Tag Archives: Genetics + Biology

Pushing the limits of cytogenetic FISH

-moblog- HMG has an interesting paper of Fei Sun and Renee H. Martin – showing a first visable recombination map of the male human genome. They obtained testicular samples from 10 males where each contributed 100 pachytene-stage cells. Chromosomes were identified by blue CREST centromere coloring and yellow MHL1 coloring of crossing over sites. Unfortunately the paper is not so easy to read but they have excellent figures. On average there are 50 cross-overs per set (which is more than I expected). The total number goes down from 52 at age 30y to 46 at age 80y (which may explain the higher chance of aneuploidy at a higher age). Individual crossover frequencies look extremely variable, chromosomal locations are clustering at different site -see my recent blog on recombinogenic sequences. Activity at centromeres was always low while chromosome 21q showed a high individual variablity. Why was there never detailed workup of physical and linkage map? Nay, nay.

Kernel function

Slashdot corbettw writes “This article on Yahoo Science News describes a new finding that explains how the thalamus is used by your brain to essentially boot your brain, and provide for central processing and control of all impulses going to and from the cortex. The article describes its function as an operating system, but from the description it actually seems closer to the functions of a kernel.” That’s true if we see a kernel as abstraction layers for hardware, especially for memory, processors and I/O that allows hardware and software to communicate. It is probably a monolithic kernel that executes all the code in the same address space. Nay, nay.

Role of Faust

-moblog- Edge The Third Culture has a long portrait of Craig Venter: “… His enemies have nicknamed him Darth Venter and accused him of putting the future of biology in jeopardy … journalists have cast him in the role of Faust…” The Celera genome admired in the East Room of the White House had been a composite of 5 different people including Venters own DNA (read about DNA sources). He is now going to make his private DNA public as well as an autobiography. Is anybody interested in reading any of the two? Nay, nay.

Allelic specific expression

This topic has fascinated me since I read the Pastinen paper from the Hudson group (with updates in Science and Hum Mol Gen; the field probably started with the Yan paper). We had even written a DFG grant application that was not funded.

ASE uses a rather simple principle where the allelic ratio of a heterocygous SNP within a RNA transcript is taken as a measure of gene expression from the different chromosomes (that are carrying either the one or the other SNP allele). A ratio of 0.5 indicates equal expression and becomes distorted if a gene on one chromosome is imprinted or silenced by another way. The ratio can be rather easily determined by MALDI-TOF genotyping of cDNA by pooling protocols. I wonder why this hasn´t been more used as it is probably a more precise measurement than the artificially “self-normalized” expression ratios in classical gene-expression profiling (as Fan pointed out recently).

ASE seems to be much more common than I thought: 53% of all genes showed allele expression differences in at least one individual. Having such a screening instrument at hand, it could even help to clear our SNP genotyping lists. Yea, yea.

Geneticists and NBIA-PKAN

Geneticists continue to publish about “Hallervorden-Spatz” or “former Hallervorden-Spatz” syndrome.

The German NBIA patient group advocates for many years that these names should be abandoned (the American patient group even formally changed its name 2003). NBIA is a rare inherited neurological movement disorder characterized by the progressive degeneration of the nervous system; NBIA means “neurodegeneration with brain iron accumulation”. Another frequently used disease synonym is pantothenate kinase-associated neurodegeneration (PKAN).

The clinical syndrome has been described by the neurologist Julius Hallervorden and the neuropathologist Hugo Spatz. Robert Jay Lifton does not h>ave any material about Hallervorden and Spatz in “The Nazi Doctors: Medical Killing and the Psychology of Genocide but Ernst Klee in “Auschwitz, die NS-Medizin und ihre Opfer” and Benno Müller-Hill in “Murderous science” mentions both. Professor Hugo Spatz (1888-1969) was docent in Munich 1923, director of Kaiser-Wilhelm-Institut Berlin 1937-1945 and director of Max-Planck-Institut für Hirnforschung Gießen 1948-1957. Professor Julius Hallervorden (1882-1965) was department head at Kaiser-Wilhelm-Institut Berlin 1938-1945 and at MPI for Brain Research from 1948 on.

The former director of Max-Planck association Professor Hubertus Markl mentioned their involvement in Nazi euthanasia in his lecture on Oct 14, 2000 at MDC in Berlin-Buch (own translation): “Recent research showed that brains of hundreds of euthasia victims killed between 1939 and 1944 in Brandenburg-Görden, were mis-used for research purposes. In a single case Julius Hallervorden was present in person, while children were killed in Görden and brains consecutively analysed in his laboratory… As a biologist it remains for me to declare that this is an eternal dishonor for German bioscience.”

The sib similiarity problem

We have done affected sib pair studies for many years with moderate success as we already described five years ago. Professor John Edwards brought to my attention the “sib similiarity problem“, that is still not widely known. ASP studies are based on “the premise that a set of ASPs will share more than the expected proportion of alleles at a disease-susceptibility locus with the implication that these were the sole cause for excess sharing”. This is not necessarily true and may be one reason of the failure of ASP studies. More or less by chance, I found that that the observation of 1 discordant sib in ASP families be an extremely powerful. “Being sane in an insane world” e.g. being healthy while having most of the risk alleles and all the environment risk that made the sibs ill. Yea, yea.

Who is who in German genetic research?

You may want to start with names listed at Laborjournal. Aside from universities major institutes are with Max Planck and Helmholtz. Main funding comes by DFG (Deutsche Forschungsgemeinschaft, who lists all their projects at GEPRIS) and by BMBF (German Ministry of Research) with a few projects online at National Genome Research Network.

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.

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.


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.

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.