Category Archives: Genetics

More about parents and self

I would be interested to learn more about the rate of non-matching parent-child SNP assays (preferably Affymetrix technology as current Illumina chips do not include low MAF variants).

This could tell us something about the role of de novo somatic mutations: Read more in a recent TIGS paper by Kenneth Weiss. Has anyone checked different tissues of the same individual and looked for mosaics? Or traced the fate of blood transfusions? Or followed up a single individuals over a couple of years?

This idea is also fuelled by a recent Cell paper that shows Sticker’s sarcoma to be transmitted among dogs by licking or biting tumor-affected areas. Yea, yea.

From misunderstanding to dogma

The Nature Reviews Genetics Timeline features an interesting story on human chromosome numbers. Theophilus Painter in his 1921 Science paper wrote: “In my own materials the counts range from 45 to 48 apparent chromosomes” which was interpreted for obvious reasons to be 46 or 48 (Painter probably saw a bended chr1 as 2 different ones). Textbooks then reported 48 human chromosomes for 3 decades until the classical paper of Tijo in 1956 paper who confirmed 46 human chromosomes. Gartler believes that Tijos unusal background have made him likely to question authority. Yea, yea.

What’s in a name?

What’s in a name? That which we call a rose. By any other word would smell as sweet. From Romeo and Juliet (II, ii, 1-2).

Geographical distribution of names may indicate spreading of gene variants – a fact that has been ignored so far in genetic research. If you are interested in European names, here are some interesting links. It is now even possible to draw your name on a map – on the fly. Yea, yea.

Here is map of my name (yes, a couple of errors, but the locations are close to what I have found in our 70 year old family register).

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Not invited to Lindau?

Lindau at Lake Constance hosts the annual Nobel laureate meeting. In addition some 500 young students from all over the world can listen to the Laureates’ lectures and to engage in discussions with them. Not invited? There are some excellent interviews available (for 2003-2005 but we are all waiting for 2006).

Interested in the history of DNA discovery? There is a wonderful Linus Pauling website that has it all: A wealth of primary sources – over three hundred letters, manuscripts, photographs, published papers, audio-visual snippets and more – provide an important scholarly perspective on the DNA story. Yea, yea.

Matchcode

If you are invited to a party just mention genetically modified (GM) food and you will be center of the crowd. There are many national and internationally bodies that deal with GM food (see the dissertation of Scholderer). As far as we do not know what makes and allergen and allergen, I would always care when introducing any modification. There is a way round, however, that GM food can also have less allergen content – just found a preprint of a gene-silenced tomato. This German-Spanish group managed by RNAi silencing to reduce protein Lyc e 3 with led to reduced skin reactivity of tomato allergic probands. BTW – do you renember our fake food hypothesis? Yea, yea. BTW The best tomato bread can be found in Barcelona.

Taqman ® based genotyping – What´s new?

You may have read the contribution of Monika Werner and me in “Pharmacogenetics” about “Methods of Genotyping”.

A point that we did not cover when describing the 5-prime-nuclease assay is the neverending miniaturisation of assays. At a recent HUGO meeting I have already seen British Kbioscience offering an extremely flat, black, ca. 8 x 12 x 0.2 cm, 1,536 well plastic plate (size recalled from memory) that is sealed after filling in primer / mastermix and DNA. Up to 1,000 sealed plates are then water-bathed for temperature cycling.

A few days ago another system made it on my desk: U.S. BioTrove sent me a demo array that is about 6,4 x 2 x 0,01 cm has precoated primer holes for 3,072 assays where you just add your DNA + mastermix before sealing and cycling it on a conventional thermocycler.

No fool like an old fool

PLOS Genetics – one of the ever rising stars – reports detailed expression profiling of aging human, mouse, fly and worm. When looking at muscle (in part also brain and kidney), Jacob Zahn et al from Stanford UMC found chloride transport and mitochondrial electron transport chain most severely affected by age. Is that a biological explanation for two common geriatric problems, e.g. exsicosis and falls? BTW detoxification by CYP26B1 increased, so aging does not necessarily mean involution. Most frightening: a 41 y old expressed like 10-20 y older and a 64 y old like 30 y younger. Yea, yea.

Bigger is better

John Todd has always been advocating that we should use larger sample sizes in our genetic association studies. I agree, it is also true that larger sample sizes will lead to smaller p-values. In his recent nature genetics comment he now suggest a p of less than 10 up minus 8 to be relevant. Yes, all of his 6 examples show that significance level but only 1 provides functional evidence (the SLE study). All other studies including Todd`s own studies are number-crunchers. I fear that in the absence of functional data 10-8 may not even be sufficient. Think of 500,000 SNPs, 20 possible traits, 5 genetic models and 20 competing groups – this multiplies to 10-9. Interestingly, the SLE study, showed a p of 10-16! Having good functional evidence I would be even willing to accept 10-2. May I point you to an excellent study describing a new rSNP by means of CHIP and expression analysis of de Gobbi – using just a couple of families. Yea, yea.

Time bomb – revisited

I revisited a 2005 paper on “Folic acid – vitamin and panacea or genetic genetic time bomb“. From the abstract: “We live in a health-conscious age — many of us supplement our diet with essential micronutrients … so-called ‘functional foods’ … We examine this issue in relation to the B-group vitamin folic acid, and ask whether supplementation with this vitamin could introduce a strong genetic selection pressure…” As I found this paper highly interesting, here is my analysis, how the story goes on:

  1. Martinez-Frias, ML. Folic acid: a public-health challenge. LANCET.
  2. Kafadar, AM. C677T gene polymorphism of methylenetetrahydrofolate reductase (MTHFR) in meningiomas and high-grade gliomas. ANTICANCER RESEARCH.
  3. Kelemen, LE. The role of folate receptor alpha in cancer development, progression and treatment: Cause, consequence or innocent bystander?. INTERNATIONAL JOURNAL OF CANCER.
  4. Nazarenko, MS. Frequencies of C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase gene at the early stage of human development. RUSSIAN JOURNAL OF GENETICS.
  5. Ferguson, LR. Nutrigenomics – Integrating genomic approaches into nutrition research. MOLECULAR DIAGNOSIS & THERAPY.
  6. Soloway, PD. Gene nutrient interactions and evolution. NUTRITION REVIEWS.
  7. Eichholzer, M.. Folic acid: a public-health challenge. LANCET.
  8. Houghton, LA. [6S]-5-Methyltetrahydrofolate is at least as effective as folic acid in preventing a decline in blood folate concentrations during lactation. AMERICAN JOURNAL OF CLINICAL NUTRITION.
  9. Ejarque, I. A bioinformatic approach to epigenetic susceptibility in non-disjunctional diseases. BIOLOGICAL AND MEDICAL DATA ANALYSIS, PROCEEDINGS.
  10. Sweeney, MR. Evidence of unmetabolised folic acid in cord blood of newborn and serum of 4-day-old infants. BRITISH JOURNAL OF NUTRITION.
  11. Lucock, MD. The antifolate activity of tea catechins. CANCER RESEARCH.
  12. Kelemen, LE. Multivitamin and alcohol intake and folate receptor alpha expression in ovarian cancer. CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION.
  13. Allegrucci, C. Human embryonic stem cells as a model for nutritional programming: An evaluation. REPRODUCTIVE TOXICOLOGY.

Supersize me and the fake food hypothesis

Is there any sense of genetic studies aiming at an association with body mass index? Will there ever be a public health strategy or any medical intervention based on a genetic marker?
I am recalling what Christoph – a friend of mine at medical school and a now professor for child psychiatry – once told me when he was working on his thesis about anorexia: “You only need to weight them for a diagnosis”. As there are now lots of weighing machines out there, there are plenty of DNAs (intended for different outcomes!), which might be a reason of the 5946 “obesity and gene” papers.
Will this help anybody? I fear, that responsibility is even shifted to “poor genes” (of course I acknowledge that there might be gene nutrient interactions – Paul Soloway wrote a nice essay on that). My view – developed with my wife over many years – is that that the obesity epidemics is largely an environmental trait of poor eating habits, wrong orientation on dress models and not enough physical activity. I recall also Professor Walter Willett – who has been my former advisor in Nutritional Epidemiology – that things can be quite simple. Check for his “Low Glycemic Index” on the web, find a sports club for biking, jogging or walking, concentrate on eating and use small spoons and forget about diets.
There is long-standing discussion, how the body signals by “being hungry” that something is missing (sorry, only 1 historic reference). Of course this works also in non-humans: Have you ever seen supersized animals? My guess is, that the well developed and unconscious food recognition process is largely fooled by pre-processed food that contains additives changing appearance, taste and smelling. So, you have now heard the first time about the fake food hypothesis. I do not believe so much in voluntarily overeating – it seems much more an involuntary repeated intake to find someting useful.
Coming back to our start: Imagine that
drugs that can block hunger (as we now learned the search for required food ingredients) and imagin that the developed world continues to eat their currently preferred food: Everybody will then need a professional nutrionists to balances his/her daily intake. So, we better save tax payer money for these BMI-gene studies. Yea, yea.

A hitch in the glitch of the switch

The CD14 / allergy story never ends – after many years and numerous contradictory reports. A new comment in the AJRCCM concludes that “further research is required” – at this time “research into the area of gene-by-environment interaction where large-scale studies, advanced assessment of environmental exposure of and experimental investigations of interactions are needed”. Is there any sense with neverending loops (except playground for hamster)? Nay, nay.

How deep is deep enough?

In case that the common disease / common variant is leading to nirvana, we urgently need to resequence common genes in large populations. 2kb long CRP is a particular good candidate which might be a reason why Crawford from Uwash resequenced ~500 individuals. They found indeed potentially relevant codings SNPs – of course rare (<1%) but they are there! There is a greater number in African-Americans than other populations and more than half are private to a single population (BTW more than half in dbSNP can not be validated). Of course tag SNPs would not discover them. Yea, yea.

Where we recombine

Finally, and long awaited, there is a first detailed analysis of mutational hotspots in the human genome by Myers from the McVean group in Oxford. There are roughly 1k-2k hotspots per chromosome, each 1kb-2kb long while there are no 200 kb without apparent recombination. Recombination avoids repeats, exons and L1 elements but likes GC as well as the THE1A/B 7mer CCT.CCC.T and the 8mer CCA.CGT.GG. As rec laways needs double strand breaks, are these also the first cancer motifs found? Yea, yea.