A reference map of the human protein interactome, bioRxiv, 2019-04-11
AbstractGlobal insights into cellular organization and function require comprehensive understanding of interactome networks. Similar to how a reference genome sequence revolutionized human genetics, a reference map of the human interactome network is critical to fully understand genotype-phenotype relationships. Here we present the first human “all-by-all” binary reference interactome map, or “HuRI”. With ~53,000 high-quality protein-protein interactions (PPIs), HuRI is approximately four times larger than the information curated from small-scale studies available in the literature. Integrating HuRI with genome, transcriptome and proteome data enables the study of cellular function within essentially any physiological or pathological cellular context. We demonstrate the use of HuRI in identifying specific subcellular roles of PPIs and protein function modulation via splicing during brain development. Inferred tissue-specific networks reveal general principles for the formation of cellular context-specific functions and elucidate potential molecular mechanisms underlying tissue-specific phenotypes of Mendelian diseases. HuRI thus represents an unprecedented, systematic reference linking genomic variation to phenotypic outcomes.
biorxiv systems-biology 200-500-users 2019In the Body’s Eye The Computational Anatomy of Interoceptive Inference, bioRxiv, 2019-04-10
AbstractA growing body of evidence highlights the intricate linkage of exteroceptive perception to the rhythmic activity of the visceral body. In parallel, interoceptive inference theories of emotion and self-consciousness are on the rise in cognitive science. However, thus far no formal theory has emerged to integrate these twin domains; instead most extant work is conceptual in nature. Here, we introduce a formal model of cardiac active inference, which explains how ascending cardiac signals entrain exteroceptive sensory perception and confidence. Through simulated psychophysics, we reproduce the defensive startle reflex and commonly reported effects linking the cardiac cycle to fear perception. We further show that simulated ‘interoceptive lesions’ blunt fear expectations, induce psychosomatic hallucinations, and exacerbate metacognitive biases. Through synthetic heart-rate variability analyses, we illustrate how the balance of arousal-priors and visceral prediction errors produces idiosyncratic patterns of physiological reactivity. Our model thus offers the possibility to computationally phenotype disordered brain-body interaction.
biorxiv neuroscience 200-500-users 2019Whole genome phylogenies reflect long-tailed distributions of recombination rates in many bacterial species, bioRxiv, 2019-04-08
AbstractAlthough homologous recombination is accepted to be common in bacteria, so far it has been challenging to accurately quantify its impact on genome evolution within bacterial species. We here introduce methods that use the statistics of single-nucleotide polymorphism (SNP) splits in the core genome alignment of a set of strains to show that, for many bacterial species, recombination dominates genome evolution. Each genomic locus has been overwritten so many times by recombination that it is impossible to reconstruct the clonal phylogeny and, instead of a consensus phylogeny, the phylogeny typically changes many thousands of times along the core genome alignment.We also show how SNP splits can be used to quantify the relative rates with which different subsets of strains have recombined in the past. We find that virtually every strain has a unique pattern of recombination frequencies with other strains and that the relative rates with which different subsets of strains share SNPs follow long-tailed distributions. Our findings show that bacterial populations are neither clonal nor freely recombining, but structured such that recombination rates between different lineages vary along a continuum spanning several orders of magnitude, with a unique pattern of rates for each lineage. Thus, rather than reflecting clonal ancestry, whole genome phylogenies reflect these long-tailed distributions of recombination rates.
biorxiv evolutionary-biology 200-500-users 2019Genetic Associations with Mathematics Tracking and Persistence in Secondary School, bioRxiv, 2019-04-05
Maximizing the flow of students through the science, technology, engineering, and math (STEM) pipeline is important to promoting human capital development and reducing economic inequality1. A critical juncture in the STEM pipeline is the highly-cumulative sequence of secondary school math courses2–5. Students from disadvantaged schools are less likely to complete advanced math courses, but debate continues about why6,7. Here, we address this question using student polygenic scores, which are DNA-based indicators of propensity to succeed in education8. We integrated genetic and official school transcript data from over 3,000 European-ancestry students from U.S. high schools. We used polygenic scores as a molecular tracer to understand how the flow of students through the high school math pipeline differs in socioeconomically advantaged versus disadvantaged schools. Students with higher education polygenic scores were tracked to more advanced math already at the beginning of high school and persisted in math for more years. Molecular tracer analyses revealed that the dynamics of the math pipeline differed by school advantage. Compared to disadvantaged schools, advantaged schools tracked more students with high polygenic scores into advanced math classes at the start of high school, and they buffered students with low polygenic scores from dropping out of math. Across all schools, even students with exceptional polygenic scores (top 2%) were unlikely to take the most advanced math classes, suggesting substantial room for improvement in the development of potential STEM talent. These results link new molecular genetic discoveries to a common target of educational-policy reforms.
biorxiv genetics 200-500-users 2019Breaking barriers The effect of protected characteristics and their intersectionality on career transition in academics, bioRxiv, 2019-04-02
Lay summaryIn the past decade the scientific community has been trying to tackle the historical underrepresentation of women in science and the fact that gender can constitute a barrier to career success. However, other characteristics, such as being of an ethnic minority or coming from an under-privileged background, have received less attention. In this study we find that ethnicity and socioeconomic status impact detrimentally on career progression in early career scientists, despite the fact that gender is more likely to be reported as a barrier. Our data suggest we need to widen the discussion regarding diversity and equality in science to incorporate potential barriers to career success in addition to gender.AbstractThe academic disciplines of Science Technology Engineering and Mathematics (STEM) have long suffered from a lack of diversity. While in recent years there has been some progress in addressing the underrepresentation of women in STEM subjects, other protected characteristics have received less attention. In this study, we survey early career scientists in the fields of ecology, evolutionary biology, behaviour, and related disciplines. We (i) quantitatively examine the effect of protected characteristics and their intersectionality on career transition, and (ii) provide practical suggestions, based on the qualitative responses of those surveyed, for overcoming some of the barriers we identified. We found that socioeconomic background and ethnicity impacted negatively on the quantitative measures of career progression we examined. Respondents that were female, LGBT, and from a lower socioeconomic background were more likely to report having faced a barrier, and the most frequent barrier named was related to gender. Our results suggest that respondents may have felt more confident discussing the experiences they have had related to their gender, potentially because there is now widespread discourse on this subject. However, respondents were less likely to discuss barriers they have faced in relation to ethnicity and socioeconomic status, despite the fact that the data indicates these are more detrimental to career progression. This may reflect the fact that these characteristics have received less attention, and are therefore deemed more sensitive. We hope that this study will stimulate wider discussion, and help to inform strategies to address the underrepresentation of minority groups in STEM subjects.
biorxiv scientific-communication-and-education 200-500-users 2019