Tag Archives: Genetics + Biology

Anticipating trouble

Science magazine today reports another ego trip.

A U.S. company [454] has begun to trickle out information on a unique DNA study it calls “Project Jim,” a crash effort to sequence the entire genome of a single individual. The results are likely to be made public this summer. Anonymity is out of the question: It has already been announced that the genome belongs to James D. Watson, winner of the Nobel Prize and co-discoverer of DNA’s structure. Watson won’t be alone: Harvard Medical School has approved a plan by computational geneticist George Church to sequence and make public the genomes of well-informed volunteers—including his own. And J. Craig Venter says his nonprofit institute will soon release a complete version of his genome.

My daily newsletter says that Roche is going to acquire 454 for $155M and plans to use the sequencer for IVD applications, I hope they will forget “Project Jim” somewhere on a harddisk.

Collins: Testimony on the threat of genetic discrimination

The testimony of Francis Collins before the subcommittee on Health is now online

A recent NIH study of families at risk for hereditary nonpolyposis colorectal cancer … revealed that the number concern expressed by participants regarding genetic testing was about losing health insurance, should the knowledge of their genetic test result be divulged or fall into the “wrong hands” … Unless Americans are convinced that their genetic information will not be used against them, the era of personlized medicine may never come to pass. The rest would be a continuation of the current one-size-fits-all medicine, ignoring the abundant scientific evidence that the genetic differences among people help explain why some of us benefit from a therapy while others do not.

Autosomal inheritance of sex-linked marker

While optimizing the analysis strategy for a 500,000 SNP Affymetrix array set, I found 6 autosomal SNPs that show highly significant sex-dependent allele differences: rs2809868, rs4862188, rs2880301, rs3883011, rs3883013 and rs3883014.


Sure, there could be autosomal marker that influences male/female outcome but there is a more likely explanation: All SNPs have paralogue sequence stretches on the Y chromosome that are co-amplified during PCR. From the initial genotyping results it is most likely that only the Y chromosomal stretch is being mutated in SNP 4, 13 and 15.2.

These SNPs are perfect sex marker, as they include an autosomal control allele (in comparison to pure Y markers like SNPs in SRY). They are always unambiguous (in contrast to pure X marker where only heterocygotes are informative).

They even offer advantage to commercial STR kits of the Amelogenin/Amely gene situated (in the Y parautosomal region) as they would not be affected by excess homologous X chromosomal material as often found in forensic situations. In addition, they might overcome some other weakness of the Amelogenin test where a second assay is usually recommended.

If you will ever see a case-control study that is highlighting any of these SNPs, you can be sure that this study had a distorted male-female ratio between case and controls.

The other way around

One of my favorite pictures is the Orangenesser by Baselitz – his speciality is to paint his subjects the other way around to free the subject from its content (this is at least what art curators say).

DNA inversion rearrangements seem to be also more frequent in the human genome as previously thought, see the following PNAS preprint:

Three such regions … on chromosomes 3, 15, and 19, were analyzed. … The results obtained indicate that recurrent genomic rearrangements occur at relatively high frequency in somatic cells. Interestingly, the rearrangements studied were significantly more abundant in adults than in newborn individuals, suggesting that such DNA rearrangements might start to appear during embryogenesis or fetal life and continue to accumulate after birth.

(more on arts and DNA)

More paranormal inheritance

A funny study in PNAS is broadening our view of paranormal inheritance by showing germline chimerism in marmosets:

Using microsatellite DNA markers, we show here that chimerism in marmoset (Callithrix kuhlii) twin … somatic tissue .. found to be chimeric. Notably, chimerism was demonstrated to be present in germ-line tissues, an event never before documented as naturally occurring in a primate. In fact, we found that chimeric marmosets often transmit sibling alleles acquired in utero to their own offspring.

Bad news for all who believe in human paternity testing and 99,999999% probability – and more strange stories (semi-identical twins discovered – hermaphrodite reveals previously unknown type of twinning) at the Nature news blog.

The epigenetic landscape

What I always feared, but couldn’t believe, is now confirmed by renowned experts in a new Cell editorial

Historically, the word “epigenetics” was used to describe events that could not be explained by genetic principles.

It goes back to Conrad Waddington – and describes now such bizarre and inexplicable features like paramutation in maize, position effetc variegation in Drosophila and methylation in humans. There is a nice analogy of the classical 1957 epigenetic landscape figure of Waddington where the course of the ball is influenced by hillls and valleys where it finally arrives – the Pinball arcade game

known factors that may regulate epigenetic phenomena are shown direcing the complex movements of pinballs (cells) across the elegant landscape … no specific order of molecular events is implied; as such a sequence remains unknown. Effector proteins recognize specific histone modifications…


About replication validity of genetic association studies and illogical journal policies

Also outside the genetics community many people wonder why Popper’s account of falsifiability has so readily be abandoned. Karl Popper used falsification in “Logic of Scientific Discovery” as a criterion of demarcation between what is and what is not genuinely scientific.

Paul K. Feyerabend, one of Poppers many famous scholars at the London School of Economics- defended in “Against Method” (Feyerabend 1993) the view that there are no methodological rules which can be always used by scientists. He objected to any single prescriptive scientific method (like falsification) as any such method would limit the activities of scientists, and restrict scientific progress. Progress instead occurs where new theories are not consistent with older theories; a new theory also can never be consistent with all relevant facts: this make falsification attempts useless. Feyerabend advocated in a rather anarchistic view that scientific pluralism improves the critical power of science and not any schematic rules like profile population x with SNP panel y and describe all p less than z to finally develop new treatment t.

Many reasons why genetic association studies failed have been already identified (see Buchanan et al. 2006). Usually high impact journals get spectacular claims first; half-way down between Popper and Feyerabend, the editorial board looks for falsifiability by claiming additional populations.

As expected, effect sizes will not be exactly the same in different populations; often only neighbouring SNP “rescue” the initial claim. It has never been decided by a formal process, what does it mean if a third or fourth population doesn’t show up with the same result. It has never been clarified that falsifiability means that the exactly same SNP needs to be associated in all population studies or just a haplotype (or just a microsatellite allele) somewhere in that genomic region.

Nevertheless replication validity – in the context of generalization – is permanently used to prove “true” or “meaningful” association that ultimately deserve a high impact factor. Humans look different and they seem different in genetic terms: the high individual variablity in expressing a disease trait may reflect not only reflect a highly variable environment but also highly individual genetic pathway. We are willing to accept a causal mutation found in just one family with a monogenic trait often there seems no way to convince an editorial board that a strong association found in just one study sample is an important discovery that may severely impact exactly this population (given additional functional proof of otherwise static gene variant).

The absence of large linkage signals and the absence of reproducible genetic associations with nearly all complex diseases may indicate only individual risk gene combinations. It seems to be that we need to listen to another scholar of Popper – Thomas Kuhn — to change the current paradigma.


14-6-07 Finally, Nature published some guidelines for interpretation of association studies

Many receive advice, few profit by it

The AJHG preprint server has an important paper about the effect of rare missense alleles. By combining information from HGMD, human – chimpanzee divergence and 4 other datasets (NIEHS-EGP, Seattle SNPs, JSNP and a resequencing approach of 58 genes in >1,500 chromosomes) they attack the Chakravarti hypothesis of “common diseases – commmon variants”

It remains uncertain why such polymorphisms can persist without being eliminated by purifying selection. Currently, two major lines of reasoning exist that explain this apparent paradox. The first considers various complex evolutionary scenarios and treats positive or balancing selection as a major force that can drive medically detrimental mutations to high frequencies. The second line of reasoning postulates a high mutation rate as a major factor that determines the cumulative frequency of detrimental polymorphisms in the population.

Anyway, here is the main outcome


I am fascinated by circadian clocks that enable organisms to cope with daily environmental changes by adjusting biological processes. This certainly impacts health and quality of life in regulating sleep; particular interesting is entrainment, the synchronisation to the external day.

Here is a link to an EU project that I recently came across during a poster session – euclock. Another study funded by the “Gottlieb Daimler- und Karl Benz-Stiftung” can be found at the clock work site.


Falling asleep

A new study in Science now finds that facts and experiences were better recalled from memory when subjects were cued with a scent during the memorization process and again during slow wave sleep.

Re-exposure to the odor during slow-wave sleep (SWS) improved the retention of hippocampus-dependent declarative memories but not of hippocampus-independent procedural memories. Odor re-exposure was ineffective during rapid eye movement sleep or wakefulness or when the odor had been omitted during prior learning. Concurring with these findings, functional magnetic resonance imaging revealed significant hippocampal activation in response to odor re-exposure during SWS.

I wonder how this could be used for preparing presentations, situations where a persons typically fall asleep during or after the session ;-)

Face recognition, face value

With a new child, people are always asking if the baby looks like the father or the mother – probably a prehistoric social reflex to confirm that this is your offspring that you are caring about.
Face recognition clearly is a science of its own – a lot of heuristics and Bayesian computing – more at face-rec.org – and even a big business if you think of automatic passport control or age determination for goods that are only allowed for adults.
Face recognition works quite robust as I found in the advanced online demo at betaface.com. A new browser plugin from polar rose will even allows to annotate web pictures – Orwell meets Flickr.