Category Archives: Genetics

Genetics

Supersize me II

Some of you may remember the fake food hypothesis that relates the obesity epidemic to the introduction of highly processed industrial food. JCI now has a nice review on the satiation signal and the complex system that may be disturbed.
Microbe content might also be important in this context click | click | click, however, even the adoptive transfer might be a secondary effect – everything in biochemistry follows mass equilibrium constants. The poorer resorption in the lean may lead to a different colonialization and vice versa. Will the adoptive transfer really show lasting effects longer than 2 weeks (in the mouse study)? Isn´t colonialization not influenced by diet (in the human study)?

gutsensing.png

Yea, yea.

 

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Genetics, Philosophy

Enter without knocking if you can

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This was posted at the door of Max Delbrück (1906-2006) in Pasadena – and quoted from the wonderful biography of E.P. Fischer his last Ph.D. student.
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“Licht und Leben” (or “light and life”) is a wonderful narrative that I really enjoyed, with a lot of informative figures and tables.
I wonder why this biography never appeared in English, why neither institutes in Berlin, Cologne or Constance (where Delbrück teached) are even linking to it. E.P. Fischers book tells the story about an interesting man dedicated to science – who learned physics and applied sound principles to biology. “Enter without knocking” does not have any special meaning (as E.P. Fischer confirmed me) it was simply a rough-running door. Besides the biographical sketch and the detailed description of phages and phycomyces (p15) there are many moments in time that I really liked very much.
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Hershey (with whom he shared the Nobel in 1969) should give a lecture and asked about the background of the audience. Max Delbrück answered by a postcard 6/1/1943: think of “complete ignorance and infinite intelligence” – the lecture became a success.
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Delbrück always emphasized (p 148) that data should only be augmented by those who can put old data into new hypotheses. He even said “enough data” as thinking about current experiments is being as important as doing new ones. Both, thinking and doing experiments, should even be more important than publishing (his lifetime list has 115 items). Writing up results should serve as a method to connect what is currently known and what will be known. Delbrück even suggested to spend – “one day per week without pipettes”.
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From an interview (p 240): “Genetic engeneering may possibly be a large thread for the future but possible also the biggest hope”.
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Delbrück was a great admirer of Eliot, Rilke and of Beckett. Samuel Beckett in “Waiting for Godot” probably inspired “Licht und Leben” (p 260): “We give birth astride a grave, the light gleams an instant, then there is night once more.”

Addendum

Page 239 contains a mystery: In 1978 Delbrück gave a lecture at Caltech where he wanted to include a citation from Kierkegaard: “Wissen ist eine Sache der Einstellung, eine Leidenschaft, eigentlich eine unerlaubte Einstellung. Denn der Zwang zum Wissen ist wie Trunksucht, wie Liebesverlangen, wie Mordlust, in dem sie einen Charakter aus dem Gleichgewicht wirft. Es stimmt doch gar nicht, daß der Wissenschaftler hinter der Wahrheit her ist. Sie ist hinter ihm her. Er leidet unter ihr.” Delbrück, however, could not find the correct source, even announced to pay 50$ for it. I also looked at my library but couldn´t locate it – who knows the source?

 

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Genetics

More -omics

Genomeweb Daily News has a short -omics story

describing the 2-year-old project as one that will “have more immediate impact on medicine and medical practices than the Human Genome Project,” the University of Alberta said researchers have catalogued “2,500 metabolites, 1,200 drugs, and 3,500 food components that can be found in the human body.”

Here is the the Human Metabolome Database by Genome Alberta that reports slightly different figures on the intro page (attn HMDB is not identical to the Human Mitochondrial Database!)

The database is designed to contain or link three kinds of data: 1) chemical data, 2) clinical data, and 3) molecular biology/biochemistry data. The database currently contains more than 2100 metabolite entries including both water-soluble and lipid soluble metabolites as well as metabolites that would be regarded as either abundant (>1 mM) or relatively rare (<1 nM). Additionally, approximately 5500 protein (and DNA) sequences are linked to these metabolite entries.

The NAR Jan issue has the accompanying paper:

Metabolomics is a newly emerging field of ‘omics’ research concerned with the high-throughput identification, quantification and characterization of the small molecule metabolites in the metabolome.

 

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Genetics

(Re)programming adult into pluripotent cells

Last August I found an interesting paper in Cell that could mark a scientific breakthrough. In a step down approach the authors were able to reduce a mix of 24 transcription factors to 4 that were still able to induce a mouse embryonic stem cell signature (by using a fusion cassette of ß-galactosidase and neomycin resistance into Fbx15 gene).
The magic cocktail consisted of Oct3/4 and Sox2 (both embryonic stem cell core factors that directly target Fbx15), c-My (does global histone acetylation) and Klf4 (represses p53 directly).
My first question is if this cocktail reprogramms differentiated cells or if it just selects rare progenitors otherwise hidden under more fibroblast cells. My second question is if these are fully reprogrammed cells – or if the Fbx15 signature is somewhat misleading. My third question: Is this effect mouse specific?
I have now checked ISI if any paper is already citing this work – it seems that we need more patience. Yea, yea.

 

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Genetics

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?

Addendum

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.

 

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Allergy, Genetics

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.

 

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Genetics, Software

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.

 

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Allergy, Genetics, Vitamins

Vitamin D and asthma

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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…

 

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Genetics, Noteworthy

A longe fuse

Mutation accumulation in the human genome is a largely neglected research field. Most mutations have a very small effect (if any) and may be compensated by environmental improvements. I have already argued in that way in my 2003 Triple T paper and will reiterate it soon in PLOS medicine (just found that James Crow 1997 in PNAS and 2000 in nat gen rev had the same opinion). In principle, the improvement of sanitation and better medical care is leading to a retention of mutations that would be otherwise subject of purifying selection.
Another important factor seems to be the increase of parental age in Western societies. A 20 year old man had about 150 chromosome replications while a 40 year old had about 610 replications. To count the number of your somatic mutations, you need to add all events of your lifetime plus the age of your father at birth minus 9 months … Even with the high fidelity of polymerases, DNA replication remains an error prone process leading eventually to an increase of germline mutations (as may be seen with achondroplasia, Apert syndrome, neurofibromatosis and prostate cancer). With the increasing age of fathers we are now nearly doubling the absolute number of mutations every generation – and we keep them in the pool in contrast to previous centuries. Crow in PNAS 1997 even said

I do regard mutation accumulation as a problem. It is something like the population bomb, but it has a much longer fuse

timebomb.png

Addendum 20 Nov 2013

In another post, I detailed the 3,93 figure derived from cancer tissues. The best human estimate at the moment is in this Cell paper that shows a rate between 2.0 and 3.8 x 10^-8 cells. Sperm sequencing may not represent a good model as there are too many degenerate cells.

Addendum 1 Jan 2021

Here is a new nature medicine paper on cell turnover.

What I do not understand – shouldn’t we  have a much higher leukemia rate in the population? Leukemia is only  on the11th place.

Addendum 29 Apr 2021

Another Nature study shows

Differentiated cells in blood and colon displayed remarkably similar mutation loads and signatures to their corresponding stem cells, despite mature blood cells having undergone considerably more divisions. We then characterized the mutational landscape of post-mitotic neurons and polyclonal smooth muscle, confirming that neurons accumulate somatic mutations at a constant rate throughout life without cell division, with similar rates to mitotically active tissues …

this could be the answer to my previous question

These mutations may result from the interplay between endogenous DNA damage and repair that occurs in cells at all times. The similar mutation burden and signatures in granulocytes and hae- matopoietic stem cells, despite a different divisional load, could also be consistent with a time-dependent rather than a division-dependent accumulation of somatic mutations during haematopoiesis

although it will need independent corroboration before making any conclusion that damage repair is more important than replication.

 

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Genetics

Autophagy

Crohn`s disease is still a mystery. Associated gene variants have been described in CARD15, DLG5, SLC22A4, CARD4, TNFSF15, IL23R and many more genes that explain altogether less than one quarter of the disease risk. My friends in Kiel now add ATG16L1 to this list. They looked for nonsynonymous SNPs and voila rs2241880 (A/G*, T300A*) a new disease SNP is born.
What is remarkable in their study that the top 9 SNPs (as judged by significance in the range of 10^-14>p<10^-4) could NOT be replicated for whatever reason. I guess it would be even worse to see also panel C in this table. Expression of ATG16L1 is rather weak in the small intestine, not influenced by the reported SNP, not different in the gut of Crohns patients and not related to disease location. Genecards say that the subcellular location of ATG16L1 is close to a peripheral membrane protein complex known as preautophagosomal structure. Autophagy is an intracellular degradation system delivering cytoplasmic components to the lysosomes (L is not related to ligand or L1 transposon but indicates "like"). The gene has been tested so far in yeast and mouse. Unfortunately, information about ATG16L1 is scarce but there is some work on yeast ATG16 (which seems to miss the domain with the disease SNP).
Some authors believe that macroautophagy is process induced by nutrient starvation in eukaryotic cells, which could explain some of the Crohns’ disease characteristics. Autophagy seems to have some developmental effect and may be related to even more diseases. It seems that there are now even more mysteries to solve, yea, yea.

 

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Genetics

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?

 

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Genetics

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.

 

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Genetics

Quick database edit from webbrowser

Frequently, I need to change only one single field in a database. For that purpose I am using a short php script – it basically outputs all fields and highlights them with a javascript popup where you can do any changes (or even delete a row) while a “return” writes the change back to the database.

sc_edit.png

You will immediately see, where the script needs some adaptation – all the trick is in line 28.
line 2: your database
line 5,9…: your mytable
line 23: your columns

|wj_dbedit.php|

 

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Genetics

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.

 

CC-BY-NC Science Surf accessed 05.11.2025