Precision Medicine Advancements Using Whole Genome Sequencing, Noninvasive Whole Body Imaging, and Functional Diagnostics, bioRxiv, 2018-12-18

ABSTRACTWe report the results of a three-year precision medicine study that enrolled 1190 presumed healthy participants at a single research clinic. To enable a better assessment of disease risk and improve diagnosis, a precision health platform that integrates non-invasive functional measurements and clinical tests combined with whole genome sequencing (WGS) was developed. The platform included WGS, comprehensive quantitative non-contrast whole body (WB) and brain magnetic resonance imagingangiography (MRIMRA), computed tomography (CT) coronary artery calcium scoring, electrocardiogram, echocardiogram, continuous cardiac monitoring, clinical laboratory tests, and metabolomics. In our cohort, 24.3% had medically significant genetic findings (MSF) which may contribute to increased risk of disease. A total of 206 unique medically significant variants in 111 genes were identified, and forty individuals (3.4%) had more than one MSF. Phenotypic testing revealed 34.2% of our cohort had a metabolomics profile suggestive of insulin resistance, 29.2% had elevated liver fat identified by MRI, 16.4% had clinically important cardiac structure or cardiac function abnormalities on cardiac MRI or ECHO, 8.8% had a high cardiovascular risk on CT coronary artery calcium scoring (Agatston calcium score > 400, Relative Risk of 7.2), 8.0% had arrhythmia found on continuous rhythm monitoring, 6.5% had cardiac conduction disorders found on EKG, 2% had previously undetected tumors detected by WB MRI, and 2.5% had previously undetected aneurysms detected by non-contrast MRIMRA. Using family histories, personal histories, and test results, clinical and phenotypic findings were correlated with genomic findings in 130 study participants (63.1%) with high to moderate penetrance variants, suggesting the precision health platform improves the diagnostic process in asymptomatic individuals who were at risk. Cardiovascular and endocrine diseases achieved considerable clinical associations between MSFs and clinical phenotypes (89% and 72%, respectively). These findings demonstrate the value of integrating WGS and noninvasive clinical assessments for a rapid and integrated point-of-care clinical diagnosis of age-related diseases that contribute to premature mortality.

biorxiv genomics 0-100-users 2018

Self-repair protects microtubules from their destruction by molecular motors, bioRxiv, 2018-12-18

Microtubules are dynamic polymers that are used for intracellular transport and chromosome segregation during cell division. Their instability stems from the low energy of tubulin dimer interactions, which sets the growing polymer close to its disassembly conditions. Microtubules function in coordination with kinesin and dynein molecular motors, which use ATP hydrolysis to produce mechanical work and move on microtubules. This raises the possibility that the forces produced by walking motors can break dimer interactions and trigger microtubule disassembly. We tested this hypothesis by studying the interplay between microtubules and moving molecular motors in vitro. Our results show that the mechanical work of molecular motors can remove tubulin dimers from the lattice and rapidly destroy microtubules. This effect was not observed when free tubulin dimers were present in the assay. Using fluorescently labelled tubulin dimers we found that dimer removal by motors was compensated for by the insertion of free tubulin dimers into the microtubule lattice. This self-repair mechanism allows microtubules to survive the damage induced by molecular motors as they move along their tracks. Our study reveals the existence of coupling between the motion of kinesin and dynein motors and the renewal of the microtubule lattice.

biorxiv cell-biology 100-200-users 2018

Endogenous variation in ventromedial prefrontal cortex state dynamics during naturalistic viewing reflects affective experience, bioRxiv, 2018-12-17

AbstractHow we process ongoing experiences is shaped by our personal history, current needs, and future goals. Consequently, brain regions involved in generating these subjective appraisals, such as the vmPFC, often appear to be heterogeneous across individuals even in response to the same external information. To elucidate the role of the vmPFC in processing our ongoing experiences, we developed a computational framework and analysis pipeline to characterize the spatiotemporal dynamics of individual vmPFC responses as participants viewed a 45-minute television drama. Through a combination of functional magnetic resonance imaging, facial expression tracking, and self-reported emotional experiences across four studies, our data suggest that the vmPFC slowly transitions through a series of discretized states that broadly map onto affective experiences. Although these transitions typically occur at idiosyncratic times across people, participants exhibited a marked increase in state alignment during high affectively valenced events in the show. Our work suggests that the vmPFC ascribes affective meaning to our ongoing experiences.

biorxiv neuroscience 100-200-users 2018

The Case For and Against Double-blind Reviews, bioRxiv, 2018-12-16

To date, the majority of authors on scientific publications have been men. While much of this gender bias can be explained by historic sexism and discrimination, there is concern that women may still be disadvantaged by the peer review process if reviewers' unconscious biases lead them to reject publications with female authors more often. One potential solution to this perceived gender bias in the reviewing process is for journals to adopt double-blind reviews whereby neither the authors nor the reviewers are aware of each other's identities and genders. To test the efficacy of double-blind reviews, we assigned gender to every authorship of every paper published in 5 different journals with different peer review processes (double-blind vs. single blind) and subject matter (birds vs. behavioral ecology) from 2010-2018 (n = 4865 papers). While female authorships comprised only 35% of the total, the double-blind journal Behavioral Ecology did not have more female authorships than its single-blind counterparts. Interestingly, the incidence of female authorship is higher at behavioral ecology journals (Behavioral Ecology and Behavioral Ecology and Sociobiology) than in the ornithology journals (Auk, Condor, Ibis), for papers on all topics as well as those on birds. These analyses suggest that double-blind review does not currently increase the incidence of female authorship in the journals studied here. We conclude, at least for these journals, that double-blind review does not benefit female authors and may, in the long run, be detrimental.

biorxiv scientific-communication-and-education 100-200-users 2018

Large-scale analyses of human microbiomes reveal thousands of small, novel genes and their predicted functions, bioRxiv, 2018-12-14

AbstractSmall proteins likely abound in prokaryotes, and may mediate much of the communication that occurs between organisms within a microbiome and their host. Unfortunately, small proteins are traditionally overlooked in biology, in part due to the computational and experimental difficulties in detecting them. To systematically identify novel small proteins, we carried out a large comparative genomics study on 1,773 HMP human-associated metagenomes from four different body sites (mouth, gut, skin and vagina). We describe more than four thousand conserved protein families, the majority of which are novel; ~30% of these protein families are predicted to be secreted or transmembrane. Over 90% of the small protein families have no known domain, and almost half are not represented in reference genomes, emphasizing the incompleteness of knowledge in this space. Our analysis exposes putative novel ‘housekeeping’ small protein families, including a potential novel ribosomally associated protein, as well as ‘mammalian-specific’ or ‘human-specific’ protein families. By analyzing the genomic neighborhood of small genes, we pinpoint a subset of families that are potentially associated with defense against bacteriophage. Finally, we identify families that may be subject to horizontal transfer and are thus potentially involved in adaptation of bacteria to the changing human environment. Our study suggest that small proteins are highly abundant and that those of the human microbiome, in particular, may perform diverse functions that have not been previously reported.

biorxiv microbiology 0-100-users 2018

Population structure of modern-day Italians reveals patterns of ancient and archaic ancestries in Southern Europe, bioRxiv, 2018-12-14

European populations display low genetic diversity as the result of long term blending of the small number of ancient founding ancestries. However it is still unclear how the combination of ancient ancestries related to early European foragers, Neolithic farmers and Bronze Age nomadic pastoralists can fully explain genetic variation across Europe. Populations in natural crossroads like the Italian peninsula are expected to recapitulate the overall continental diversity, but to date have been systematically understudied. Here we characterised the ancestry profiles of modern-day Italian populations using a genome-wide dataset representative of modern and ancient samples from across Italy, Europe and the rest of the world. Italian genomes captured several ancient signatures, including a non-steppe related substantial ancestry contribution ultimately from the Caucasus. Differences in ancestry composition as the result of migration and admixture generated in Italy the largest degree of population structure detected so far in the continent and shaped the amount of Neanderthal DNA present in modern-day populations.

biorxiv genomics 0-100-users 2018