IL4 cluster revisited

27.11.2006 admin

I am interested in 5q31 and the IL4 cluster since I met David Marsh in the lobby of a hotel in Heidelberg around 1993. David was one of the founding fathers of asthma genetics and I renember how he vividly told me that he has a forthcoming Science paper on the IL4 cluster and IgE. The cluster is still one of the best allergy regions where the signalling through IL4 and IL13 now gets more interest than the work of any of his competitors.
Nature genetics now has an update on the 3-dimensional resolution of the genomic region. It is not cristallographic work as might be expected but a nice study of the chromatin structure that is leading to a coordinated expression of these cytokines. SATB1 (special AT-rich sequence binding protein 1) is thought to anchor specialized sequences letting DNA loops come into interaction. I wonder if there might be even a direct physical interaction of the IL4 and IL13 promotor and if there will be any SNP influencing that interaction? David (who died of brain cancer in 1998) would have really liked this work. Yea, yea.

Genetics

The first methylome available

26.11.2006 admin 1 Comment

-moblog- Having spent this weekend in Heidelberg city at a meeting of the German NGFN project I had the opportunity to listen to an excellent talk of Stephan Beck who works at the Wellcome Trust Sanger Center.

Epigenetics is the connecting link between the rather fixed genome and the variable transcriptome. To start with the end of the talk: Beck predicts for the near future highly parallel SNP, expression and methylation arrays. Although the first methylome has just been published 4 weeks ago by the Arabidopsis community (as with RNAi the plant people again at the forefront) there is still a long way ahead for a first human methylation map.

The latest information may be retrieved from www.epigenome.org, www.epigenome-noe.net, www.epitron.eu,
www.heroic-ip.eu and the German National Methylome Project on chromosome 21 (please google for the link). The methylome is largely an European initiative – the two US epigenome projects do not have any website so far. The network site has some introductory texts; Beck was also refering to a 2006 PLOS paper by Akhtar.

Currently there are 4 human chromosomes under work covering 873 genes (hopefully I captured this correctly as this was a very dense talk). 70% of genes examined so far are either clearly methylated or they are not methylated by testing 12 different tissues. Sperm stands out from all other tissues – which is not unexpected. Tissues originating from the same developmental background have similar methylation patterns – also not unexpected. A preliminary analysis of expression patterns shows that if the 5 prime end is methylated expression is suppressed- also not unexpected.

Fascinating: the colon cells that certainly have a close interaction with the environment do NEITHER show age NOR sex specific differences. Fascinating too: The most frequently methylated regions are ECRs (evolutionary conserved sequences) for whatever reason. Promotor methylation dips around the transcription start sites – from the plots I would say plus and minus 2000bp. Methylation seem to be also conserved between mouse and human tissues while methylation status seems stable over time.

Current bisulfite sequencing is still laborious, expensive and takes quite a long time while immunoprecipitation using MeDIP is getting an alternative. The Sanger people also did a study usinge Nimble(R) gene 50 mers where Ensembl and UCSC will soon have these data for display. Finally, methylation appears in blocks. TagMVPs (your guess is correct, these are tags for methylation variant profiles) construction is straightforward where the estimated 40 million CpG sites will probably be covered by less than 10 percent tagMVP – Haplo epi types are now called hepitypes, yea, yea.

Addendum

Methyl Primer ExpressÂ® Software â€“ is a free software package to simplify and automate the primer design process in methylation experiments. The bisulfite kit is not free ;-)

Addendum

A new textbook and a nice preview

Allergy

Hotel Dieu

26.11.2006 admin

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.

Uncategorized

Do you know …

26.11.2006 admin

…. why the language of the internet is English and not French? It is an interesting hypothesis that the yellow fever which decimated Napoleons troops in Santo Domingo was a crucial factor in the decision to sell Lousiana in 1803. Although German was also a science language around 1900, it certainly became discreted by two world wars. Yea. Yea.

Genetics

Science is about recognizing errors

26.11.2006 admin

-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.

Joke, Software

email@nirvana.info

25.11.2006 admin

-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.

Genetics, Philosophy

Nice to know

25.11.2006 admin

-moblog- There are many things “nice to know” but only a few “need to know”. Molecular epidemiologists having access to large datasets sometimes forget what most people on earth “want to know” – how to prevent and cure human disease.

Genetics

Nothing makes sense except in the light of a hypothesis

24.11.2006 admin

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) â€”
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.

Addendum

The mouse data are now also online.

Genetics

Hap world map?

23.11.2006 admin

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 hörâ€™ 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.

Philosophy

Da steh’ ich nun, ich armer Tor!

23.11.2006 admin

[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 stehâ€™ 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 â€“
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 â€“
Dafür ist mir auch alle Freudâ€™ 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 habâ€™ ich weder Gut noch Geld,
Noch Ehrâ€™ und Herrlichkeit der Welt.
Es möchte kein Hund so länger leben!

Joke, Philosophy

World record

22.11.2006 admin

Just found this note at the bottom of a paper offered by Ingenta Connect:
The paper is the result of public funded research, written by researcher who is only partially paid for his work while both referees were not paid for their work. Yea, yea.

Joke, Software

Calibrate!

22.11.2006 admin

This is a quick link to Eye of Science, a website with impressing micro photographs. Calibrate your monitor first at sriker, then goto Eye of Science. Oliver Meckes is quoting Albert Einstein

People should be ashamed to use the wonders of science and technology if they donâ€™t know any more about it than a cow knows about the botany of the grass it relishes in eating.

Genetics

Men r’sponding to women

22.11.2006 admin

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.

Uncategorized

Materials and Methods

22.11.2006 admin

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.

Genetics

Not an academic project, not an industry project

21.11.2006 admin

Not an academic project, not an industry project, but still earn money with knowledge? Innocentive posted the request #4470259 for an ALS biomarker. Deadline is Nov 06, 2008 and you will get $1,000,000 USD for problem solving. Yea, yea.