Papers of the week – Copy Number Variations

Dennis' paper of the weekVariations on Copy Numbers. In the third issue of our series on the papers of the week I will focus on the detection and annotation of the most common form of structural variation encountered in genomes. Deletions, duplications and inversions are frequent events, which are surprisingly hard to deal with using sequencing-based tools. Hence, this is an area of active development.

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The human genome is way too complicated for me

What has become of that simple 21,000-gene genome of ours? Today even the definition of gene is no longer clear. What biotypes belong to lncRNAs and what’s the job of unitary pseudogenes? For geneticists dog-paddling in complex diseases another surprise came last year with the announcement that roughly 80% of the genome has some sort of function. Confused? Grab this issue of Genome Research and read the review by Mudge and colleagues, who discuss many examples of the transcriptional complexity within the human genome. Continue reading

From unaffected to Dravet Syndrome – extreme SCN1A phenotypes in a large GEFS+ family

The two faces of SCN1A. Even though the range of phenotypes associated with mutations in SCN1A can be conceptualized as a continuum, there are usually two distinct entities in clinical practice: the severe, epileptic encephalopathy of Dravet Syndrome due to de novo mutations and the usually mild fever-related epilepsies in autosomal dominant GEFS+ families. While Dravet Syndrome can also be seen in some families with Genetic Epilepsy with Febrile Seizures Plus (GEFS+), this is a rare phenomenon; there is usually little overlap between Dravet Syndrome and GEFS+. Within the Israel Epilepsy Family Project, we came across such a family with overlapping phenotypes. This recently published large GEFS+ family probably has the widest phenotypic range reported to date. Continue reading

Papers of the week (w47)

Dennis' paper of the weekThursday again already? Well, after the positive feedback from colleagues and friends I must continue. I like ambitious goals and hope that the epilepsy genetics community finds this new series on papers of the week helpful. Let’s start with a Science paper by McConnell and collaborators on somatic copy number variations in neurons, a paper that was also mentioned in a recent post. I wanted to know more about the single cell sequencing methodology. Continue reading

Pharmacogenomics for epilepsy

The treatment options for epilepsy must undoubtedly be improved. More than 20 antiepileptic drugs are licensed but in 30% of patients seizures are not controlled, despite treatment with a number of anti epileptic drugs and the response to medication is difficult to predict. Antiepileptic medications can cause severe adverse reactions and increase the risk of fetal malformations in women taking them during pregnancy. The differences in drug response and the occurrence of rare adverse reactions are believed to be caused by variants in the genetic makeup of individuals. Knowledge of these variants would help us to predict drug response and adverse drug reactions. This personalized treatment would help us to select medications for each individual.

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SHANK3, epilepsy, and the excitatory/inhibitory imbalance

Postsynaptic. SHANK proteins are elements of the postsynaptic density, linking synaptic transmission with the cytoskeleton. Deletions in SHANK2 and SHANK3 are known genetic risk factors for a broad range of neurodevelopmental disorders. The role of the reciprocal duplications, however, has remained unclear. In recent paper in Nature, a novel mouse model expressing a SHANK3 transgene is investigated. The results of a mere 1.5 fold overexpression of the protein are dramatic, hinting at unanticipated mechanisms that regulate the balance between excitation and inhibition.  Continue reading

Papers of the week

Dennis' paper of the week

My name is Dennis Lal, I am working on the genetics of rolandic epilepsy and idiopathic generalized epilepsies within the EuroEPINOMICS consortium. Like many scientists, I read a lot of publications, or well, at least the abstract. Roland and Ingo asked me repeatedly to write a post but I was afraid of losing too much time. But as a young and naive scientist you have to give things a try.That’s why I started commenting on my favorite papers of the week, collected here. This “experiment” is currently at 35 minutes (after several rounds of editing) and I aim to finish this blog post below 60 minutes.

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Epigenetic signatures – profiling the epilepsies beyond genetics

What is epigenetics? In a single idea: the molecular memory of a cell. The system stores information of previously external (e.g. environmental) or internal (e.g. developmental) stimuli, learns from this experience and responds. A collection of specific tags tells genes whether to be ON or OFF. Hardcore epigeneticists claim that an epigenetic tag should be meiotically and/or mitotically heritable, self-perpetuating, and reversible. DNA methylation is the mechanism coming closest to this ideal. A more liberal definition not focusing on heritability refers to any structural adaptation of the chromatin template that regulates gene expression. This would also include posttranslational histone tail modifications, incorporation of histone variants, chromatin remodeling processes, and action of non-coding RNAs. The large variety, flexibility, interdependence and potential synergistic effects of epigenetic mechanisms could provide the molecular basis for any phenotypic variation in physiological and pathological conditions. In epilepsy research this is especially interesting with regard to the stimulus-driven activity and connectivity of post-mitotic neurons in the adult brain. We set out to study methylation for the most common form of epilepsy in adults. Continue reading

“Dark social” or “Who is afraid of email?”

Heathrow. Dark social? Threat? I’ll get back to that. I am writing this wrap-up post for the SpotOn 2013 meeting overlooking the British Airways planes on their way to take-off. In the last two days, we caught a glimpse of what online science communication is about. On Saturday, we had our own session #solo13blogs on using blogs for peer-to-peer science communication. As a science communication newbie, I am happy that our session was well received and stimulated quite some discussion. I have taken away three things from this meeting – a new understanding of our readership, an appreciation for Open Access and data sharing, and finally, a fear of the destructive power of dark social that also applies to epilepsy genetics research. But first things first. Continue reading

SpotOn London, Open Access and the Higgs boson

#solo13. Some strange symbols that made it onto our blog originate on Twitter. The “#” (hash) precedes a hashtag, which indicates a Twitter topic. “@” (at) is called a handle, a possibility to contact people. As you might remember from our previous announcements, Roland and me are currently participating in SpotOn 2013, a conference for online science communication. The meeting is held at the British Library in London. This is just a brief update on what #solo13 was about today. Continue reading