Month: June 2014

Inteins are genetic parasites

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Gene invasion in distant eukaryotic lineages: discovery of mutually exclusive genetic elements reveals marine biodiversity
The ISME Journal (2013) 7, 1764–1774
http://www.nature.com/ismej/journal/v7/n9/full/ismej201370a.html
Adam Monier, et al.
Inteins are rare, translated genetic parasites mainly found in bacteria and archaea, while spliceosomal introns are distinctly eukaryotic features abundant in most nuclear genomes.
Using targeted metagenomics, we discovered an intein in an Atlantic population of the photosynthetic eukaryote, Bathycoccus, harbored by the essential spliceosomal protein PRP8 (processing factor 8 protein).  …
We hypothesize that intein propagation is facilitated by marine viruses; and, while intron gain is still poorly understood, presence of a spliceosomal intron where a locus lacks an intein raises the possibility of new, intein-primed mechanisms for intron gain.

Keywords: invasive elements; inteins; polymorphic introns; horizontal transfer; metagenomics; viridiplantae

The origins and distributions of introns and inteins remain one of the greatest mysteries of molecular and evolutionary biology.
Spliceosomal introns are distinctly eukaryotic features abundant in almost all nuclear genomes.
These non-coding elements interrupt coding regions (exons) of genes and are excised from the nascent mRNA prior to translation.
In contrast, inteins (internal protein) are much rarer genetic elements found in protein-coding genes from all three domains of life and viruses.
These in-frame intervening sequences are in coding regions of genes and are translated as part of the host protein. After self-catalyzed excision by the intein, the host protein flanking regions known as exteins (external protein) are ligated by a peptide bond. This intein-mediated process has been dubbed protein-splicing and maintains host protein functional integrity.

De novo mutations: 74 SNVs per genome

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Current estimates of the average mutation frequencies for the different types of de novo genomic variation observed per generation per genome.

De novo mutations in human genetic disease
Nature Reviews Genetics 13, 565-575 (August 2012)
http://www.nature.com/nrg/journal/v13/n8/full/nrg3241.html
Joris A. Veltman, et al.

New mutations have long been known to cause genetic disease, but their true contribution to the disease burden can only now be determined using family-based whole-genome or whole-exome sequencing approaches.

In this Review we discuss recent findings suggesting that de novo mutations play a prominent part in rare and common forms of neurodevelopmental diseases, including intellectual disability, autism and schizophrenia.
De novo mutations provide a mechanism by which early-onset reproductively lethal diseases remain frequent in the population.
These mutations, although individually rare, may capture a significant part of the heritability for complex genetic diseases that is not detectable by genome-wide association studies.

Pathological pain and the neuroimmune interface

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Pathological pain and the neuroimmune interface
Peter M. Grace, et al.
Nature Reviews Immunology  14, 217–231 (2014)
http://www.nature.com/nri/journal/v14/n4/full/nri3621.html

Reciprocal signalling between immunocompetent cells in the central nervous system (CNS) has emerged as a key phenomenon underpinning pathological and chronic pain mechanisms.
Neuronal excitability can be powerfully enhanced both by classical neurotransmitters derived from neurons, and by immune mediators released from CNS-resident microglia and astrocytes, and from infiltrating cells such as T cells.

In this Review, we discuss the current understanding of the contribution of central immune mechanisms to pathological pain, and how the heterogeneous immune functions of different cells in the CNS could be harnessed to develop new therapeutics for pain control.

Given the prevalence of chronic pain and the incomplete efficacy of current drugs — which focus on suppressing aberrant neuronal activity — new strategies to manipulate neuroimmune pain transmission hold considerable promise.

GWAS explains only a small proportion of the total heritability

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By exploiting allied phenotypic data, it is possible to examine the genetic contribution to such aspects of disease biology (including prognosis) by comparing the genetic profiles of patients with contrasting clinical phenotypes—a so-called ‘within-cases’ analysis.

Prognosis in autoimmune and infectious disease: new insights from genetics
Clinical & Translational Immunology (2014) 3, e15
http://www.nature.com/cti/journal/v3/n5/full/cti20148a.html
James C Lee, et al.

Keywords: autoimmunity; FOXO3; genetics; infection; prognosis

despite the apparent success, GWAS results have only explained a relatively small proportion of the total heritability of each disease.[3]
Work is now underway to try to identify the ‘missing heritability’ through a variety of complementary methods, including:

  • whole-genome sequencing (to identify rare variants that may have larger effect sizes) and
  • studies to examine interactions between a given gene and other genes (epistasis) and
  • between genes and the environment.

related:
https://franzcalvo.wordpress.com/2014/06/29/are-vitamins-good-for-you

Are vitamins good for you?

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Nutrition: Vitamins on trial
After decades of study, researchers still can’t agree on whether nutritional supplements actually improve health.
Melinda Wenner Moyer
Nature 510, 462–464 (26 June 2014)
http://www.nature.com/news/nutrition-vitamins-on-trial-1.15459

But scientific opinion about the use of vitamin supplements by millions of seemingly healthy people has never been more divided.

“The tools we’ve had in the past have been so crude — it’s like we’ve been looking through a dirty window with the curtains closed,”

one of the many complexities of nutrient metabolism.
Nutrition scientists now recognize that risk curves are J- or U-shaped: nutrients have beneficial effects at low doses and toxic effects at high doses.
The magnitude of the response differs, too, depending on where individuals start on the curve — their baseline status.

Are supplements useless?
The current state of research offers only an equivocal half-answer: ‘maybe yes’ for some individuals, nutrients and doses, and ‘maybe no’ for others.
“Nutrition is complex, and I don’t think we’re necessarily going to find one formula that works for everybody,” says Mayne.

related article on within-cases analysis:
https://franzcalvo.wordpress.com/2014/06/29/gwas-explains-only-a-small-proportion-of-the-total-heritability

Retraction: STAP papers

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The STAP papers have been retracted (July 2, 2014), but the original Nature publications are not yet labeled as such:
http://www.nature.com/news/stap-retracted-1.15488
http://www.the-scientist.com//?articles.view/articleNo/40408/title/STAP-Papers-Retracted
http://www.npr.org/blogs/health/2014/07/02/327672110/easy-method-for-making-stem-cells-was-too-good-to-be-true

Stimulus-triggered fate conversion of somatic cells into pluripotency
Nature  505, 641–647 (30 January 2014)
Haruko Obokata, et al.
http://www.nature.com/nature/journal/v505/n7485/full/nature12968.html

Here we report a unique cellular reprogramming phenomenon, called stimulus-triggered acquisition of pluripotency (STAP), which requires neither nuclear transfer nor the introduction of transcription factors.
In STAP, strong external stimuli such as a transient low-pH stressor reprogrammed mammalian somatic cells, resulting in the generation of pluripotent cells.
Through real-time imaging of STAP cells derived from purified lymphocytes, as well as gene rearrangement analysis, we found that committed somatic cells give rise to STAP cells by reprogramming rather than selection.
STAP cells showed a substantial decrease in DNA methylation in the regulatory regions of pluripotency marker genes.

Blastocyst injection showed that STAP cells efficiently contribute to chimaeric embryos and to offspring via germline transmission.

We also demonstrate the derivation of robustly expandable pluripotent cell lines from STAP cells.
Thus, our findings indicate that epigenetic fate determination of mammalian cells can be markedly converted in a context-dependent manner by strong environmental cues.

Maintenance of neuronal identity

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Maintenance of postmitotic neuronal cell identity
Evan S Deneris, et al.
Nature Neuroscience  17, 899–907 (July 2014)
http://www.nature.com/neuro/journal/v17/n7/full/nn.3731.html

The identity of specific cell types in the nervous system is defined by the expression of neuron type–specific gene batteries.
How the expression of such batteries is initiated during nervous system development has been under intensive study over the past few decades.

However, comparatively little is known about how gene batteries that define the terminally differentiated state of a neuron type are maintained throughout the life of an animal.

Here we provide an overview of studies in invertebrate and vertebrate model systems that have carved out the general and not commonly appreciated principle that neuronal identity is maintained in postmitotic neurons by the sustained, and often autoregulated, expression of the same transcription factors that initiate terminal differentiation in a developing organism.
Disruption of postmitotic maintenance mechanisms may result in neuropsychiatric and neurodegenerative conditions.

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Serotonergic transcriptional networks …
2012
http://www.nature.com/neuro/journal/v15/n4/full/nn.3039.html

Action potential firing in distal axons (2011)

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Slow integration leads to persistent action potential firing in distal axons of coupled interneurons
Mark E J Sheffield, et al.
Nature Neuroscience  14, 200–207 (2011)
http://www.nature.com/neuro/journal/v14/n2/abs/nn.2728.html

The conventional view of neurons is that synaptic inputs are integrated on a timescale of milliseconds to seconds in the dendrites, with action potential initiation occurring in the axon initial segment.

We found a much slower form of integration that leads to action potential initiation in the distal axon, well beyond the initial segment.
In a subset of rodent hippocampal and neocortical interneurons, hundreds of spikes, evoked over minutes, resulted in persistent firing that lasted for a similar duration.
Although axonal action potential firing was required to trigger persistent firing, somatic depolarization was not.
In paired recordings, persistent firing was not restricted to the stimulated neuron; it could also be produced in the unstimulated cell.
Thus, these interneurons can slowly integrate spiking, share the output across a coupled network of axons and respond with persistent firing even in the absence of input to the soma or dendrites.

associated News and Views:
Integration and autonomy in axons
Nature Neuroscience  14, 128–130 (2011)
http://www.nature.com/neuro/journal/v14/n2/full/nn0211-128.html