Pupil size and decision making, timing evolutionary innovation and understanding ATP allosteric functions: the PLOS Comp Biol September issue

Here’s our pick of the highlights from September’s PLOS Computational Biology.

The precision with which people make decisions can be predicted by measuring pupil size before they are presented with any information about the decision. According to Peter Murphy and colleagues, spontaneous, moment-to-moment fluctuations in pupil size can predict how a selection of participants varied in their successful decision making. A larger pupil size indicated poorer upcoming task performance, due to more variability in the decisions made once the relevant information was presented. The authors also found that certain individuals who had the largest pupils overall also tended to be the least consistent in their decisions.

Our September issue image: Matching drug binding pockets in protein models using sequence order-independent structure alignments. Image Credit: Michal Brylinski.

Our September issue image: Matching drug binding pockets in protein models using sequence order-independent structure alignments. Image Credit: Michal Brylinski.

Evolutionary adaptation can be described as a biased, stochastic walk of a population of sequences in a high dimensional sequence space. The population explores a fitness landscape and the mutation-selection process biases the population towards regions of higher fitness. Krishnendu Chatterjee and colleagues estimate the time scale that is needed for evolutionary innovation, using the length of the genetic sequence that needs to be adapted as their key parameter. The authors show that a variety of evolutionary processes take exponential time in sequence length, and propose a specific process, ‘regeneration processes’, which allows evolution to work on polynomial time scales. In this view, evolution can solve a problem efficiently if it has solved a similar problem already.

Endogenous adenosine-5’-triphosphate (ATP) can be regarded as a substrate and an allosteric modulator in cellular signal transduction. By analysing the properties of allosteric and substrate ATP-binding sites, Shaoyong Lu and colleagues found that the allosteric ATP-binding sites are less conserved than the substrate ATP-binding sites. Allosteric ATP molecules adopt both compact and extended conformations in the allosteric binding sites, while substrate ATP molecules adopt extended conformations in the substrate binding sites. The authors’ results provide an overall understanding of ATP allosteric functions responsible for regulation in biological systems.


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This week in PLOS Biology

In PLOS Biology this week, you can read about the notion of the “balance of nature“, female mate choice in fruit flies, and the role of heterochromatin in chromosome cohesion.


The “Balance of Nature”—Evolution of a Panchreston

Simberloff Flickr Paxson Woelber

Image credit: Flickr user Paxson Woelber

In this new perspective, Daniel Simberloff discusses the notion of a “balance of nature”. He takes us on a historical tour,  from the early Greeks – who believed balance was maintained by the gods (with aid from human and animal sacrifice) – via the interventionist God of the Middle Ages, to the delicate balance implied by Darwin, with constant emphasis on competition. Recent research, by contrast, recognises the term as somewhat defunct, and the more dynamic aspects of nature, punctuated with natural and human-induced disturbances, are emphasised. Yet the idea of a “balance” lives on in the popular imagination.


Sticky Chromosomes Get Stretched

The characteristic ‘X’ shape of chromosomes during cell division arises because the sister chromatids remain connected at the centromere, a region of the chromosome that contains long stretches of repetitive and physically compacted DNA called heterochromatin. A new study in PLOS Biology this week dissected the roles of heterochromatin and the centromeres in cohesion of sister chromatids. Raquel Oliveira, William Sullivan and colleagues tested fruit fly strains where stretches of heterochromatin were inappropriately inserted in chromosomal regions distant from the centromere. They found that this did cause increased cohesion (through greater loading of the clamp protein Cohesin), and therefore induced stretching of the chromosomes during cell division. This finding could be of some relevance to human cancers, where rearrangements involving heterochromatic regions often occur.


To Mate or not to Mate: How Female Flies Choose

Joseph Schinaman and Rui Sousa-Neves

Image credit: Joseph Schinaman and Rui Sousa-Neves

Although male courtship has been studied extensively in Drosophila, the neural basis for female receptivity remains unknown (see also this paper on a related topic). Joseph Moeller Schinaman, Rui Sousa-Neves and colleagues attempted to map some of the circuitry of female mate choice, exploiting a quirk of flies that have mutations in the gene encoding the transcription factor DATILÓGRAFO. The gene is named – in Portuguese – after the odd typist-like leg movements of the mutant flies, but the researchers also noticed that the female mutants had no interest in the males. They established that DATILÓGRAFO was required in three regions of the brain, including the olfactory lobe, for normal mating receptivity.

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This Week in PLOS Biology

In PLOS Biology this week, you can read about social learning in chimps, how the central and peripheral nervous systems stay separate, how the bird wrist evolved, synchronising circadian clocks and a protein essential to the TFIIH complex.

Social Learning of Tool Use in Wild Chimpanzees

KB leaf sponge moss - Cat Hobaiter (1)

Image credit: Cat Hobaiter

Chimpanzees are widely considered as the most ‘‘cultural’’ of all non-human animals, despite the lack of direct evidence for the spread of novel behaviours through social learning in the wild. In their new paper, Catherine Hobaiter, Thibaud Gruber and colleagues developed new dynamic social network analyses to test the spread of two behaviours in a group of wild chimps in Budongo Forest, Uganda. These behaviours were ‘moss sponging’ (using moss to produce a sponge) and ‘leaf sponge re-use’ (using a sponge discarded by another individual). They found strong evidence for social transmission of moss sponging among this group of chimps.

See moss-sponging behaviour in chimps in these videos:




Separating Nervous Systems – it’s All in the Wrapper

Kucenas Cody J. Smith

Image credit: Cody J. Smith

The points where axons cross between the central and peripheral nervous systems (CNS and PNS) are known as transition zones, but the mechanisms that establish and maintain this precise segregation are unknown. Cody Smith, Sarah Kucenas and colleagues used in vivo time-lapse imaging in zebrafish to identify a novel cell type responsible for stopping CNS-residing glia from entering the PNS. They call these cells ‘motor exit point glia’. These results identify an aspect of peripheral nerve composition that may be pertinent in human health and disease.


How Dinosaur Arms Turned into Bird Wings

Since their emergence from early dinosaurs, birds have reduced the number of bones in their wrist, but the origins and identity of those remaining are hard to trace. Wrists went from straight to bent and hyperflexible, allowing birds to fold their wings neatly against their bodies when not flying. In their new paper in PLOS Biology, João Francisco Botelho, Alexander Vargas and colleagues draw on the fields of embryology and paleontology to resolve this puzzle. Their study integrates paleontological and developmental data (including immunostaining of embryos across a wide range of species) and clarifies the relationship between each of the four ossifications in birds and those found in non-avian dinosaurs. Read more in the accompanying Synopsis.


Synchronise Watches!

Circadian molecular clocks are essential for maintaining daily cycles in animal behaviour and we have a good understanding of how these clocks work in individual pacemaker neurons. However, the accuracy of these individual clocks is meaningless unless they are synchronized with one another. Ben Collins, Justin Blau and colleagues discovered that in the fruit fly Drosophila melanogaster, circadian pacemaker neurons are regulated by two synchronizing signals (the neuropeptide PDF and glutamate) that are released at opposite times of day, generating rhythmic changes in intracellular cyclic AMP.


XPD – Different Jobs in Repair and Transcription


Image credit: pbio.1001954

The multiprotein complex TFIIH is crucially involved in two fundamental cellular processes—the transcription of genes by RNA polymerase II and the repair of UV-damaged DNA by a mechanism called nucleotide excision repair (NER). A helicase enzyme called XPD is part of the TFIIH complex, but it’s unclear which properties of XPD are required for which of TFIIH’s two cellular roles. Jochen Kuper, Caroline Kisker and colleagues found that in DNA repair, this protein works as an enzyme, but for transcription it is merely required as a structural protein to hold TFIIH together.



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Expanding the Homepages of Knowledge: the Topic Pages Collection in PLOS Computational Biology

Back in 2012 PLOS Computational Biology began an experiment that aimed to combine the prestige and rigorous peer review associated with publishing in a scientific journal and the dynamic nature and easily accessible language of Wikipedia. Over two years and six articles later, today sees the launch of PLOS Computational Biology’s Topic Pages Collection with the publication of the seventh Topic Page, “Multi-state Modeling of Biomolecules”.

Image Credit: PLOS

Image Credit: PLOS

Topic Pages aim to fill the gaps in current computational biology topics on Wikipedia. New submissions are drafted and undergo open peer review on a publically-viewable PLOS Wiki. Once a Topic Page is accepted, a static, citable version is published in PLOS Computational Biology and indexed in PubMed, while, under the guidance of one of the journal’s Topic Pages Editors, Daniel Mietchen, a living version of the document is uploaded to the corresponding Wikipedia article.

 “I was fascinated by the idea of spreading knowledge through Wikipedia and its cross linking capabilities, and thought that it was absolutely essential that experts in the field of computational biology and bioinformatics (as well as other fields) be more actively and widely involved in the process,”

says Topic Pages Editor Shoshana Wodak, who has overseen the review process for all seven articles.

“Having the Topics pages rigorously reviewed is a guarantee of quality, which Wikipedia contributions usually don’t have, and their concomitant publication in a respected journal offers authors the incentive to do the work. It also offered us the possibility of increasing the transparency and efficiency of the reviewing process, by allowing [and] encouraging reviewers to engage in a direct dialog with the authors.”

Melanie Stefan, an author on ‘ Multi-state modeling of biomolecules’, as well as the fifth Topic Page, ‘Cooperative Binding’, agrees:

“As scientists, it is our duty to pursue knowledge, but it is also our duty to share this knowledge with the world…I also like the fact that a Topic Page is less static than a traditional review article. Once it is published, it acquires a life of its own: People can add to it, amend it and alter it to reflect the latest developments in the field. This is a tremendously exciting process.”

For those considering a pre-submission inquiry to the collection, Spencer Bliven, Topic Page author and host of the PLOS Wiki has these words of advice:

“Learn to love the wiki environment. While the syntax can be a bit difficult at first, collaborating on a wiki page is much easier than trying to shuffle Word documents back and forth. I would also caution authors to avoid viewing the paper possessively, but to consider it a community project from the start. After publication, your Topic Page will most likely receive significant edits. This is a good thing, but it requires being a bit humble about your own writing skills.”

Finally, Topic Pages Editor Daniel Mietchen offered his thoughts on possible future paths the initiative could take:

“In principle, [the] direction [I would like to see] would be “higher, further, faster”: higher community engagement (e.g. through more Topic Pages, or more functionality, e.g. a prominent “Edit on Wikipedia” button, or links to Wikipedia from all PLOS abstracts), further journals (both within and beyond PLOS), and faster processes – even ignoring for a moment the problem of finding reviewers (which affects all journals, not just at PLOS), the publication process at PLOS (which is reasonably fast by industry standards) is very slow from a wiki (which means “quick”) perspective.

Another important direction to aim at would be to try to come closer to the workflows of researchers by publishing media files or data-related notes as Topic Pages tailored to Wikimedia Commons or Wikidata. The issue images at PLOS journals already go in this direction…”

With two more Topic Pages currently in peer review, the project is still looking for additional proposals; take a look at the author guidelines and get in touch at ploscompbiol[at]plos.org if you would like to be involved.

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This week in PLOS Biology

In PLOS Biology this week, you can read about a new mechanism for incomplete puberty and infertility, and the control of embryonic tissue separation by ephrin/Eph pairs.


Rab3α Scaffolding and the Control of Puberty

de Roux

Image credit: pbio.1001952

Brooke Tata, Lukas Huijbregts, Nicolas de Roux and colleagues have described a new genetic syndrome, observed in three brothers, involving a complex set of symptoms such as incomplete puberty and non-autoimmune diabetes. Genetic analyses of the family revealed that they suffered from deletion of 15 nucelotides from the DMXL2 gene. This gene encodes Rabconnectin-3α, a protein involved in scaffolding the regulators of small GTPase Rab3α intracellular trafficking (see also this recent PLOS Biology paper).  The authors found involvement for the protein in both GnRH secretion in the brain and insulin secretion in the pancreas – providing clues as to how decreased DMXL2 could be responsible for incomplete puberty and diabetes in this syndrome. Read more in the accompanying synopsis.


Embryonic Tissue Separation Depends on Specific Combinations of Ligand and Receptor Pairs

Image credit: pbio.1001952

Image credit: pbio.1001955

How embryonic tissues separate from each other to shape the developing organism is a fundamental question in developmental biology. In vertebrates, this process relies on local repulsive reactions specifically generated at contacts between cells of different types. We believe from recent evidence that the interaction is between surface proteins called ephrins and Eph receptors on the opposing groups of cells. However it’s been unclear how this repulsion is restricted to the tissue boundary and doesn’t take place within the tissues themselves. A new paper by Nazanin Rohani, Francois Fagotto and colleagues used a Xenopus model, and found that the concentration and binding affinities of specific ligand–receptor pairs largely explain the specificity of this key developmental program. Read more in the accompanying synopsis.


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This week in PLOS Biology

In PLOS Biology this week, you can read about plant extinction at the end of the Cretaceous, human tolerance to HIV and control of plant responses to hypoxia.


The End-Cretaceous Impact Winter Killed Off Slow-Growing Plants

Blonder striking imageFINAL

Image credit: Benjamin Blonder

Sixty-six million years ago the Chicxulub bolide impacted the Earth, marking the Cretaceous–Paleogene boundary. We all know about the association between this event and the extinction of the non-avian dinosaurs, but what about the plants? In a new research paper, Benjamin Blonder, Brian Enquist and colleagues have addressed the survival strategies of the plants (half of which went extinct at this time). Using >1000 fossil leaves, spanning a 2-million-year interval, they used leaf minor vein density and leaf mass per area as proxies for carbon assimilation and carbon investment. Their results supported the hypothesis that an impact winter would have selected against slow-growing evergreen species, a possible cause of the modern dominance of high-productivity deciduous angiosperm forests. Read more in the accompanying synopsis.

Human tolerance against HIV

Flickr NIAID

Image credit: NIAID

Roland Regoes and colleagues, in their new research article, have addressed the strategies of ‘tolerance’ and ‘resistance’ in humans, in the context of HIV. They asked used the Swiss HIV Cohort Study to ask if humans vary in their tolerance to HIV, and whether there is a genetic basis for tolerance. CD4+ T-cell increase was used as a proxy for tolerance, and viral load decline for resistance in a well-studied cohort of infected individuals. They found that tolerance and resistance had independent genetic origins and also that individuals who are heterozygous for the HLA-b immunity gene are more tolerant. Younger people were more tolerant to HIV infection. These findings add to our understanding of how hosts tolerate infections and could open new avenues for treating infections.

DNA Binding Protein Controls Plant Transcription when Oxygen is at a Premium

Plants need to be able to maintain respiration during hypoxic events, such as waterlogging of their roots during flooding. The main regulator of the response to these events has been identified as RAP2.12, which is produced under normal conditions, but then degraded. In hypoxic conditions this degradation stops. Now Beatrice Giuntoli, Pierdomenico Perata and colleagues have addressed the flipside of this: what prevents an inappropriately excessive hypoxic response? They found that the transcription factor HRA1 is needed, and creates a negative feedback loop with RAP2.12. The authors argue that this could have implications for breeding flood-resistant crops.

Category: Biology, Climate, Disease, Ecology, Environment, Evolution, Genetics, Infectious disease, Molecular biology, Plant biology, PLOS Biology, Research | Leave a comment

Modelling cell interaction, deciding on optimal paths and tracking tumour evolution: The PLOS Comp Biol August Issue

Here is our selection of PLOS Computational Biology highlights for August.

Using a model of collective learning to understand how individual learning affects consensus group decisions. Image credit: Albert Kao

During the embryonic development of multicellular organisms, millions of cells cooperatively build structured tissues, organs and whole organisms, a process called morphogenesis. It is still not entirely understood how the behaviour of so many cells is coordinated to produce complex structures. In response to this question, Roeland Merks et al. propose a new computational model that shows a simple form of mechanical cell-cell communication suffices for reproducing the formation of blood vessel-like structures in cell cultures. These findings advance our understanding of biomechanical signalling during morphogenesis, and introduce a new set of computational tools for modelling mechanical interactions between cells. Combining the present mechanical model with aspects of previously proposed mechanical and chemical models may lead to a more complete understanding of in vitro angiogenesis.

Human behaviour has long been recognised to display a hierarchical structure, in that we organise tasks into subtasks, which fit into extended goal-directed activities. Arranging actions hierarchically has well established benefits, allowing behaviours to be represented efficiently by the brain, and allowing solutions to new tasks to be discovered easily. But how do we learn to subdivide our goals in this way?  Matthew M. Botninick et al. have developed a mathematical account for how we differentiate between hierarchies and choose the optimal path. The authors then presented results from four behavioural experiments, suggesting that human learners spontaneously discover optimal action hierarchies.

Errors in sample annotation or labelling often occur in large-scale genetic or genomic studies and are difficult to avoid completely during data generation and management. For integrative genomic studies, it is critical to identify and correct these errors. On that basis, Jun Zhu et al. developed a computational approach, Multi-Omics Data Matcher (MODMatcher), to identify and correct sample labelling errors in multiple types of molecular data, which can be used in further integrative analysis.

Often, accurately characterizing a tumour requires analysing multiple samples from the same patient. To address this need, Li Ding et al. present SciClone, a computational method that identifies the number and genetic composition of subclones by analysing the variant somatic mutations. They used it to detect subclones in leukemia and breast cancer samples that, though present at disease onset, are not evident from a single primary tumour sample. By doing so, they tracked tumour evolution and identified the spatial origins of cells resisting therapy.

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This week in PLOS Biology

In PLOS Biology this week you can read about citizen science oceanography, de-differentiation and drug resistance in cancer, fine-tuning of DNA repair and action potential initiation in cortical neurons.

Crowdsourcing the Collection of Oceanographic Data


Image credit: Rachelle Lauro

In a new Community Page, Frederico Lauro and colleagues argue that the vast size of the oceans and the costs of research inhibit the gathering of oceanographic data. They propose using ‘Citizen Scientists’ to improve spatial and temporal density of observations - i.e. by fitting simple, low-cost instrumentation to sailing vessels. Examples of the types of data that could be collected include biological samples, surface weather conditions and debris sightings.


Striking the Balance in DNA Repair

Du thumb2Double-strand breaks in DNA strands can have catastrophic consequences if left unrepaired. The repair process requires careful resection of one strand, maintaining a delicate balance of nuclease activities so as to achieve accurate repair without erosion of the end of the DNA strand. New research by Jia-Min Zhang, Li-Lin Du and colleagues identified a key protein – Pxd1 in the fission yeast Schizosaccharomyces pombe which helps coordinate the multi-enzyme activities taking place during DNA repair. This protein minimizes the potentially deleterious consequences of the process by inhibiting one nuclease while activating another.


Blocking Multi-Drug Resistance in Tumours

There are often two key features of the most dangerous cancerous tumours – they tend to be both de-differentiated (i.e. have regressed to an earlier developmental stage) and multi-drug resistant. In their research article published this week in PLOS Biology, Catherine Del Vecchio, Piyush Gupta and colleagues asked how these two things might be linked. They found that PERK-Nrf2 signalling was involved with therapy resistance in poorly differentiated breast cancer cells. Nrf2 is activated when the cancer cells de-differentiate. Their results suggest a novel therapeutic role for drugs that block this signalling pathway, which when coupled with chemotherapy might improve the responsiveness of resistant tumours to treatment.


Sodium Channels Bring Variety to Inhibitory Interneurons

SExcitatory neurons in the cortex of the brain are regulated by inhibitory neurons, but it appears that not all inhibitory neurons are the same.  Tun Li, Yousheng Shu and colleagues investigated two different populations of neurons (parvalbumin- and somatostatin-expressing) in the cerebral cortex. They found that they had varying electrical properties, caused by the presence of different types of sodium channels in their membranes.

Category: Biology, Cancer, Cell signalling, Climate, Community, Disease, Ecology, Environment, Molecular biology, Neuroscience, PLOS Biology, Research | Leave a comment

This week in PLOS Biology

In PLOS Biology this week, you can read about the evolution of symbiosis, the role of Epstein-Barr virus in disease and the neural correlates of social status in macaques.


Epstein-Barr Virus: a Smoking Gun? 

Sugden thumb

Image credit pbio.1001939

In a new Essay, Bill Sugden examines the evidence that links this ubiquitous human pathogen to cancer and multiple sclerosisEpstein-Barr virus is notorious for causing multiple kinds of cancer. It has also been increasingly linked to multiple sclerosis. What evidence now supports or can be sought potentially to strengthen this linkage?




 Neural Circuitry of Social Hierarchy

Noonan pic

Image credit pbio.1001940

In their new research paper, MaryAnn Noonan, Matthew Rushworth and colleagues tease apart the neural correlates of social status. This neuroimaging study reveals that individual variation in brain circuits in structures below the cerebral cortex of rhesus macaques is associated with experience at different ends of the social hierarchy. Read the accompanying Primer.


Symbiosis Plasmids Bring Their Own Mutagen to the Party 

Image credit pbio.1001942

Image credit pbio.1000280

The symbiotic bacteria that form nitrogen-fixing nodules in leguminous plants started off as free-living soil bacteria, but how do they make the transition to cohabiting so intimately with plants? Philippe Remigi, Catherine Masson-Boivin and colleagues use an experimental evolution approach to show that stress-responsive error-prone DNA polymerase genes ease the evolution of the soil bacterium Ralstonia solanacearum into a legume endosymbiont by accelerating adaptation of the bacterial genome to its new plant host. Read more in the accompanying Synopsis.

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How Much of Your Genome Is Functional?

On the 24th of July, 2014 PLOS Genetics published an article entitled: “8.2% of the Human Genome Is Constrained: Variation in Rates of Turnover across Functional Element Classes in the Human Lineage”. Two weeks later the article had been viewed 12,307 times, it already had one citation, and had been shared on social media 436 times. This means that, on average, 36 people had been viewing the article online every hour.

Unlike many other papers that might attract this level of interest through traditional press coverage, this article was primarily picked up by social media. This flurry of activity was in part driven by coverage in ifls, which has been shared on Facebook 12,200 times. However, it wasn’t just a social media piece, it has also been featured in Nature, Sci-news, the Guardian, the French Tribune, and the International Business Times.

It is pleasing to see that the article has received lots of views of course. I think article metrics like views and shares on social media (such as twitter and facebook) are important metrics because they are nearly instantaneous measures of impact (compared to citations) and they imply there is a public interest in the research. I believe science communication is important, particularly for publicly funded research such as this. The open access publishing at PLOS helps promote science communication.” – Chris Rands (author)

What made this article such a hit? The paper explores how much of the human genome can be considered ‘functional’. While scientists were able to successfully sequence the human genome over a decade ago, it has been unclear how much of the genome is doing something useful. In 2012 some members of the ENCODE consortium suggested that as much as 80% of the genome might be considered functional. Chris Rands and colleagues argue that this might be as little as 8.2%; ten times less than the ENCODE estimate.


The researchers used a computational approach to compare the whole DNA sequences of various mammals, including human, horse, bush baby, panda, and mouse. Image Credit: George Lu CC BY Flickr

Natural selection is expected to preserve important DNA, removing insertion and deletion (indel) mutations from these genomic regions. In order to find the sequences with evidence of functionality, Chris Rands and colleagues identified areas of the human genome that have been unusually evolutionarily stable with respect to these indel mutations. The researchers used a computational approach to compare the complete DNA sequences of various mammals, including human, horse, bush baby, panda, and mouse.

Using this method they estimate that between 7.1-9.2% of the human genome can be considered ‘functional’. If this is the case, then the majority of the human genome can experience mutations without affecting fitness. Coding exons, bound motifs and DNase1 footprints make up around 9% of the human genome. These are areas that we would expect to be considered functional, based on what we know about their roles within the genome. While these areas will not encompass all of the functional sections and there may be sequences outside of these sections that are functional, it could be taken as an indication that the estimate that Chris Rands and colleagues suggest is in the right ballpark.


Mouse as a model organism may miss many subtle aspects of human noncoding biology. Image Credit: Duncan Hull CC BY Flickr

As well as an indication of DNA functionality Chris Rands tells PLOS Genetics that We find that only 2.2% the human genome is ‘functional’ and shared with mouse too; the remaining 6% has gained ‘functionality’ in the human lineage since humans diverged from their common ancestor with mice 80 million years ago.”

 Their findings could therefore provide a more quantitative basis for assessing the relevance of model organisms to specific questions of human biology.

“Although the main media message about the paper has been about the proportion of the human genome that is ‘functional’, the main novel research contribution is about the turnover of ‘functional’ sequence as it is lost and gained over time. Given we estimate that approximately 3 times as much sequence is ‘functional’ in the human genome as is ‘functional’ and shared with mouse, this implies that mouse as a model organism may miss many subtle aspects of human noncoding biology, although the real practical implications of this tentative conclusion remain to be fully explored.”


Category: Biology, Evolution, Genetics, Genomics, Metrics, Open access, PLOS Genetics, Publishing, Research | 2 Comments