Tag Archives: Genetics + Biology

DNA data travel across Europe

heise.de reports that a top German politician wants to apply the Prüm contract also to the EU. The Prüm contract signed in May 2006 by Germany, France, Luxembourg, Netherlands, Austria and Spain regulates anti terror measurements and cross border prosecution of crimes. Mainstay of these activities are databases that allow the exchange of DNA and fingerprint data. Within the first 6 weeks of activity (as by November 2006) they report 1500 German hits in Austrian records (8 million inhabitants) and 1400 Austrian hits in German records (82 million inhabitants) if I understand that correctly. What does this now mean to have a German or a British or Swiss passport? For a respectable citizen and for a desperado?


5-2-07 update U.S.

6-3-07 update Germany

Allein im vergangenen Jahr nahmen die deutschen Polizeibehörden laut einer BKA-Statistik 72.280 Verdächtigen den genetischen Fingerabdruck ab, “immer häufiger auch bei eher geringfügigen Straftaten”, kritisiert Datenschützer Weichert.

Banned DNA tests

The Korea Herald writes – as noticed by Hsien Hsien Lei

The government yesterday released a set of new regulations to ban or restrict genetic tests in 20 categories amid ethical concerns over DNA tests … According to the new guidelines, DNA labs will be banned from conducting tests in 14 categories including body mass, intelligence, strength, propensity for violence, longevity, mental health, diabetes, blood pressure and asthma.

Although I do not believe that genetic testing for “asthma genes” will make any sense without the context of scientific studies, I think that such regulations are overdue – at least when genetic testing does not provide any benefit but may pose harm. If you have asthma or not, is a clinical question – and the answer will be an appropriate treatment or not. If you ever will get asthma is a question that nobody can answer. Even if genetic prediction will be ever possible, there is still no preventive measurement (at least by Jan 18, 2006, 16:14:23) . Yea, yea.

I am the guy with the hammer, and everything is a nail

We could think in more general terms about this quote from an interesting benchmarking paper. (I renember a DFG referee saying that I am no expert for the applied study. Vice versa we all see studies where everything is treated with a hammer.)
With a lot of data on my desk, however, I am more interested in the technical conclusions of the paper and feel quite comfortable with their opinion that commercial RDBMSs are not always the best choice. These RDBMSs include more and more features, and missing features are included in add-on packages from third party vendors. With these ever increasing features also useless overhead is being increased with penalty for performance.
A redesign for special databases like those used in genetic epidemiology and bioinformatics therefore seems to be invitable. Some may have already noticed my preference for SQLite, HDF-5, NetCDF.

  • Do we really need client-server mode?
  • We may ask if not 90% of all tasks can be done in presorted arrays (or materialized views).
  • Why can`t processes run completely in virtual memory without disk I/O?
  • Is there any chance to compile to machine code for better performance?
  • Why not ordering task for priority with those having minimum latency being the first in the row?

Yea, yea.

Vitamin D and asthma

My previous work on vitamin D focused mainly on allergy but according to new research of Bosse et al vitamin D also stimulates bronchial smooth muscle and airway remodeling

Genetic variants in the vitamin D receptor (VDR) gene were recently associated with asthma. The biological mechanisms explaining this association is unknown, but are likely to involve many cell types given the pleiotropic effect of its ligand … The most significant network of up-regulated genes included genes involved in morphogenesis, cell growth and survival as well as genes encoding structural proteins, which are potentially involved in airway remodelling.

Another study published more or less at the same time by Wittke shows

Conversely, WT splenocytes, Th2 cells and hematopoetic cells induced some symptoms of experimental asthma when transferred to VDR KO mice, but the severity was less than that seen in the WT controls … Lipopolysaccharide (LPS) induced inflammation in the lungs of VDR KO mice was also less than in WT mice. Together the data suggest that vitamin D and the VDR are important regulators of inflammation in the lung…

Pol III cross country skiing over nucleosome rocks

The relationship of gene expression and DNA methylation looks still like a mystery to me but fortunately there is now a second Arabidopsis paper that has some news. As the authors write in the discussion the mechanism how DNA methylation interferes with transcript initiation is still unclear – it is assumed that methylated DNA is carrying repressive histone modifications.
A clear (and repeated) finding, however, is the strong influence of DNA methylation on gene expression, where LOW and HIGH expressed genes are not so much methylated than MEDIUM expressed genes. Another bias of methylation is found AWAY from gene ends. Gene size seems to be also somehow relevant for gene expression. Taken that all together they develop a model of Pol III moving along DNA strand between nucleosome rocks (POL III may disrupt these rocks that cross country skiiers cannot ;-) ).
Version A: Far distant nucleosomes – the transiting RNA polymerase exposes cryptic initiation sites that allow aberrant transcipts be processed by dicer into siRNA that will methylate DNA (and create nucleosomes?)
Version B: Average distant nucleosomes – continuous flow of disrupted nucleosomes by closely spaced polymerase working along DNA strand – normal situation?
Version C+D: Close distance nucleosomes – high polymerase density – polymerase stalling and collision – as a repression mechanism?

Vivat rex

Ever since I heard 1976 about the Lyon hypothesis (described already in 1961 by Mary Frances Lyon) of X inactivation I wondered how this works on a molecular level – locking this chromosome in a separate nuclear compartment, condense it or encase it? Silencing a whole chromosome probably needs a concerted action of higher order DNA structure, histone code modification and primary sequence features. The last seems to be indeed relevant as C. elegans X has a target for gene expression repression by the dosage compensation complex – small rex motifs (X recruitment elements) ?CAGGGG and ?GTAATTG. The strength of DCC recruitment is correlated with rex motif number BUT rex motifs are not enriched on X – so certainly more features need to synergize for X repression. Yea, yea.

Cell podcast with an interesting fact

Cell has a first podcast online. It features interviews with two of this year’s Nobel Laureates, Dr. Craig Mello and Dr. Roger Kornberg, as well as a talk to Dr. Paul Nurse about current funding prospects in the US ( “dont give up”). It is quite easy to hear that on my morning ride – and liked very much Craig Mello saying (please wind forward to 6:19) “the entire genome is probably described in some level” which is quite different to the prevailing junk theory. Yea, yea.

Dangerous DNA – nullomers or nullintells

New Scientist reports that

Could there be forbidden sequences in the genome – ones so harmful that they are not compatible with life? One group of researchers thinks so. Unlike most genome sequencing projects which set out to search for genes that are conserved within and between species, their goal is to identify “primes”: DNA sequences and chains of amino acids so dangerous to life that they do not exist.

Read the full article – I am hesitating what to say now, yea, yea.

A tragedy if you don’t feel pain

A highly successfull study of the molecular pathways of nociception (and identification of a loss of function mutation in the alpha subunit of SCN9A, a voltage gated sodium channel) has a sad story from Northern Pakistan

The index case for the present study was a ten-year-old child, well known to the medical service after regularly performing ‘street theatre’. He placed knives through his arms and walked on burning coals, but experienced no pain. He died before being seen on his fourteenth birthday, after jumping off a house roof.

It is so difficult for us humans to accept that pain has an important function in life, yea, yea.

Here’s lookin’ at you, kid

In German Humphrey Bogart’s immortal expression “Here’s lookin’ at you, kid” was translated “Ich seh’ Dir in die Augen, Kleines” which translates back to “I look in your eyes, honey”. Seems that this was a spontaneous idea of Bogart on 3rd July 1942 in the Burbank Studios of Warner Brothers if we believe this website.

I am now looking in your eyes with a new study by my long-term penpal David Duffy – 3 OCA2 intron 1 SNPs (rs7495174-rs6497268-rs11855019) are sufficient to explain most human eye colors: T-G-T/T-G-T diplotype is found in 62% blue/gray, 28% green/hazel and 10% brown eyes.

In a (soon to be published) study of European population stratification we also typed 2 OCA2 SNPs but unfortunately not the same ones; I checked also the Affymetrix 500K panel but it doesn`t included these SNPs as well.

3 Rs

The 3 Rs of regulating animal research are Refinement (to minimize suffering), Reduction and Replacement (to minimize the number of animals used). A Nature news feature now has a critical appraisal of current knockout projects where each of the 25,000 genes will be knocked out in the next future. Although current technology represent an advantage over recent undirected mutagenesis projects

… the number of mice needed to establish a line stretches from 50 to several 100. On top of this, another couple of 100 animals are needed for basic analysis of genetic make-up and phenotype…

Many genes cannot be knocked out – some knockouts may even be lethal.
We are also not so much interested in permanent destruction of genes in all tissues but in conditional and temporal shutdown of gene function.
And many researchers are not so much interested in the current 129 background than in BL6 (at least in immunology and allergology).
Finally (in human genetics) we are not dealing with knockouts but with multiple genomic variants of a gene. The question therefore is

Is the spirit of the knockout projects in line with [3R] principle[s]?

although I acknowledge that these industrial projects may generate many “nice to know” facts.

A revival of DNA pooling

My interest in DNA pooling was always strong; we have developed methods doing this on the mass spec platform and applied it to the HLA region. I had, however, doubts if testing pools by less accurate methods like chip hybridization will work. The January issue of the AJHG now has a fascinating article how pooling may even work on the Affymetrix platform. Yea, yea.


DNA pooling can be even used in family context, see Wen Chung Lee in Cancer Epidemiology 2005 or Neil Risch in Genome Research 1998.

Genetic tango

Science daily reports an interesting study how a protein recognizes a particular DNA binding site

Structural changes in both the protein and DNA, sometimes with the DNA within the complex kinked or sharply bent, allow for the specific contacts needed for a tight DNA-protein fit. Scientists think DNA is largely passive in this genetic tango. But new findings by Anjum Ansari, associate professor of biophysics at the University of Illinois at Chicago, suggest DNA may not be the wallflower that many had assumed…

Yea, yea.

454 or 0815 or 4911

In a recent book chapter we discussed new genotyping and sequencing technologies. Our concluding remarks haven´t changed so much – it seems that realtime detection of single molecules is still not possible; micro electropheresis based methods have already reached their limit while sequencing by hybridization has severe restrictions when it comes to de novo (or re-) sequencing of whole genomes. At least for research purpose I expect that whole genome re-sequencing will replace current SNP based disease mapping. So far, sequencing by synthesis seems to be one of the few HT methods that already works at that scale. The 454 platform consists of 3 consecutive steps:

  1. DNA library preparation starts with genomic DNA (after fragmentation and adaptor ligation the single-stranded template DNA libraries are isolated and assessed (takes ~4 hours)
  2. sstDNA is emulsificated, then amplified and recovered on beads before sequencing primer are being annealed (takes 1 day)
  3. After washing, so called PicoTiterPlates are prepared and a process started that looks like a combination of pyrosequencing reaction, correct me if I am wrong, a pyrophospate dependent enzyme cascade emitting light being recorded by a CCD camera that watches each of the ~200,000 holes (takes ~6 hours according to a recent paper in GenomXPress 2/06, figures at 454.com)

With an average read length of 100 bp and 200,000 fragments (resulting in 20 Mb) in 6 hours, the throughput is about 60fold compared to Sanger sequencing. The recent Neanderthal paper raises five arguments why the 454 sequencing platform is extremely well suited for analyses of bulk DNA extracted from ancient remains.

  1. … it circumvents bacterial cloning, in which the vast majority of initial template molecules are lost during transformation and establishment of clones.
  2. … because each molecule is amplified in isolation from other molecules it also precludes template competition, which frequently occurs when large numbers of different DNA fragments are amplified together.
  3. … its current read length of 100–200 nucleotides covers the average length of the DNA preserved in most fossils.
  4. … it generates hundreds of thousands of reads per run, which is crucial because the majority of the DNA recovered from fossils is generally not derived from the fossil species, but rather from organisms that have colonized the organism after its death.
  5. … because each sequenced product stems from just one original single-stranded template molecule of known orientation, the DNA strand from which the sequence is derived is known. This provides an advantage over traditional PCR from double-stranded templates, in which the template strand is not known, because the frequency of different nucleotide misincorporations can be deduced … damage that affects different bases differently.

Except of the low read length most of these observations would benefit large scale resequencing projects in human individuals. My main point for starting ASAP resequencing projects: So far we have not achieved a dense resolution of the genome while deep resequencing project (for example at the CRP locus) got astonishing results. We do not even know what is going on in the “noncoding” regions. Finally deletions and CNVs have been largely neglected – another look at this question in the EJHG.
The question remains, what does 454 mean – my inquiry is still pending. As far as I know 0815 was a machine gun in World War I and is a synomym for something repeatedly boring while 4911 is a street number and stands for a perfume. Yea, yea.

Human breeding

There have been always attempts to make humans better – an idea that attracted people nearly every century. Ovid created Galatea from a statue, Goethe’s homunculus originated from a test tube, Mary Shelly created her monster from corpses, Bulgakows proletarian derived from a dog and Sloterdijks Menschenzüchtung by a fancy idea. There is only a minor difference at the end of 2006 – technical possibilities of genetic testing and genetic engineering are much higher developed. Yea, yea.