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Genetics

The first methylome available

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-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.

pb250021.JPG

Addendum

Methyl Primer Express® Software – 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

 

CC-BY-NC Science Surf accessed 05.11.2025
Allergy

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.

p8250074_shiftn.png

 

CC-BY-NC Science Surf accessed 05.11.2025
Uncategorized

Do you know …

…. 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.

 

CC-BY-NC Science Surf accessed 05.11.2025
Genetics

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.

 

CC-BY-NC Science Surf accessed 05.11.2025
Joke, Software

email@nirvana.info

-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.

 

CC-BY-NC Science Surf accessed 05.11.2025
Genetics

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.

Addendum

The mouse data are now also online.

 

CC-BY-NC Science Surf accessed 05.11.2025
Genetics

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.

 

CC-BY-NC Science Surf accessed 05.11.2025
Philosophy

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!

 

CC-BY-NC Science Surf accessed 05.11.2025
Joke, Software

Calibrate!

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 don’t know any more about it than a cow knows about the botany of the grass it relishes in eating.

 

CC-BY-NC Science Surf accessed 05.11.2025
Genetics

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.

 

CC-BY-NC Science Surf accessed 05.11.2025
Uncategorized

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.

 

CC-BY-NC Science Surf accessed 05.11.2025
Genetics, Philosophy

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.

 

CC-BY-NC Science Surf accessed 05.11.2025