

Another paper finds

… that there are multiple disease susceptibility alleles in the region.

See you soon again, yea, yea.

-moblog- Last week I asked an author for some additional information that was not available in his online supplement. He responded immediately, I saw the email arriving in Thunderbird, but when I wanted to read it a couple of hours later I couldn’t find it – neither in in the inbox, spam nor trash folder. Bugtraq has identical user reports – which makes me believe that also Activesync sometimes drops items form the todo list, mainly the important ones. Computer are only a higher ordering system for managing the chaos but there is no reason to believe in impeccability. Yea, yea.

Nothing makes sense except in the light of a hypothesis

Looking again at human variation it seems that my recent estimate of 99,9% sequence identity is wrong as shown in an nature editorial yesterday and of course the new paper with the first copy number map of the human genome

3,080 million ‘letters’ of DNA in the human genome
22,205 genes, by one recent estimate
10 million single-letter changes (SNPs) —
that’s only 0.3% of the genome
1,447 copy-number variants (CNV),
covering a surprisingly large 12% of the genome
About 99.5% similarity between two random people’s DNA

I am organizing my literature in folders where the CNV section is still very thin but labelled as high priority – this seems to be adequate as the new study shows that the CNV emcompass hundreds of genes and functional elements.

Notably, the CNVRs encompassed more nucleotide content per genome than SNPs, underscoring the importance of CNV in genetic diversity and evolution

The Wellcome Trust has a nice website about copy number variants. If you want to read more, you will find information about the methods (array-based comparative genome hybridisation, cytogenetics, population genetics, comparative genomics and bioinformatics) as well as the questions that drive CNV research.
Again it seems that disease genetics is not only about stupid nucleotide polymorphisms (SNP), it is a whole bunch of chromosome aberration, segmental duplication, insertions and deletions – there is a good chance that these new data will improve our complex disease mapping efforts. I am quite confident that CNVs are not randomly distributed in the genome

CNV genes encode disproportionately large numbers of secreted, olfactory, and immunity proteins, although they contain fewer than expected genes associated with Mendelian disease […] Natural selection appears to have acted discriminately among human CNV genes. The significant overabundance, within human CNVs, of genes associated with olfaction, immunity, protein secretion, and elevated coding sequence divergence, indicates that a subset may have been retained in the human population due to the adaptive benefit of increased gene dosage.

There is a good chance of retrieving even posthoc CNV information from SNP arrays by taking into account relative signal intensity. Yea, yea.


The mouse data are now also online.

Hap world map?

A new study of 12 Mb DNA sequence in 927 individuals representing 52 populations now finds good portability of of tag SNPs between the 4 hapmap groups and any of the 52 populations (except some African populations like the Mandenka, Bantu, Yoruba, Biaka Pygmy, Mbuti Pygmy and San). The paper has some exceptional well done graphics – and I am quite happy that the resolution of European nations leaves some gaps for our forthcoming ECRHS papers (a poster had already been on display at the 3rd Annual International HapMap Project in Cambridge, Massachusetts).

“Die Botschaft hör’ ich wohl, allein mir fehlt der Glaube” (Goethe, “I hear the message well…”). The usefulness of tagSNPs in disease association studies still remains to be shown (I still renember comments like cr.. map). At present I neither believe in rare variants nor in common common variants but a permanent reshuffling of rare, frequent and highly abundant variants. Yea, yea.

Da steh’ ich nun, ich armer Tor!

[sorry in German, one of my favorite poems, Goethe – Faust you are right]

Habe nun, ach! Philosophie,
Juristerei und Medizin,
Und leider auch Theologie!
Durchaus studiert, mit heißem Bemühn.
Da steh’ ich nun, ich armer Tor!
Und bin so klug als wie zuvor;
Heiße Magister, heiße Doktor gar,
Und ziehe schon and ei zehn Jahr
Herauf, herab und quer und krumm
Meine Schüler an der Nase herum –
Und sehe, dass wir nichts wissen können!
Das will mir schier das Herz verbrennen.
Zwar bin ich gescheiter als alle die Laffen,
Doktoren, Magister, Schreiber und Pfaffen;
Mich plagen keine Skrupel noch Zweifel,
Fürchte mich weder vor Hölle noch Teufel –
Dafür ist mir auch alle Freud’ entrissen,
Bilde mir nicht ein, was Rechts zu wissen,
Bilde mir nicht ein, ich könnte was lehren,
Die Menschen zu bessern und zu bekehren.
Auch hab’ ich weder Gut noch Geld,
Noch Ehr’ und Herrlichkeit der Welt.
Es möchte kein Hund so länger leben!

Men r’sponding to women

We know much about the differences between men and women – the X is the default pathway and the Y under the microscope looks as worn down and “misshapen as a stubbed-out cheroot“. There turns out to be something really new. So far all effects of Y genes on sex determination have been attributed to SRY, the testis determining gene (NR0B1, FOXL2 and WNT04 are probably ovary-determining).
The careful analysis of an Italian pedigree now described a new gene that can reversal XX to male when being disrupted: It is R-spondin 1 (or RSPO1), a growth factor that may act through ß-catenin stabilization and synergize with Wnt.
Do you know renember the nice cartoon of the Y chromosome with the HUH? selective hearing loss ;-) it is finally RSPO1. Yea, yea.

Materials and Methods

Usually “materials and methods” section is in the second paragraph; some journals put it also at the end of a paper. As a reviewer I have always insisted that this heading should be extended to “Patients, materials and methods” while in epidemiology we frequently use the term subjects (BTW epidemiologists have a rather militaristic vocabulary: recruited, cohorts :-) ). The anonymous reviewer of a previous paper now pointed out: Use the phrase “participant” throughout and not “subjects” which has reductionist connotations. I promise to use “participants” from now on, yea, yea.

Peer production

firstmonday has an interesting article about the limits of self-organization and “laws of quality”. Given 52 million tracks in the Gracenote database, 1 million entries in Wikipedia and 17,000 books in project Gutenberg, Paul Duguid throughly examines the two laws of quality

  • Linus law: “given enough eyeballs, all bugs are shallow” which means that almost every error will be discovered and ultimately fixed
  • Graham law: “people just produce whatever they want; the good stuff spreads, and the bad gets ignored”

Although more professionalized, similar principles operate in science. With these large genetic studies, I have the feeling that most errors occur at the interfaces, during hand-shaking of disciplines. There are certainly only a few people that can design a study, examine a patient, go to the laboratory, analyze and annotate the data and publish them. This means that even many eyeballs can not look around the corner and that it will take many years for the “good stuff to spread”. Yea, yea.

Pharmacogenetic tests on the market

Certainly one of the best web resources for pharmacogenetics is the PharmGkB database that collects all kind of data about the relationships among drugs, diseases and genes. Of course you could sequence your genome or run expression profiling on a liver sample. However, you are probably here to find out what (serious!?) pharmacogenetic tests are already on the market.

Much can be said about the usefulness of such tests; I have doubts if there will ever be such personalized treatment as I can foresee some logistic problems to validate it ;-) More likely are group based therapies, maybe restricted to geographic ancestry. Here is a (first and very) preliminary collection of commercially available pharmacogenetic tests:

  • CYP2D6, CYP2C9 and CYP2C19 collectively account for about 40 percent of drug metabolism mediated by cytochrome P-450 (Roche). The AmpliChip CYP450 Test is the world’s first pharmacogenetic microarray-based test approved for clinical use. CYP2D6 metabolizes codeine into morphine. A variation in CYP2D6 varies with race and leads to a lower elimination rate of the antidepressants Prozac (a selective serotonin reuptake inhibitors); the alternatively used drug Celexa is metabolized by CYP2C19 (as well as omeprazole). Other examples include clopidogrel (metabolized by CYP3A4) and cyclophosphamide (by CYP2B6) and vitamin K (by CYP2C9)
  • NAT2*5A, NAT2*6A, NAT2*7A/B and NAT2*14A carriers are rapid and slow acetylators for example of isoniazid or procainamide (Roche)
  • HER2+ women may get herceptin (Roche, Bayer, PathVysion)
  • TP, DPD are the rate limiting catabolic enzymes of 5-fluorouracil metabolism (Roche)
  • Mitochondrial A155G variants are tested for aminogylcoside side effect (Humatrix)
  • A Warfarin sensitivity test will be in clinical use next year (Kimball Genetics). It will test for variations in CYP2C9 and VKORC1
  • An UGT1A1 gene variant is associated with leukopenia if prescribed camptosar, a drug for colon cancer (Oncoscreen)
  • A TPMT variant is associated with slow metabolism of 6-mercaptopurine, used in the treatment of childhood leukemia and inflammatory bowel diseases (Pharmaco-Gendia)
  • Epigenomics is currently developing tests based on DNA methylation
  • Tyrosine kinase inhibitor gleevec inhibits the ABL, ARG, SCF/KIT, and PDGFRA and PDGFRB kinases in CML. Mutations in ABL can arise as secondary mutations in previously sensitive leukemias (Pharmaco-Gendia)

Needless to say that I have excluded here specific HIV mutations that may induce resistance to particular drugs (as I learned last week on a bioinformatics meeting here by Thomas Lengauer). I have also excluded all kind of sex-specific marker (e.g. SRY testing) and the whole nutrigenomics stuff.

Who knows more, for example about lansoprazole effectiveness, UGT1A9 and mycophenolic acid, UGT1A1 and irinotecan, COMT genotype and amphetamine response, pharmacogenetics of COX-2 inhibitors, and GRP78 responsiveness to chemotherapy? Is there any commercial test available for these genes? It seems that somebody should start a wiki on that, yea, yea.

Addendum 31-12-09

Here is another gene list; only 6 tests have been approved by the FDA; Nature reports about Oncotype DX and Prostate Px as well as MammaPrint. See also an UK based paper

HLA-B*5701 was most commonly tested to identify those at risk of abacavir hypersensitivity among patients with HIV. A number of barriers to testing were identified, including lack of clinician knowledge and a lack of scientific evidence.