Biology subjects

Lin, M.

Publications and source records attributed to Lin, M..

9 recordsLinked to original sources

bioRxiv2018

Fast two-photon volumetric imaging of an improved voltage indicator reveals electrical activity in deeply located neurons in the awake brain

Imaging of transmembrane voltage deep in brain tissue with cellular resolution has the potential to reveal information processing by neuronal circuits in living animals with minimal perturbation. Multi-photon voltage imaging in vivo, however, is currently limited by speed and sensitivity of both indicators and imaging methods. Here, we report the engineering of an improved genetically encoded voltage indicator, ASAP3, which exhibits up to 51% fluorescence responses in the physiological voltage range, sub-millisecond activation kinetics, and full responsivity under two-photon illumination. We also introduce an ultrafast local volume excitation (ULOVE) two-photon scanning method to sample ASAP3 signals in awake mice at kilohertz rates with increased stability and sensitivity. ASAP3 and ULOVE allowed continuous single-trial tracking of spikes and subthreshold events for minutes in deep locations, with subcellular resolution, and with repeated sampling over multiple days. By imaging voltage in visual cortex neurons, we found evidence for cell type-dependent subthreshold modulation by locomotion. Thus, ASAP3 and ULOVE enable continuous high-speed high-resolution imaging of electrical activity in deeply located genetically defined neurons during awake behavior.

neuroscience↗

bioRxiv2018

Detecting spatiotemporal pattern of tuberculosis and the relationship between ecological environment and tuberculosis, a spatial panel data analysis in Guangxi, China

Guangxi is one of the provinces having the highest reported incidence of tuberculosis (TB) in China. However, spatial and temporal pattern and causation of the situation are still unclear. In order to detect the spatiotemporal pattern of TB and the association with ecological environment factors in Guangxi Zhuang autonomous region, China, We performed a spatiotemporal analysis with prediction using time series analysis, Morans I global and local spatial autocorrelation statistics, and space-time scan statistics, to detect temporal and spatial clusters. Spatial panel models were employed to identify the influence factors. The time series analysis shows that the number of reported cases peaked in spring and summer and decreased in autumn and winter with the annual reported incidence of 113.1/100,000 population. Morans I global statistics were greater than 0 (0.363 - 0.536) during the study period. The most significant hot spots were mainly located in the central part. The east part exhibited a low-low relation. By spacetime scanning, the clusters identified were similar to that of the local autocorrelation statistics, and were clustered toward the early of 2016. Duration of sunshine, per capita gross domestic product (PGDP), the recovery rate of TB and participation rate of new cooperative medical care insurance in rural areas had a significant negative association with TB. In conclusion, the reported incidence of TB in Guangxi remains high. The main cluster was located in the central part of Guangxi, a region where promoting the productivity, improving TB treatment pathway and strengthening environmental protective measures (increasing sunshine exposure) are urgently needed.

epidemiology↗

bioRxiv2018

A synthetic non-histone substrate provides insight into substrate targeting by the Gcn5 HAT and sirtuin HDACs

Gcn5 and sirtuins are highly conserved HAT and HDAC enzymes that were first characterised as regulators of gene expression. Although histone tails are important substrates of these enzymes, these proteins also target many non-histone substrates that participate in diverse biological processes. The mechanisms used by these enzymes to choose their non-histone substrates is unclear. In this work, we use a unique synthetic biology approach in S. cerevisiae to demonstrate that a shared target sequence can act as a determinant of substrate selection for Gcn5 and sirtuins. We also exploit this system to define specific subunits of the Gcn5-containing ADA complex as regulators of non-histone acetylations proteome-wide.

molecular biology↗

bioRxiv2018

Native tau structure is disrupted by disease-associated mutations that promote aggregation

Tauopathies are neurodegenerative diseases characterized by intracellular amyloid deposits of tau protein. Missense mutations in the tau gene (MAPT) correlate with aggregation propensity and cause dominantly inherited tauopathies, but their biophysical mechanism driving amyloid formation is poorly understood. Many disease-associated mutations localize within taus repeat domain at inter-repeat interfaces proximal to amyloidogenic sequences, such as 306VQIVYK311. Using cross-linking mass spectrometry, intramolecular FRET, recombinant protein and synthetic peptide systems, in silico modeling, and cell models, we conclude that the aggregation prone 306VQIVYK311 motif forms metastable compact structures with the upstream sequence that modulates aggregation propensity. Disease-associated mutations, isomerization of a critical proline, or alternative splicing are all sufficient to destabilize this local structure and trigger spontaneous aggregation. These findings provide a biophysical framework to explain the basis of early conformational changes that may underlie genetic and sporadic tau pathogenesis.

biophysics↗

bioRxiv2018

Genome-wide association study of 1 million people identifies 111 loci for atrial fibrillation

To understand the genetic variation underlying atrial fibrillation (AF), the most common cardiac arrhythmia, we performed a genome-wide association study (GWAS) of > 1 million people, including 60,620 AF cases and 970,216 controls. We identified 163 independent risk variants at 111 loci and prioritized 165 candidate genes likely to be involved in AF. Many of the identified risk variants fall near genes where more deleterious mutations have been reported to cause serious heart defects in humans or mice (MYH6, NKX2-5, PITX2, TBC1D32, TBX5),1,2 or near genes important for striated muscle function and integrity (e.g. MYH7, PKP2, SSPN, SGCA). Experiments in rabbits with heart failure and left atrial dilation identified a heterogeneous distributed molecular switch from MYH6 to MYH7 in the left atrium, which resulted in contractile and functional heterogeneity and may predispose to initiation and maintenance of atrial arrhythmia.

genetics↗

bioRxiv2017

Genome-wide analysis yields new loci associating with aortic valve stenosis

Aortic valve stenosis (AS) is the most common valvular heart disease, characterized by a thickened and calcified valve causing left ventricular outflow obstruction. Severe AS is a significant cause of morbidity and mortality, affecting approximately 5% of those over 70 years of age1,2,3. Little is known about the genetics of AS, although recently a variant at the LPA locus4 and a rare MYH6 missense variant were found to associate with AS5. We report a large genome-wide association study (GWAS) with a follow-up in up to 7,307 AS cases and 801,073 controls. We identified two new AS loci, on chromosome 1p21 near PALMD (rs7543130; OR=1.20, P=1.2x10-22) and on chromosome 2q22 in TEX41 (rs1830321; OR=1.15, P=1.8x10-13). Rs7543130 also associates with bicuspid aortic valve (BAV) (OR=1.28, P=6.6x10-10) and aortic root diameter (P=1.30x10-8) and rs1830321 associates with BAV (OR=1.12, P=5.3x10-3 and coronary artery disease (CAD) (OR=1.05, P=9.3x10-5). These results indicate that AS is partly rooted in the same processes as cardiac development and atherosclerosis.

genetics↗

bioRxiv2017

Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies

In genome-wide association studies (GWAS) for thousands of phenotypes in large biobanks, most binary traits have substantially fewer cases than controls. Both of the widely used approaches, linear mixed model and the recently proposed logistic mixed model, perform poorly - producing large type I error rates - in the analysis of phenotypes with unbalanced case-control ratios. Here we propose a scalable and accurate generalized mixed model association test that uses the saddlepoint approximation (SPA) to calibrate the distribution of score test statistics. This method, SAIGE, provides accurate p-values even when case-control ratios are extremely unbalanced. It utilizes state-of-art optimization strategies to reduce computational time and memory cost of generalized mixed model. The computation cost linearly depends on sample size, and hence can be applicable to GWAS for thousands of phenotypes by large biobanks. Through the analysis of UK Biobank data of 408,961 white British European-ancestry samples for >1400 binary phenotypes, we show that SAIGE can efficiently analyze large sample data, controlling for unbalanced case-control ratios and sample relatedness.

genomics↗

bioRxiv2017

GeTFEP: a general transfer free energy profile for transmembrane proteins

Free energy of transferring amino acid side-chains from aqueous environment into lipid bilayers, known as transfer free energy (TFE), provides important information on the thermodynamic stability of membrane proteins. In this study, we derived a TFE profile named General Transfer Free Energy Profile (GeTFEP) based on computation of the TFEs of 58 {beta}-barrel membrane proteins ({beta}MPs). The GeTFEP agrees well with experimentally measured and computationally derived TFEs. Analysis based on the GeTFEP shows that residues in different regions of the TM segments of {beta}MPs have different roles during the membrane insertion process. Results further reveal the importance of the sequence pattern of transmembrane strands in stabilizing {beta}MPs in the membrane environment. In addition, we show that GeTFEP can be used to predict the positioning and the orientation of {beta}MPs in the membrane. We also show that GeTFEP can be used to identify structurally or functionally important amino acid residue sites of {beta}MPs. Furthermore, the TM segments of -helical membrane proteins can be accurately predicted with GeTFEP, suggesting that the GeTFEP captures fundamental thermodynamic properties of amino acid residues inside membrane, and is of general applicability in studying membrane protein.

biophysics↗

bioRxiv2017

An Unexpectedly Complex Architecture for Skin Pigmentation in Africans

Fewer than 15 genes have been directly associated with skin pigmentation variation in humans, leading to its characterization as a relatively simple trait. However, by assembling a global survey of quantitative skin pigmentation phenotypes, we demonstrate that pigmentation is more complex than previously assumed with genetic architecture varying by latitude. We investigate polygenicity in the Khoe and the San, populations indigenous to southern Africa, who have considerably lighter skin than equatorial Africans. We demonstrate that skin pigmentation is highly heritable, but that known pigmentation loci explain only a small fraction of the variance. Rather, baseline skin pigmentation is a complex, polygenic trait in the KhoeSan. Despite this, we identify canonical and non-canonical skin pigmentation loci, including near SLC24A5, TYRP1, SMARCA2/VLDLR, and SNX13 using a genome-wide association approach complemented by targeted resequencing. By considering diverse, under-studied African populations, we show how the architecture of skin pigmentation can vary across humans subject to different local evolutionary pressures.\n\nHighlightsO_LISkin pigmentation in Africans is far more polygenic than light skin pigmentation in Eurasians.\nC_LIO_LIKhoeSan[§] populations, which diverged early in human prehistory from other populations, have lightened skin pigmentation compared to equatorial Africans.\nC_LIO_LISkin color is highly heritable in the KhoeSan, but pigmentation variability is not well explained by previously discovered pigmentation genes.\nC_LIO_LIWe perform the first GWAS for pigmentation in African KhoeSan populations and identify canonical pigmentation loci near TYRP1 and in SLC24A5, as well as novel associations surrounding SMARCA2 and other genes.\nC_LI

genetics↗