I am detailing in a forthcoming paper in “Allergy”, that the contradicting results found with ADAM33 (the first positionally cloned asthma gene) probably results from a rather poor design of all follow-up studies.
It does not make so much sense to repeat over and over the same few SNP marker; instead a full resquencing of the linkage region would be necessary. From the analysis of public LD maps it is even possible that neighboring genes may be responsible for the observed associations.
I have also doubts if the SNP-centric view is always leading to success. BTW there is a new database of over 400,000 non-reduandt indels of which 280,000 are validated by comparison with other human or chimpanzee genomes (see Mills et al., the indels are available in dbSNP under the “Devine_lab” handle).
Tag Archives: Genetics + Biology
Best of two worlds
Finally, linkage and association data can be used together after downloading new software using genotype inference.
It reduces the number of genotyping reactions and increases the power of genome-wide association studies. Our method combines sparse marker data from a linkage scan and high-resolution SNP genotypes for several individuals to infer genotypes for related individuals.
Sure, we
- could already test association only in linked families
- knew that linkage genome scans will improve the power of association
- could evaluate by stepc if a polymorphisms explains a linkage result
but this seems to be the best recycling for our old fashioned linkage data. Yea, yea.
Some are hybrids, some are not
Microchimerism is an interesting phenomenon that describes the hosting of foreign cells in an individuum – the prefix micro relates to the rather low counts of foreign cells (see the self discussion).
It is believed (but unproven) that most cases of microchimerism relate to the persistence of fetal cells in the maternal organism. The background of microchimerism is extremely complicated as highlighted in a recent review about the immunology of placentation in mammals. This paper has some nice cartoons about the types of placentation (epitheliochorial, endothelichorial and haemochorial) where the invasive potential of fetal trophoblast cells is the culprit of reciprocal (?) cell traffic between mother and fetus. The highest risk is found in women with induced abortion; cell count is ranging from 0 to 21 male cells per 100,000 female cells in peripheral blood; transfer may occur from mother <-> child, twin <-> twin, or sib <-> mother <-> sib.
Microchimerism has been examined in transplantation medicine (where the recipient replaces the outer donor organ epithelium), in blood transfusion and HCT, as well as in some autoimmune diseases (systemic sclerosis, SLE, thyroiditis, PBC). A clinical review reports that fetal cells have been found to persist for many years, probably for a lifetime.
I have doubts if that is true as I am not aware of any quantitative long-term study. Nearly all studies identified only male cells in women although now genomic studies of single cells are possible allowing a much better identification of foreign cells. If you are looking for a PhD thesis, microchimerism could be your field!
I already wondered if microchimerism could lead to genotyping errors, a question that can now easily be tested on the garbage of genotyping labs: We usually have genotyping errors in the 1-10 o/oo range; sometimes we see also triallelic SNPs. As far as I can renember, microchimerism has never been analyzed in the allergy field, although allergy can transplanted as well as asthma. Yea, yea.
Getting older – still the same?
Jonathan Keller is taking a picture every day since Oktober 1998. As seen on Youtube – with more series on the web. “Sie haben sich gar nicht verändert”. “Oh!”, sagte Herr Keuner und erbleichte (Bert Brecht).
Are genes becoming more important with increasing age?
I found an apparent paradox between two studies. John Whitfield did a twin study in Australia and concluded that shared environmental effects decreased with age (from about 50% to 10%) while additive genetic effects increased. The new Sardinian study found higher heritabilities among younger individuals and explained that by an increase of environmental insults with age. Nice said, but who is right?
HUGO Changing Offensive Gene Names
Hsien Hsien Lei has a good comment on gene names approved by Human Genome Organisation (HUGO) Gene Nomenclature Committee which are nevertheless offending . Some of the inappropriate names are LFNG – lunatic fringe homolog (Drosophila), MFNG manic fringe homolog (Drosophila) as well as SHH sonic hedgehog homolog (Drosophila). There are many more names that arise only from a particular culture (like death executioner Bcl-2); it seems also a particular kind of humour to call a deaf mouse Beethoven. Yea, yea.
Why we should believe professional cyclists
I renember a nice meeting in South Sardinia in 2002 (see my figure below) where a lot of famous people gathered for interesting talks in a wonderful surrounding.
A spin off from this Ogliastra Genetics Park – as the authors called it – is now a paper in PLOS Genetics that examines the heritability of 98 quantitative cardiovascular traits in 6,148 Sardinians.
Although the authors did not measure hematocrit, RBC related counts had an extremely high heritability (MCV 0.76, MCH 0.78). Hemoglobin was somewhat lower (0.47) which might in part be attributable due to some local selection factors. This result comes largely unexpected, as the high heritability of the MCV was not known so far.
In the absence of any assay for exogeneous EPO, hematocrit is used as an indirect parameter for testing athletes. I already wondered why cyclists are having such high values (if we exclude illegal drug use). This seems to be a genetically trait by self-selection – an anemic cyclist will not participate in the Tour de France. Yea, yea.
Addendum
Here is an answer to the question what makes a champion ;-)
On the “Self”
If I would ever find the time, I would write a book on the “self”. Inspired by the Eccles/Popper book that I bought as a student, I always wondered how different the self is being defined in sociology, psychology/psychiatry, philosophy and theology.
As my current focus is more on genetics and immunology, I found a paper by Francisco Borrego on the “missing self” quite interesting as it highlights the genetic self is determined mainly by MHC class I molecules, where only NK cells transfected with H-2Dd were able to confer resistance for being self-attacked. It would be nice if other disciplines could also provide such simple answers, yea, yea.
Addendum
I have another suggestion: Zfp608 protects mouse mothers against immune-mediated attack by fetal cells.
Is there also a “digiself“?
Our identity has, for many years, existed quite independent of our physical incarnation in government, financial and other institutional databases. We are not real to the bank or other authorities unless we can produce something that links our physical self to our “real identity” in their database. We have many versions of this digital identity – or digiSelf, as I like to call it – spread among many databases, each with its unique characteristics, and inferred behaviours. Each one is more real to the institution – and ironically, to the people in that institution – than our physical self, what we consider to be our real self.
Genetic code and God’s language -cont’d-
There is a new book by Francis Collins “The language of God“, one of the leading persons in human genome sequencing. As the commentary says:
Continue reading Genetic code and God’s language -cont’d-
The Rosetta stone and the genetic code
The Rosetta stone (I took the picture above earlier this year in the British museum) has become the key to decipher Hieroglyphic as it contained the same text also in Demotic Egyptian and Greek. Discovered by a French in 1799, brought to England in 1802 it become eventually translated in 1822 by Jean-François Champollion.
Continue reading The Rosetta stone and the genetic code
Ethnographic studies at Oktoberfest
Having many years of experience with ethnographic studies at Oktoberfest München, I am fascinated by a new Cell paper that shows distinct behavioral responses to ethanol. This is something that I alread assumed (although I did not known about this particular RhoGAP18B isoform only about ADH deficiency). Will the knowledge of more and more mutations in the lifestyle area raise ethical problems? Yea, yea.
Once again genetic testing
I have argued earlier that the free decision of an individual to allow genetic testing, will also reveal data on genetic relatives that have never consented to that procedure.
A new review by Bruce Weir now confirms that “it is reasonably straightforward to find the probability of the genotypes of individuals when their relationship is known…” My current work lets me also assume that with 500,000 SNP data at hand, much individual characteristics of the donor can be reconstructed – there are no anonymous DNAs datasets as some people still believe.
I even fear that genetic testing will increase for example in “homeless” (in vitro fertilized) individuals as these people will want to prevent sibling marriage – see for example the a-China DNA project. Other people may be curious about their genealogy, others about drug side effect prediction, lifestyle, assurance questions…
With every new dataset, available datasets will gradually decrease their anonymity level. I fear that anonymity is not so much a dichotomous property, it is much more a likelihood ratio to stay unknown under the probability to be known. Yea, yea.
Addendum
Time online of Dec 17, 2006 reports that the British police is holding the DNA records of more than 1m innocent people — eight times more than ministers have previously admitted. I wonder if this will affect participation rate of the UK Biobank that targets health of lifestyle, environment and genes in 500,000 people.
Sleep well
Just came to my attention that there is research of sleep related genes, the usual stuff of protein kinases, dopaminergic receptor, and serotonine transporter. Also this research community seem to have the common difficulty of the complex disease gene mappers – to understand a phenomenon (not a trait) as systemic function, an intrinsic property of a multicellular and multiwired brain, yea, yea.
Addendum
More strange phenotypes orgasm frequency, pain, human memory performance.
Addendum
Read also the what-we-could-have-learned-from-linkage-studies.
Heritable mutation or not?
moblog – Tsun Leung Chan is now reporting a heritable germline epimutation of MSH2 in a family with hereditary colorectal cancer another case of “paranormal” inheritance. They find a mosaic germline methylation pattern (which might even be a symptom of another mutation that affects the demethylation-de novo methylation pattern of MSH2 during embryogenesis?). If my hypothesis is true these families should even show more genes with different methylation patterns, yea, yea.
Addendum 28/5/08
Another attempt to answer this question comes by a study of the MLH1 promotor
Pro: MLH1 promoter methylation was found in a patient and his mother giving evidence for a familial predisposition for an epimutation in MLH1. Contra: a de novo set-up of methylation in one patient, a mosaic or incomplete methylation pattern in six patients, and no evidence for inheritance of MLH1 promoter methylation in the remaining families.
What could have been learned from linkage studies
What makes the difference between genetic linkage and association studies? Simply speaking, for linkage you need to inherit a particular marker allele from your parents where it does not matter if a child in another family inherits another allele (pending it shares it with its affected sibling). With association studies this matters.
As we found with the much relaxed linkage strategy so many minor diverse loci, I assume a rather heterogeneous origin of complex diseases. There is no doubt about the importance of genes, but about the sharing of the same genetic abnormality. An (anonymous) position paper on basic Asthma Research Strategy II in Clin Exp All 2006; 36: 1326 says
The average size of effect on asthma and related traits from common SNPs is small. For instance, seven common SNPs in the IL13 gene jointly accounted for only 0,5% of the variance of total IgE … With a heritability of circa 60% for total IgE this implies that hundreds of genes, each with small effects, may be involved in IgE regulation.
Families presenting with a complex system disease will all have unique patterns how they arrive at the same clinical endpoint. Alpha-delta-gamma asthma, theta-kappa-jota schizophrenia or $%&# diabetes – are they combining lets say 3000 variations in 300 genes of 30 metabolic-signalling pathways to 1 disease of variable onset, severity and prognosis? Yea, yea.