Biology subjects

Huang, H.

Publications and source records attributed to Huang, H..

42 records · Page 3Linked to original sources

bioRxiv2017

Mapping protein interactions of sodium channel NaV1.7 using epitope-tagged gene targeted mice

The voltage-gated sodium channel NaV1.7 plays a critical role in pain pathways. Besides action potential propagation, NaV1.7 regulates neurotransmitter release, integrates depolarizing inputs over long periods and regulates transcription. In order to better understand these functions, we generated an epitope-tagged NaV1.7 mouse that showed normal pain behavior. Analysis of NaV1.7 complexes affinity-purified under native conditions by mass spectrometry revealed 267 NaV1.7 associated proteins including known interactors, such as the sodium channel {beta}3 subunit (Scn3b) and collapsin response mediator protein (Crmp2), and novel interactors. Selected novel NaV1.7 protein interactors membrane-trafficking protein synapototagmin-2 (Syt2), G protein-regulated inducer of neurite outgrowth 1 (Gprin1), L-type amino acid transporter 1 (Lat1) and transmembrane P24 trafficking protein 10 (Tmed10) together with Scn3b and Crmp2 were validated using co-immunoprecipitation and functional assays. The information provided with this physiologically normal epitope-tagged mouse should provide useful insights into the pain mechanisms associated with NaV1.7 channel function.

neuroscience↗

bioRxiv2017

Prevailing homozygous deletion of interferon and defensin genes in human cancers

Interferons and defensins are antimicrobial peptides that can also induce anti-tumor immunity. By analyzing the copy number profiles of 10,759 patients across 31 cancer types, we found the homozygous deletions of interferon and defensin genes are prevailing in most human cancers, and that patients with these homozygous deletions exhibited significant reduced overall survival or disease-free survival. We further demonstrated that the homozygous deletion of interferon and defensin genes significantly impacted the expression of genes regulated by tumor necrosis factor (TNF) and IFN{gamma}. Our findings suggested a novel immune escape mechanism that disrupts the tumor cells ability to be recognized, and have implications for personalized immunotherapy.

immunology↗

bioRxiv2016

Detecting hierarchical 3-D genome domain reconfiguration with network modularity

Mammalian genomes are folded in a hierarchy of topologically associating domains (TADs), subTADs and looping interactions. The nested nature of chromatin domains has rendered it challenging to identify a sensitive and specific metric for detecting subTADs and quantifying their dynamic reconfiguration across cellular states. Here, we apply graph theoretic principles to quantify hierarchical folding patterns in high-resolution chromatin topology maps. We discover that TADs can be accurately detected using a Louvain-like locally greedy algorithm to maximize network modularity. By varying a resolution parameter in the modularity quality function, we accurately partition the mouse genome across length scales into a hierarchical nested structure of network communities exhibiting a wide range of sizes. To distinguish high probability subTADs from the full detected set, we developed and applied a new hierarchical spatial variance minimization method. Moreover, we identified a large number of dynamically altered communities between pluripotent embryonic stem cells and multipotent neural progenitor cells. Cell type specific boundaries correlate with trends in dynamic occupancy of the architectural protein CTCF, thereby validating their biological relevance. Together, these data demonstrate the utility of metrics from network science in quantifying a nested hierarchy of dynamic 3D chromatin communities across length scales. Our findings are significant toward unraveling the link between higher-order genome folding and gene expression during healthy development and the deregulation of molecular pathways linked to disease.

genomics↗

bioRxiv2016

Selection on the FADS region in Europeans

AbstractFADS genes encode fatty acid desaturases that are important for the conversion of short chain polyunsaturated fatty acids (PUFAs) to long chain fatty acids. Prior studies indicate that the FADS genes have been subjected to strong positive selection in Africa, South Asia, Greenland, and Europe. By comparing FADS sequencing data from present-day and Bronze Age (5-3k years ago) Europeans, we identify possible targets of selection in the European population, which suggest that selection has targeted different alleles in the FADS genes in Europe than it has in South Asia or Greenland. The alleles showing the strongest changes in allele frequency since the Bronze Age show associations with expression changes and multiple lipid-related phenotypes. Furthermore, the selected alleles are associated with a decrease in linoleic acid and an increase in arachidonic and eicosapentaenoic acids among Europeans; this is an opposite effect of that observed for selected alleles in Inuit from Greenland. We show that multiple SNPs in the region affect expression levels and PUFA synthesis. Additionally, we find evidence for a gene-environment interaction influencing low-density lipoprotein (LDL) levels between alleles affecting PUFA synthesis and PUFA dietary intake: carriers of the selected, derived allele have diminished increases in LDL cholesterol with a higher intake of PUFAs. We hypothesize that the selective patterns observed in Europeans were driven by a change in dietary composition of fatty acids following the transition to agriculture, resulting in a lower intake of arachidonic acid and eicosapentaenoic acid, but a higher intake of linoleic acid and -linolenic acid.

genetics↗

bioRxiv2016

The origin and evolution of a pandemic lineage of the kiwifruit pathogen Pseudomonas syringae pv. actinidiae

Recurring epidemics of kiwifruit (Actinidia spp.) bleeding canker disease are caused by Pseudomonas syringae pv. actinidiae (Psa), whose emergence coincided with domestication of its host. The most recent pandemic has had a deleterious effect on kiwifruit production worldwide. In order to strengthen understanding of population structure, phylogeography and evolutionary dynamics of Psa, we sampled 746 Pseudomonas isolates from cultivated and wild kiwifruit across six provinces in China, of which 87 were Psa. Of 234 Pseudomonas isolated from wild Actinidia spp. none were identified as Psa. Genome sequencing of fifty isolates and the inclusion of an additional thirty from previous studies show that China is the origin of the recently emerged pandemic lineage. However China harbours only a fraction of global Psa diversity, with greatest diversity found in Korea and Japan. Distinct transmission events were responsible for introduction of the pandemic lineage of Psa into New Zealand, Chile and Europe. Two independent transmission events occurred between China and Korea, and two Japanese isolates from 2014 cluster with New Zealand Psa. Despite high similarity at the level of the core genome and negligible impact of within-lineage recombination, there has been substantial gene gain and loss even within the single clade from which the global pandemic arose.\n\nSIGNIFICANCE STATEMENTBleeding canker disease of kiwifruit caused by Pseudomonas syringae pv. actinidiae (Psa) has come to prominence in the last three decades. Emergence has coincided with domestication of the host plant and provides a rare opportunity to understand ecological and genetic factors affecting the evolutionary origins of Psa. Here, based on genomic analysis of an extensive set of strains sampled from China and augmented by isolates from a global sample, we show, contrary to earlier predictions, that China is not the native home of the pathogen, but is nonetheless the source of the recent global pandemic. Our data identify specific transmission events, substantial genetic diversity and point to non-agricultural plants in either Japan or Korea as home to the source population.

epidemiology↗

bioRxiv2016

A comprehensive survey of genetic variation in 20,691 subjects from four large cohorts

The Nurses Health Study (NHS), Nurses Health Study II (NHSII), Health Professionals Follow Up Study (HPFS) and the Physicians Health Study (PHS) have collected detailed longitudinal data on multiple exposures and traits for approximately 310,000 study participants over the last 35 years. Over 160,000 study participants across the cohorts have donated a DNA sample and to date, 20,691 subjects have been genotyped as part of genome-wide association studies (GWAS) of twelve primary outcomes. However, these studies utilized six different GWAS arrays making it difficult to conduct analyses of secondary phenotypes or share controls across studies. To allow for secondary analyses of these data, we have created three new datasets merged by platform family and performed imputation using a common reference panel, the 1,000 Genomes Phase I release. Here, we describe the methodology behind the data merging and imputation and present imputation quality statistics and association results from two GWAS of secondary phenotypes (body mass index (BMI) and venous thromboembolism (VTE)).\n\nWe observed the strongest BMI association for the FTO SNP rs55872725 ({beta}=0.45, p=3.48x10-22), and using a significance level of p=0.05, we replicated 19 out of 32 known BMI SNPs. For VTE, we observed the strongest association for the rs2040445 SNP (OR=2.17, 95% CI: 1.79-2.63, p=2.70x10-15), located downstream of F5 and also observed significant associations for the known ABO and F11 regions. This pooled resource can be used to maximize power in GWAS of phenotypes collected across the cohorts and for studying gene-environment interactions as well as rare phenotypes and genotypes.

epidemiology↗