A nice PNAS paper gives in its supplement 4 the MCM6 and mtDNA 16209 genotypes of some prehistoric bones AND of all authors – excellent! The study itself is also interesting as we learn about the true wild-type allele in early Neolithic Europeans – they could not digest milk.
Following many strange gene association studies now a 3rd study of genes and genius appeared: WashU on IQ and CHRM2 believe it or not as part of a study on the genetics of alcoholism…
Early vitamin D supplementation may have dual effects, protecting against type 1 diabetes and inducing allergy. Is that possible? Yes, individual genes variants may determine the outcome.
In addition to HLA the most prominent type 1 diabetes genes are INS – CTLA4 – PTPN22 – CD25 – IF1H1, the most prominent asthma/allergy genes ADAM33 – DPP10 – IL12 – IL4 – GPR154 – FLG. I can´t see any joint master regulator, however, we know that
Could that be a model to explain the dual involvement of vitamin D in both diseases?
The AJHG discusses an interesting phenomenon that I noticed too. While replicating a disease marker association the risk allele suddenly reversed which led me believe that there was an error in allele coding. As the authors of this new paper now show these flip-flop association may indeed a true positive association to a non causal variant.
NHANES is a great ressource for doing epidemiological research. As the NIH website provides only data import for commercial software here is my rewrite in R. First load from their site
adult.exe
youth.exe
lab.exe
lab2.exe
exam.exe
put everything in one directory and expand the self-extracting archives. Then create from each SAS file a new variable content file that will only contain variable name and tab separated start position in the .dat file. Adult.var for example would read like this:
SEQN 1
DMPFSEQ 6
DMPSTAT 11
DMARETHN 12
DMARACER 13
...
HAZNOK5R 3345
Then start the following R job with the datasets and variables that you are interested in
|wj_nhanes.R|
–Day 7 of Just Science Week–
Wouldn´t it be nice to have also a CTRL+Z action in the laboratory? For example when you have confused pellet and supernatant during pipetting? Biology at least seems to have some kind of undo action – see a series of nice papers in Cell Research. It´s not about demethylation of the parental genome, it’s about stopping and rebuilding the zygotic transcription program during the first meiotic division (that creates the haploid set of chromosomes that will be passed to the progeny).
At present there are 3 hypothesis around, how transcription is being silenced – simply by the speed up of the cell cycle, by active inhibitory (transcription) factors, or the passive deficiency of critical factors. Sun et al. now show that there is a genome-wide disscociation of chromatin factors leading to a naive state in preparing the new life cycle. Critical transcription factors and regulators remain separated for a prolonged time period and become reassociated only after pronuclear formation. It is still unclear if the second or third hypothesis fits best this process as the absence of even 1 essential transcription factor can inactivate transcription. Deletion of TBP for example will inactivate both PolI and PolII; TBP is found to dissociate among other factors.
Only a couple of structural proteins remain bound persistently (HP1alpha, HP1beta, TOPIIalpha and AcH4, with acetylated histone 4 as a positive control. Of course methyl-binding proteins, topisozymerases, and other heterochromatin binding stuff is required for normal chromatin structure where it would be nice to know which of these remain bound during this reprogramming step. So, this looks more like a reinstalling the OS than a simple undo action.
Thanks and good bye to all guest readers of the science week.
My compliments to Nicole, the latest Ph.D. student from our lab who succesfully passed her final exam today in Freising at TU München-Weihenstephan. Here is the semi-official document:
The title of her thesis is High-resolution snp scan of chromosome 6p21 in pooled samples from patients with complex diseases , a topic that has recently attracted new interest.
We apply a high-throughput protocol of chip-based mass spectrometry (matrix-assisted laser desorption/ionization time-of-flight; MALDI-TOF) as a method of screening for differences in single-nucleotide polymorphism (SNP) allele frequencies. Using pooled DNA from individuals with asthma, Crohn’s disease (CD), schizophrenia, type 1 diabetes (T1D), and controls, we selected 534 SNPs from an initial set of 1435 SNPs spanning a 25-Mb region on chromosome 6p21. The standard deviations of measurements of time of flight at different dots, from different PCRs, and from different pools indicate reliable results on each analysis step. In 90% of the disease-control comparisons we found allelic differences of <10%. Of the T1D samples, which served as a positive control, 10 SNPs with significant differences were observed after taking into account multiple testing. Of these 10 SNPs, 5 are located between DQB1 and DRB1, confirming the known association with the DR3 and DR4 haplotypes whereas two additional SNPs also reproduced known associations of T1D with DOB and LTA. In the CD pool also, two earlier described associations were found with SNPs close to DRB1 and MICA. Additional associations were found in the schizophrenia and asthma pools. They should be confirmed in individual samples or can be used to develop further quality criteria for accepting true differences between pools. The determination of SNP allele frequencies in pooled DNA appears to be of value in assigning further genotyping priorities also in large linkage regions.
–Day 4 of Just Science Week–
Quicklink to www.biolib.de (thanks to Sigrid for the link). You will find at Kurt Stübers Online Library 440 scanned historical biological books. Many of these books are currently out of print and even hard to obtain from public libraries or book sellers.
–Day 2 of Just Science Week–
Most people think that human genes are static entities inherited from generation to generation. They may be right, there are no jumping genes in humans.
In 2000, when defending my thesis in epidemiology, I even had to answer the question of the faculty: “How can allergy have a genetic cause as most allergy cases date back only 1 or 2 generations?”. I explained the concept of susceptibility genes (that were always there) plus some new environmental risk factor (that came in only recently) and passed the colloquium.
Maybe this concept was not completely wrong. By today, however, I could offer more explanations – human genes are on the move and even within 2 or 3 generations. You may still wonder – are we talking about T cell receptor recombination? Yes, this may be a possibility, but not a really new one. More noteworthy are (1) abolished purifying selection (2) population admixture and (3) increased spike in mutations. These are all are independent paths that may combine freely.
Lets start with “abolished purifying selection”. At the beginning of the last century there were much larger family sizes and a much higher infant mortality. In Europe, mortality under the age of 5 has been about 250/1.000 live born children in 1900. It dropped to 50/1.000 around 1950 and is now about 5/1.000 – the effect of improved sanitary conditions, vaccines and antibiotics. Geneticists would describe it as a reduced selection – giving immediate rise to some variants in the gene pool.
The figure is © Copyright 2006 SASI Group (University of Sheffield) and Mark Newman (University of Michigan). Thanks to John Pritchard from the Worldmapper Team to let me post it here. Territory size shows the proportion of infant deaths during the first year of their life in 2002
Second, think of population admixture. This usually refers to the composition of a population by descendants of a few founders. Except for major migration periods population composition has been kept rather stable over centuries which can be nicely seen in humans living in isolation and having enriched some diseases – examples from Finland, Hutterities, South Tirol, East Adria or Iceand. With current decrease of admixture also the prevalence of diseases frequently seen in these populations will go done. However, some people even expect that other diseases will rise – as unusual allelic variants will meet other unusual allelic variants (which has not been balanced before). This theory is still vague but has interesting aspects that may be followed up.
A third possibility why human gene variants may change within short time comes with the ever increasing age of fathers at reproduction. I came across this only very recently by a paper of Ellegren. With each additional year of the father the number of pre-meiotic cell divisions increases – leading to a permanent (germline) increase of mutations. Most of these will be irrelevant but some may spike in random genes leading eventually to health effects. Crow asks: “Is this a problem? Surely it will be eventually, but probably not immediately”.
Human genes are therefore on the move, yea, yea.
Being a former curator for a genetic disease database, I received a PM that explained why the foundation of the Human Genome Variation Society did not include most of the HUGO Mutation Database Owners — most did not join as they found it difficult to pay for membership. This reflects the overall frustration in obtaining funds for databases projects that are between research and service. Now, a new initiative for the Human Variome Project (HVP) is started to create a focus pulling the whole vision together and to assist in fundraising. Meeting details are at www.humanvariomeproject.org. I strongly support this initiative. All genetic variation databases are sharing a high interest in the community but zero interest at funding bodies (more). I have a dream…
the flyer…
–Day 1 of Just Science Week–
… said Alice in the Wonderland. Curiouser an couriouser all these gene X – trait Y – value P – association studies that are so often not reproduced. Science magazine now publishes letters of 3 independent groups contributing 6 essentially negative studies. This does not come unexpected – maybe we should look again at the original paper?
The introduction seems to be somewhat misleading — obesity is not primarily associated with another disease but with over-eating — and a heritablity of 70% is hard to believe. BTW I wonder why neither the editors, reviewers, or authors noticed the editorial errors (page 281: the 1775 cases in the text appear as 1835 cases in table 3; table 3 itself is redundant and misses genotype counts as well as the 923 FHS individuals from page 280). However, that does not explain why the association cannot be reproduced by other groups. So what could be the reason that the initial results were not be replicated?
Looking more closely at the case-control definition it seems that obesity is defined in different ways in the different populations – the German sample by cutoff BMI>30, the Polish by 90th to 97th percentile, the Nurses’ trait is never explained and the Africans are split by quartiles. How would a consistently defined look across all these populations? There seems to be also no proof why SNP rs7566605 somewhere 10000 bases away from a gene should have any biological function. Just because it “is an attractive candidate gene … [as it] … inhibits the synthesis of fatty acid” ?
More general, I believe that it is not adequate to make any conclusions about causal interference from a statistical association alone. There are many known fallacies; reasons for non replication may be simple errors during phenotyping or genotyping, inadequate statistical power, a biased analysis, selective reporting, population stratification or population unique effects. My six criteria for a meaningful association are:
Quite simple ;-), yea, yea.
Quick link: German FAZ has a series of 18 articles – great.
sorry, typo. Press telegram reports that the geneticist William French Anderson was sentenced yesterday to 14 years in prison. The reason, however, was not doing premature human experiments but molesting his assistant’s young daughter, yea, yea.
The NIH and Jackson ask for nominations of their gene targeting approach (see also A mouse for All Reasons and my previous comment on the 3 R)
KOMP is a trans-NIH initiative to generate a public resource of mouse embryonic stem (ES) cells containing a null mutation in every gene in the mouse genome. Both conditional and null knockouts are being generated. The purpose of this form is to gather input from the scientific community on which genes should have the highest priority for being knocked out.
The Cell paper also explains the hard to understand differences in knockouts
although I still have semantic problems to understand the nomenclature. Anyway my whishlist – you can do me a favor by voting for CYP27B1, VDR, CYP24A1, OPN, IL4, IL5, IL10, IL12, IL13, FLG, CCR5 and CCR9.
You can also leave some input at the Environmental Genome Project.