Biology subjects

Pearson, J.

Publications and source records attributed to Pearson, J..

13 recordsLinked to original sources

bioRxiv2018

Late Pleistocene human genome suggests a local origin for the first farmers of central Anatolia

Anatolia was home to some of the earliest farming communities. It has been long debated whether a migration of farming groups introduced agriculture to central Anatolia. Here, we report the first genome-wide data from a 15,000-year-old Anatolian hunter-gatherer and from seven Anatolian and Levantine early farmers. We find high genetic continuity ([~]80-90%) between the hunter-gatherer and early farmers of Anatolia and detect two distinct incoming ancestries: an early Iranian/Caucasus related one and a later one linked to the ancient Levant. Finally, we observe a genetic link between southern Europe and the Near East predating 15,000 years ago that extends to central Europe during the post-last-glacial maximum period. Our results suggest a limited role of human migration in the emergence of agriculture in central Anatolia.

genetics↗

bioRxiv2018

Genome Scale Epigenetic Profiling Reveals Five Distinct Subtypes of Colorectal Cancer

BACKGROUNDColorectal cancer is an epigenetically heterogeneous disease, however the extent and spectrum of the CpG Island Methylator Phenotype (CIMP) is not clear.\n\nRESULTSAn unselected cohort of 216 colorectal cancers clustered into five clinically and molecularly distinct subgroups using Illumina 450K DNA methylation arrays. CIMP-High cancers were most frequent in the proximal colons of female patients. These dichotomised into CIMP-Hl and CIMP-H2 based on methylation profile which was supported by over representation of BRAF (74%, P<0.0001) or KRAS (55%, P<0.0001) mutation, respectively. Congruent with increasing methylation, there was a stepwise increase in patient age from 62 years in the CI MP-Negative subgroup to 75 years in the CIMP-Hl subgroup (P<0.0001). There was a striking association between PRC2-marked loci and those subjected to significant gene body methylation in CIMP-type cancers (P<1.6xl078). We identified oncogenes susceptible to gene body methylation and Wnt pathway antagonists resistant to gene body methylation. CIMP cluster specific mutations were observed for genes involved in chromatin remodelling, such as in the SWI/SNF and NuRD complexes, suggesting synthetic lethality.\n\nCONCLUSIONThere are five clinically and molecularly distinct subgroups of colorectal cancer based on genome wide epigenetic profiling. These analyses highlighted an unidentified role for gene body methylation in progression of serrated neoplasia. Subgroup-specific mutation of distinct epigenetic regulator genes revealed potentially druggable vulnerabilities for these cancers, which may provide novel precision medicine approaches.

genomics↗

bioRxiv2018

Bayesian Nonparametric Models Characterize Instantaneous Strategies in a Competitive Dynamic Game

Previous approaches to investigating strategic social interaction in game theory have predominantly used games with clearly-defined turns and limited choices. However, most real-world social behaviors involve dynamic, coevolving decisions by interacting agents, which pose challenges for creating tractable models of behavior. Here, using a competitive game in which human participants control the dynamics of an on-screen avatar against either another human or a computer opponent, we show that it is possible to quantify the dynamic coupling between agents using nonparametric models. We use Gaussian Processes to model the joint distributions of players' actions and identities (human or computer) as a function of game state. Borrowing from a reinforcement learning framework, we successfully approximated both the policy and the value functions used by each human player in this competitive context. This approach offers a natural set of metrics for facilitating analysis at multiple timescales and suggests new classes of tractable paradigms for assessing human behavior.

neuroscience↗

bioRxiv2018

Salmonella effectors SseK1 and SseK3 target death domain proteins in the TNF and TRAIL signaling pathways

Strains of Salmonella utilise two distinct type three secretion systems to deliver effector proteins directly into host cells. The Salmonella effectors SseK1 and SseK3 are arginine glycosyltransferases that modify mammalian death domain containing proteins with N-acetyl glucosamine (GlcNAc) when overexpressed ectopically or as recombinant protein fusions. Here, we combined Arg-GlcNAc glycopeptide immunoprecipitation and mass spectrometry to identify host proteins GlcNAcylated by endogenous levels of SseK1 and SseK3 during Salmonella infection. We observed that SseK1 modified the mammalian signaling protein TRADD, but not FADD as previously reported. Overexpression of SseK1 greatly broadened substrate specificity, while ectopic co-expression of SseK1 and TRADD increased the range of modified arginine residues within the death domain of TRADD. In contrast, endogenous levels of SseK3 resulted in modification of the death domains of receptors of the mammalian TNF superfamily, TNFR1 and TRAILR, at residues Arg376 and Arg293 respectively. Structural studies on SseK3 showed that the enzyme displays a classic GT-A glycosyltransferase fold and binds UDP-GlcNAc in a narrow and deep cleft with the GlcNAc facing the surface. Together our data suggests that Salmonellae carrying sseK1 and sseK3 employ the glycosyltransferase effectors to antagonise different components of death receptor signaling.

microbiology↗

bioRxiv2018

Wearable Eye-tracking for Research: Automated dynamic gaze mapping and accuracy/precision comparisons across devices

Wearable eye-trackers offer exciting advantages over screen-based systems, but their use in research settings has been hindered by significant analytic challenges as well as a lack of published performance measures among competing devices on the market. In this article, we address both of these limitations. We describe (and make freely available) an automated analysis pipeline for mapping gaze data from an egocentric coordinate system (i.e. the wearable eye-tracker) to a fixed reference coordinate system (i.e. a target stimulus in the environment). This pipeline allows researchers to study aggregate viewing behavior on a 2D planar target stimulus without restricting the mobility of participants. We also designed a task to directly compare calibration accuracy and precision across 3 popular models of wearable eye-trackers: Pupil Labs 120Hz Binocular glasses, SMI ETG 2 glasses, and the Tobii Pro Glasses 2. Our task encompassed multiple viewing conditions selected to approximate distances and gaze angles typical for short- to mid-range viewing experiments. This work will promote and facilitate the use of wearable eye-trackers for research in naturalistic viewing experiments.

neuroscience↗

bioRxiv2018

Improved prediction of chronological age from DNA methylation limits it as a biomarker of ageing

DNA methylation is associated with age. The deviation of age predicted from DNA methylation from actual age has been proposed as a biomarker for ageing. However, a better prediction of chronological age implies less opportunity for biological age. Here we used 13,661 samples (from blood and saliva) in the age range of 2 to 104 years from 14 cohorts measured on Illumina HumanMethylation450/EPIC arrays to perform prediction analyses. We show that increasing the sample size achieves a smaller prediction error and higher correlations in test datasets. We demonstrate that smaller prediction errors provide a limit to how much variation in biological ageing can be captured by methylation and provide evidence that age predictors from small samples are prone to confounding by cell composition. Our predictor shows a similar or better performance in non-blood tissues including saliva, endometrium, breast, liver, adipose and muscle, compared with Horvaths across-tissue age predictor.

bioinformatics↗

bioRxiv2018

Thought Control Failure: Sensory Determinants and Functional Effects

The ability to control ones thoughts is important for mental wellbeing, attention, focus, future planning and ideation. While there is a long history of research into thought control, the inherent subjectivity of thoughts has made objective investigation, and thus mechanistic understanding difficult. Here, we report a novel method to empirically investigate thought control success and failure by objectively measuring the sensory strength of visual thoughts. We use the perceptual illusion binocular rivalry to assess emergent images in mind during two common thought control strategies: thought suppression and thought substitution. Thought suppression was ineffective, suppressed thoughts primed subsequent rivalry dominance at the same level as intentionally imagined thoughts. This priming effect was disrupted by concurrent uniform luminance and changes in retinotopic location, suggesting early visual representations/traces. While individuals showed some metacognition of thought suppression, strikingly, the perceptual effects remained even when thoughts were reported as successfully suppressed, indicating these thoughts may exist outside of reportable awareness. In contrast, thought substitution was more effective in controlling the perceptual effects and showed good metacognition. A thought control index predicted greater levels of trait mindfulness, while high levels of anxiety and schizotypy were related to poor thought control. Overall, our findings offer a novel method to track thoughts before and after they emerge into awareness and suggest that non-reportable and involuntary thoughts form visual representations pivotal to thought control failure.

neuroscience↗

bioRxiv2018

Profiling copy number alterations in cell-free tumour DNA using a single-reference

BackgroundThe accurate detection of copy number alterations from the analysis of circulating cell free tumour DNA (ctDNA) in blood is essential to realising the potential of liquid biopsies. However, currently available approaches require a large number of plasma samples from healthy individuals, sequenced using the same platform and protocols to act as a reference panel. Obtaining this reference panel can be challenging, prohibitively expensive and limits the ability to migrate to improved sequencing platforms and improved protocols.\n\nMethodsWe developed qCNV and sCNA-seq, two distinct tools that together provide a new approach for profiling somatic copy number alterations (sCNA) through the analysis of cell free DNA (cfDNA) without a reference panel. Our approach was designed to identify sCNA from cfDNA through the analysis of a single plasma sample and a matched normal DNA sample -both of which can be obtained from the same blood draw. qCNV is an efficient method for extracting read-depth from BAM files and sCNA-seq is a method that uses a probabilistic model of read depth to infer the copy number segmentation of the tumour. We compared the results from our pipeline to the established copy number profile of a cell-line, as well as the results from the plasma-Seq analysis of cfDNA-like mixtures and real, clinical data-sets.\n\nResultsWith a single, unmatched, germline reference sample, our pipeline recapitulated the known copy number profile of a cell-line and demonstrated similar results to those obtained from plasma-Seq. With less than 1X genome coverage, our approach identified clinically relevant sCNA in samples with as little as 20 % tumour DNA. When applied to plasma samples from cancer patients, our pipeline identified clinically significant mutations.\n\nConclusionsThese results show it is possible to identify therapeutically-relevant copy number mutations from plasma samples without the need to generate a reference panel from a large number of healthy individuals. Together with the range of sequencing platforms supported by our qCNV+sCNA-Seq pipeline, as well as the Galaxy implementation of this solution, this pipeline makes cfDNA profiling more accessible and makes it easier to identify sCNA from the plasma of cancer patients.

bioinformatics↗

bioRxiv2018

The Functional effects of voluntary and involuntary visual phantom color on conscious awareness

The constructive nature of vision is perhaps most evident during hallucinations, mental imagery, synesthesia, perceptual filling-in, and many illusions in which conscious visual experience does not overtly correspond to retinal stimulation: phantom vision. However, the relationship between voluntary and involuntary phantom vision remains largely unknown. Here, we investigated two forms of visual phantom color, neon phantom color spreading and voluntary color mental imagery and their effect on subsequent binocular rivalry perception. Passively viewing neon phantom color induced time sensitive, suppressive effects on spatially non-overlapping subsequent binocular rivalry. These effects could be attenuated by rotating the color-inducers, or like color imagery, by concurrent uniform luminance stimulation. The degree of neon color induced rivalry suppression predicted the degree of voluntary color imagery facilitation, both on subsequent rivalry perception. Further, these suppressive and facilitative effects were additive when experienced successively. Our results suggest potential sensory mechanistic commonalities between voluntary and involuntary phantom vision.

neuroscience↗

bioRxiv2018

Trans-ancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest GWAS to date of DSM - IV diagnosed AD. Genome - wide data on 14,904 individuals with AD and 37,944 controls from 28 case / control and family - based studies were meta - analyzed, stratified by genetic ancestry (European, N = 46,568; African; N = 6,280). Independent, genome - wide significant effects of different ADH1B variants were identified in European (rs1229984; p = 9.8E - 13) and African ancestries (rs2066702; p = 2.2E - 9). Significant genetic correlations were observed with schizophrenia, ADHD, depression, and use of cigarettes and cannabis. There was only modest genetic correlation with alcohol consumption and inconsistent associations with problem drinking. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and non - pathological drinking behaviors.

genetics↗

bioRxiv2017

Harmonic brain modes: a unifying framework for linking space and time in brain dynamics

A fundamental characteristic of spontaneous brain activity is coherent oscillations covering a wide range of frequencies. Interestingly, these temporal oscillations are highly correlated among spatially distributed cortical areas forming structured correlation patterns known as the resting state networks, although the brain is never truly at rest. Here, we introduce the concept of \"harmonic brain modes\" - fundamental building blocks of complex spatiotemporal patterns of neural activity. We define these elementary harmonic brain modes as harmonic modes of structural connectivity; i.e. connectome harmonics, yielding fully synchronous neural activity patterns with different frequency oscillations emerging on and constrained by the particular structure of the brain. Hence, this particular definition implicitly links the hitherto poorly understood dimensions of space and time in brain dynamics and its underlying anatomy. Further we show how harmonic brain modes can explain the relationship between neurophysiological, temporal and network-level changes in the brain across different mental states; (wakefulness, sleep, anaesthesia, psychedelic). Notably, when decoded as activation of connectome harmonics, spatial and temporal characteristics of neural activity naturally emerge from the interplay between excitation and inhibition and this critical relation fits the spatial, temporal and neurophysiological changes associated with different mental states. Thus, the introduced framework of harmonic brain modes not only establishes a relation between the spatial structure of correlation patterns and temporal oscillations (linking space and time in brain dynamics), but also enables a new dimension of tools for understanding fundamental principles underlying brain dynamics in different states of consciousness.

neuroscience↗

bioRxiv2016

Cortical excitability controls the strength of mental imagery

Mental imagery provides an essential simulation tool for remembering the past and planning the future, with its strength affecting both cognition and mental health. Research suggests that neural activity spanning prefrontal, parietal, temporal, and visual areas supports the generation of mental images. Exactly how this network controls the strength of visual imagery remains unknown. Here, brain imaging and transcranial magnetic phosphene data show that lower resting activity and excitability levels in early visual cortex (V1-V3) predict stronger sensory imagery. Electrically decreasing visual cortex excitability using tDCS increases imagery strength, demonstrating a causative role of visual cortex excitability in controlling visual imagery. These data suggest a neurophysiological mechanism of cortical excitability involved in controlling the strength of mental images.

neuroscience↗

bioRxiv2016

Decoding the nonconscious dynamics of thought generation

Much of economics, psychology and neuroscience have focused on thought dynamics and how they control our behavior, from individual moral choices to the irrationality of market dynamics. However, how much of our thoughts we actually control when we feel we make deliberate choices remains unknown. Here we show that the content of thoughts can be decoded from activity patterns as early as 11 seconds before individuals report having formed the volitional thought. Participants freely chose which of two differently oriented and colored gratings to think about. Using functional magnetic resonance imaging (fMRI) and pattern classification methods, we consistently classified the contents of thoughts using activity patterns recorded before and after the thought was reported. We found that activity patterns were predictive as far as 11 seconds before the conscious thought, in visual, frontal and subcortical areas. These predictive patterns contained similar information to the responses evoked by unattended perceptual gratings and were evident in individual visual areas. Interestingly, neural information present before the decision was associated with the vividness of future thoughts, suggesting that preceding nonconscious sensory-like representations can impact the content and strength of future conscious thoughts. Our results suggest that thoughts and their strength can be biased by prior spontaneous nonconscious perception-like representations, advancing theories of free will and models of intrusive and repetitive thought production.

neuroscience↗