Biology subjects

Cai, J.

Publications and source records attributed to Cai, J..

At least 109 records · Page 6Linked to original sources

bioRxiv2022

A Mechanistic Study on the Cellular Uptake, Intracellular Trafficking, and Antisense Gene Regulation of Bottlebrush Polymer-Conjugated Oligonucleotides

We have developed a non-cationic transfection vector in the form of a bottlebrush polymer-antisense oligonucleotide (ASO) conjugate. Termed pacDNA (polymer-assisted compaction of DNA), these agents show improved biopharmaceutical characteristics and antisense potency in vivo while suppressing non-antisense side effects. Nonetheless, there still lacks a mechanistic understanding regarding the cellular uptake, subcellular trafficking, and gene knockdown with pacDNA. Here, we show that the pacDNA enters human non-small cell lung cancer cells (NCI-H358) predominantly by scavenger receptor-mediated endocytosis and macropinocytosis, and trafficks via the endolysosomal pathway within the cell. The pacDNA significantly reduces a target gene expression (KRAS) in the protein level but not in the mRNA level, despite that the transfection of free ASOs causes ribonuclease H1 (RNase H)-dependent degradation of KRAS mRNA. In addition, the antisense activity of pacDNA is independent of ASO chemical modification, suggesting that the pacDNA functions as a steric blocker. TOC O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=148 SRC="FIGDIR/small/496353v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@56e08eorg.highwire.dtl.DTLVardef@1b09510org.highwire.dtl.DTLVardef@a785corg.highwire.dtl.DTLVardef@1641874_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2022

inClust: a general framework for clustering that integrates data from multiple sources

Clustering is one of the most commonly used methods in single-cell RNA sequencing (scRNA-seq) data analysis and other fields of biology. Traditional clustering methods usually use data from a single source as the input (e.g. scRNA-seq data). However, as the data become more and more complex and contain information from multiple sources, a clustering method that could integrate multiple data is required. Here, we present inClust (integrated clustering), a clustering method that integrates information from multiple sources based on variational autoencoder and vector arithmetic in latent space. inClust perform information integration and clustering jointly, meanwhile it could utilize the labeling information from data as regulation information. It is a flexible framework that can accomplish different tasks under different modes, ranging from supervised to unsupervised. We demonstrate the capability of inClust in the tasks of conditional out-of-distribution generation under supervised mode; label transfer under semi-supervised mode and guided clustering mode; spatial domain identification under unsupervised mode. inClust performs well in all tasks, indicating that it is an excellent general framework for clustering and task-related clustering in the era of multi-omics.

bioinformatics↗

bioRxiv2022

The leucine-rich repeat (LRR) domain of NLRP3 is required for NLRP3 inflammasome activation in macrophages

The NLRP3 inflammasome is a critical component of innate immunity that defends the host from microbial infections. However, its aberrant activation contributes to the pathogenesis of several inflammatory diseases. Activation of the NLRP3 inflammasome induces the secretion of proinflammatory cytokines IL-1{beta} and IL-18, and pyroptotic cell death. NLRP3 contains a leucine-rich repeat (LRR) domain at its C-terminus. Although posttranslational modifications in this LRR domain have been shown to regulate NLRP3 inflammasome activation, the role of the entire LRR domain in NLRP3 inflammasome activation remains controversial. Here, we generated mouse macrophages that express an endogenous NLRP3 mutant lacking the LRR domain. Deletion of the LRR domain destabilized endogenous NLRP3 protein and abolished NLRP3 inflammasome activation in macrophages. Furthermore, using NLRP3-deficient macrophages that are reconstituted with NLRP3 mutants lacking the LRR domain, we found that deletion of the LRR domain inhibited NLRP3 inflammasome activation. Mechanistically, deletion of the LRR domain abolished NLRP3 self-association, oligomerization, and interaction with the essential regulator NEK7. Our results demonstrate a critical role for the LRR domain in NLRP3 inflammasome activation.

immunology↗

bioRxiv2022

Genomic screening reveals UBA1 as a potent and druggable target in c-MYC-high TNBC models

Triple negative breast cancer (TNBC) accounts for over 30% of all breast cancer-related deaths, despite accounting for only 10%-15% of total breast cancer cases. Targeted therapy development has largely stalled in TNBC, underlined by a lack of traditionally druggable addictions like receptor tyrosine kinases (RTKs). Here, through full genome CRISPR/Cas9 screening of TNBC models, we have uncovered the sensitivity of TNBCs to the depletion of the Ubiquitin-Like Modifier Activating Enzyme 1 (UBA1). Targeting UBA1 with the first in-class UBA1 inhibitor TAK-243 induced unresolvable ER-stress and activating transcription factor 4 (ATF4)-mediated upregulation of pro-apoptotic NOXA, leading to cell death. In five patient derived xenograft models (PDXs) of TNBC, TAK-243 therapy led to tumor inhibition or frank tumor regression. In an intracardiac metastatic model of TNBC, TAK-243 markedly reduced metastatic burden. Importantly, there was an order of magnitude greater sensitivity of TNBC lines to TAK-243 compared to normal tissue-derived cells. Lastly, c-MYC expression correlates with TAK-243 sensitivity and cooperates with TAK-243 to induce a stress response and cell death. We posit UBA1 is an important new target in TNBC expressing high levels of c-MYC. SignificanceGenomic screening of TNBC cell lines revealed broad sensitivity to depletion of the E1 ubiquitin enzyme, UBA1. Disrupting UBA1 with the first in-class inhibitor TAK-243 in TNBC models induces ER-stress through an ATF4-NOXA axis that is dependent on c-MYC, leading to apoptosis, in vitro and in vivo, primary tumor growth inhibition and metastatic inhibition.

cancer biology↗

bioRxiv2022

Multifaceted role of RIMBP2 in promoting hearing in murine cochlear hair cells

In peripheral, the mammalian cochlea is a remarkable sensory apparatus, owning to its outer and inner hair cells (OHCs and IHCs) that amplify and transmit auditory signals to the brain, respectively. Rab3-interacting molecular (RIM) binding protein 2 (RIMBP2) is widely expressed in receptor cells and neurons, specifically in the active zones for exocytosis of synaptic vesicles (SVs), but its exact functions in the cochlea are not very well understood. We therefore generated a Rimbp2 knockout mouse model (Rimbp2-/-), which exhibited severely impaired hearing with not only elevated hearing thresholds but also increased latencies and reduced amplitudes in the Wave I of their auditory brainstem responses (ABRs). Consistent with the threshold elevation, we found significant loss of OHCs, likely through apoptosis, in the Rimbp2-/- cochlea. Consistent with changes observed in the ABR Wave I, we found greatly reduced exocytosis, both spontaneously and upon stimulation, in Rimbp2-/- IHCs. Specifically, our patch-clamp analysis on IHCs and postsynaptic spiral ganglion neurons (SGNs) revealed not only reduced readily releasable pool (RRP) of SVs but also reduced sustained release rate, along with complete blockade of fast endocytosis, in Rimbp2-/- IHCs. Lastly, with immunostaining of whole-mounted cochleae, we found that while the number of ribbon synapses in Rimbp2-/- IHCs was unchanged, their localization moved subtly but significantly towards the basal pole of IHCs. Taken together, we uncovered an unexpected role of RIMBP2 for OHC survival and a more extensive role in promoting IHC exocytosis than previously believed.

neuroscience↗

bioRxiv2022

Manipulating the 3D organization of the largest synthetic yeast chromosome

Whether synthetic genomes can power life has attracted broad interest in the synthetic biology field, especially when the synthetic genomes are extensively modified with thousands of designer features. Here we report de novo synthesis of the largest eukaryotic chromosome thus far, synIV, a 1,454,621-bp Saccharomyces cerevisiae chromosome resulting from extensive genome streamlining and modification. During the construction of synIV, we developed megachunk assembly combined with a hierarchical integration strategy, which significantly increased the accuracy and flexibility of synthetic chromosome construction and facilitated chromosome debugging. In addition to the drastic sequence changes made to synIV by rewriting it, we further manipulated the three-dimensional structure of synIV in the yeast nucleus to explore spatial gene regulation within the nuclear space. Surprisingly, we found few gene expression changes, suggesting that positioning inside the yeast nucleoplasm plays a minor role in gene regulation. Lastly, we tethered synIV to the inner nuclear membrane via its hundreds of loxPsym sites and observed transcriptional repression of the entire chromosome, demonstrating chromosome-wide transcription manipulation without changing the DNA sequences. Our manipulation of the spatial structure of the largest synthetic yeast chromosome shed light on higher-order architectural design of the synthetic genomes. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/487066v2_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@18bf586org.highwire.dtl.DTLVardef@1a471d5org.highwire.dtl.DTLVardef@12d7690org.highwire.dtl.DTLVardef@1c32510_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIDe novo synthesis of the largest eukaryotic chromosome, synIV C_LIO_LISynIV shows similar 3D structure to wild-type IV, despite thousands of changes made to it C_LIO_LI"Inside-out" repositioning of synIV in nucleus shows minor transcriptional changes C_LIO_LIMultipoint tethering synIV to inner nuclear membrane represses transcription of whole chromosome C_LI

synthetic biology↗

bioRxiv2022

STOmicsDB: a database of Spatial Transcriptomic data

Recent technological development in spatial transcriptomics allows researchers to measure gene expression of cells and their spatial locations at the almost single-cell level, which generates detailed biological insight into biological processes. However, specialized spatial transcriptomics databases are rare. Here, we present the Spatial TranscriptOmics DataBase (STOmicsDB), a user-friendly database with multifunctions including search of relevant publications and tools, public dataset visualization, customized specialized databases, new data archive, and online analysis. The current version of STOmicsDB consists of 141 curated spatial transcript datasets covering 12 species, and includes 5,618 spatial multi-omics publications and 674 tools. STOmicsDB is freely accessible at https://db.cngb.org/stomics/.

genomics↗

bioRxiv2022

Multi-ancestry genome-wide analysis identifies common genetic variants for self-reported sleep duration and shared genetic effects

Both short and long sleep duration are associated with increased risk of chronic diseases, but the genetic determinants of sleep duration are largely unknown outside of European populations. Here we report transferability of a polygenic score of 78 European ancestry sleep duration SNPs to an African (n=7,288; p=0.003), a South Asian (n=7,485; p=0.025), and a Japanese (n=13,618; p=6x10-4) cohort, but not to a cohort of Hispanic/Latino (n- XXX; p=0.71) participants. Furthermore, in a pan-ancestry (N = 483,235) meta-analysis of genome-wide association studies (GWAS) for habitual sleep duration, 5 novel and 68 known loci are associated with genome-wide significance. For the novel loci, sleep duration signals colocalize with expression-QTLs for PRR12 and COG5 in brain tissues, and pleiotropic associations are observed with cardiovascular and neuropsychiatric traits. Overall, our results suggest that the genetic basis of sleep duration is at least partially shared across diverse ancestry groups.

genomics↗

bioRxiv2021

Severe disturbance overflows the stabilizing buffer of variable biotic interactions

Recent studies have revealed that biotic interactions in ecological communities vary over time, possibly mediating community responses to anthropogenic disturbances. This study investigated the heterogeneity of such variability within a real community and its impact on population stability in the face of pesticide application, particularly focusing on density-dependence of the interaction effect. Using outdoor mesocosms with a freshwater community, we found considerable heterogeneity in density-dependent interaction variability among links in the same community. This variability mediated the stability of recipient populations, with negative density-dependent interaction variability stabilizing whereas positive density-dependence and density-independent interaction variability destabilizing populations. Unexpectedly, the mean interaction strength, which is typically considered crucial for stability, had no significant effect, suggesting that how organisms interact on average is insufficient to predict the ecological impacts of pesticides. Our findings emphasize the multifaceted role of interaction variability in predicting the ecological consequences of anthropogenic disturbances such as pesticide application.

ecology↗

bioRxiv2021

Multi-site phosphorylation of yeast Mif2/CENP-C promotes inner kinetochore assembly

Kinetochores control eukaryotic chromosome segregation by connecting chromosomal centromeres to spindle microtubules. Duplication of centromeric DNA necessitates kinetochore disassembly and subsequent reassembly on the nascent sisters. To search for a regulatory mechanism that controls the earliest steps of kinetochore assembly, we studied Mif2/CENP-C, an essential basal component. We found that Polo-like kinase (Cdc5) and Dbf4-dependent kinase (DDK) phosphorylate the conserved PEST region of Mif2/CENP-C and that this phosphorylation directs inner kinetochore assembly. Mif2 phosphorylation promotes kinetochore assembly in a reconstituted biochemical system, and it strengthens Mif2 localization at centromeres in cells. Disrupting one or more phosphorylation sites in the Mif2-PEST region progressively impairs cellular fitness and sensitizes cells to microtubule poisons. The most severe Mif2-PEST mutations are lethal in cells lacking otherwise non-essential Ctf19 complex factors. These data suggest that multi-site phosphorylation of Mif2/CENP-C is a robust switch that controls inner kinetochore assembly, ensuring accurate chromosome segregation.

cell biology↗

bioRxiv2021

Bimodal Remapping of Visual Grids

Spatially modulated neurons from the rat secondary visual cortex (V2) show grid-like firing patterns during freely foraging in open-field enclosures. However, the remapping of the V2 grid cells is not well understood. Here we report two classes of V2 grid cell populations with distinct remapping properties: one regular class with invariant grid field patterns, and the other bimodal class that has remapping induced by environmental manipulations such as changes in enclosure shape, size, orientation and lighting in a familiar environment. The bimodal V2 grid cell pattern remains stable regardless of the follow-up manipulations, but restores to the original firing pattern upon animals re-entry into the familiar environment on the next day or from the novel environment. The bimodal V2 grid cells are modulated with theta frequency during the course of remapping and stabilize quickly. We also found conjunctive bistable V2 grid cells with invariant head directional tuning. Overall, our results suggest a new grid cell mechanism in V2 that is different from the medial entorhinal cortex (MEC) grid cells. HighlightsO_LIBistable V2 grid cells display bimodal or bistable remapping C_LIO_LIV2 grid cell firing patterns are not disrupted in darkness C_LIO_LIV2 grid cells preserve theta frequency modulation during remapping C_LI

neuroscience↗

bioRxiv2021

Assessment of Plasmodium falciparum infection and fitness of genetically modified Anopheles gambiae aimed at mosquito population replacement

Genetically modified (GM) mosquitoes expressing anti-plasmodial effectors propagating through wild mosquito populations by means of gene drive is a promising tool to support current malaria control strategies. The process of generating GM mosquitoes involves genetic transformation of mosquitoes from a laboratory colony and, often, interbreeding with other GM lines to cross in auxiliary traits. These mosquito colonies and GM lines thus often have different genetic backgrounds and GM lines are invariably highly inbred, which in conjunction with their independent rearing in the laboratory may translate to differences in their susceptibility to malaria parasite infection and life history traits. Here, we show that laboratory Anopheles gambiae colonies and GM lines expressing Cas9 and Cre recombinase vary greatly in their susceptibility to Plasmodium falciparum NF54 infection. Therefore, the choice of mosquitoes to be used as a reference when conducting infection or life history trait assays requires careful consideration. To address these issues, we established an experimental pipeline involving genetic crosses and genotyping of mosquitoes reared in shared containers throughout their lifecycle. We used this protocol to examine whether GM lines expressing the antimicrobial peptide (AMP) Scorpine in the mosquito midgut interfere with parasite infection and mosquito survival. We demonstrate that Scorpine expression in the Peritrophin 1 (Aper1) genomic locus reduces both P. falciparum sporozoite prevalence and mosquito lifespan; both these phenotypes are likely to be associated with the disturbance of the midgut microbiota homeostasis. These data lead us to conclude that the Aper1-Sco GM line could be used in proof-of-concept experiments aimed at mosquito population replacement, although the impact of its reduced fitness on the spread of the transgene through wild populations requires further investigation.

microbiology↗

bioRxiv2021

Numb reduces Tau levels and prevents neurodegeneration in mouse models of tauopathy in an isoform-specific manner

Accumulation of the microtubule-associated protein Tau is linked to neuronal cell death in tauopathies, but how exactly intraneuronal Tau levels are regulated in health and disease remains unclear. Here we identify the trafficking adaptor protein Numb as an essential regulator of Tau homeostasis. Conditional inactivation of Numb in retinal ganglion cells (RGCs) increases monomeric and oligomeric Tau levels, leading to axonal blebbing followed by neuronal cell loss in aged mice. Moreover, in a mouse model of tauopathy, inactivation of Numb in RGCs and spinal motoneurons accelerates neurodegeneration, and leads to precocious hindlimb paralysis. Conversely, overexpression of the long isoform of Numb (Numb-72), but not other isoforms, decreases intracellular Tau levels by promoting the extracellular release of monomeric Tau, and AAV-mediated delivery of Numb-72 in RGCs in vivo prevents neurodegeneration in two different mouse models of tauopathy. Taken together, these results uncover Numb as a modulator of intracellular Tau levels and identify Numb-72 as a novel therapeutic factor for tauopathies.

neuroscience↗

bioRxiv2021

Construction of a solid Cox model for AML patients based on multiomics bioinformatic analysis

Acute myeloid leukemia (AML) is a highly heterogeneous hematological malignancy. The bone marrow (BM) microenvironment in AML plays an important role in leukemogenesis, drug resistance and leukemia relapse. In this study, we aimed to identify reliable immune-related biomarkers for AML prognosis by multiomics analysis. We obtained expression profiles from The Cancer Genome Atlas (TCGA) database and constructed a LASSO-Cox regression model to predict the prognosis of AML using multiomics bioinformatic analysis data. This was followed by independent validation of the model in the GSE106291 (n=251), GSE12417 (n=163) and GSE37642 (n=137) datasets and mutated genes in clinical samples for predicting overall survival (OS). Molecular docking was performed to predict the most optimal ligands to these hub genes. The single-cell RNA sequence dataset GSE116256 was used to clarify the expression of the hub genes in different immune cell types. According to their significant differences in immune gene signatures and survival trends, we concluded that the immune infiltration-lacking subtype (IL type) is associated with better prognosis than the immune infiltration-rich subtype (IR type). Using the LASSO model, we built a classifier based on 5 hub genes to predict the prognosis of AML (risk score = -0.086xADAMTS3 + 0.180xCD52 + 0.472xCLCN5 - 0.356xHAL + 0.368xICAM3). In summary, we constructed a prognostic model of AML using integrated multiomics bioinformatic analysis that could serve as a therapeutic classifier.

cancer biology↗

bioRxiv2021

CDCP: a visualization and analyzing platform for single-cell datasets

Advances in single-cell sequencing technology provide a unique approach to characterize the heterogeneity and distinctive functional states at single-cell resolution, leading to rapid accumulation of large-scale single-cell datasets. A big challenge undertaken by research community especially bench scientists is how to simplify the way of retrieving, processing and analyzing the huge number of datasets. Towards this end, we developed Cell-omics Data Coordinate Platform (CDCP), a platform that aims to share and integrate comprehensive single-cell datasets, and to provide a network analysis toolkit for personalized analysis. CDCP contains single-cell RNA-seq and ATAC-seq datasets of 474 572 cells from 6 459 samples in species covering humans, non-human primate models and other animals. It allows querying and visualization of interested datasets and the expression profile of distinct genes in different cell clusters and cell types. Besides, this platform provides an analysis pipeline for non-bioinformatician experimental scientists to address questions not focused by the submitters of the datasets. In summary, CDCP provides a user-friendly interface for researchers to explore, visualize, analyze, download and submit published single-cell datasets and it will be a valuable resource for investigators to explore the global transcriptome profiling at single-cell level.

bioinformatics↗

bioRxiv2021

Systematic analysis of the R2R3-MYB family of transcription factors in Camellia sinensis: evidence for species-specific catechin biosynthesis regulation

The R2R3-MYB transcription factor family regulates metabolism of phenylpropanoids in various plant lineages. Species-expanded or specific MYB transcription factors may regulate species-specific metabolite biosynthesis including phenylpropanoid-derived bioactive products. C. sinensis produces an abundance of specialized metabolites, which makes it an excellent model for digging into the genetic regulation of plant-specific metabolite biosynthesis. The most abundant health-promoting metabolites in tea are galloylated catechins, and the most bioactive of the galloylated catechins, epigallocatechin gallate (EGCG), is exclusively found in C. sinensis. However, the transcriptional regulation of galloylated catechin biosynthesis remains elusive. This study mined the R2R3-MYB transcription factors associated with galloylated catechin biosynthesis in C. sinensis. A total of 118 R2R3-MYB proteins, classified into 38 subgroups, were identified. R2R3-MYB subgroups specific to or expanded in C. sinensis were hypothesized to be essential to evolutionary diversification of tea-specific metabolites. Notably, nine of these R2R3-MYB genes were expressed preferentially in apical buds and young leaves, exactly where galloylated catechins accumulate. Three putative R2R3-MYB genes displayed strong correlation with key galloylated catechin biosynthesis genes, suggesting a role in regulating biosynthesis of epicatechin gallate (ECG) and EGCG. Overall, this study paves the way to reveal the transcriptional regulation of galloylated catechins in C. sinensis.

plant biology↗

bioRxiv2021

HIV-2/SIV Vpx antagonises NF-B activation by targeting p65

The NF-{kappa}B family of transcription factors and associated signalling pathways are abundant and ubiquitous in human immune responses. Activation of NF-{kappa}B transcription factors by viral pathogen-associated molecular patterns, such as viral RNA and DNA, is fundamental to anti-viral innate immune defences and pro-inflammatory cytokine production that steers adaptive immune responses. Diverse non-viral stimuli, such as lipopolysaccharide and cytokines, also activate NF-{kappa}B and the same anti-pathogen gene networks. Viruses adapted to human cells often encode multiple proteins aimed at varied NF-{kappa}B pathway targeted to mitigate the anti-viral effects of NF-{kappa}B-dependent host immunity. In this study we have demonstrated using numerous assays, in a number of different cell types, that plasmid-encoded or virus-delivered Simian Immunodeficiency Virus (SIV) accessory protein Vpx is a broad antagonist of NF-{kappa}B signalling active against diverse innate NF-{kappa}B agonists. Using targeted Vpx mutagenesis, we showed that this novel Vpx phenotype is independent of known Vpx cofactor DCAF1 and other cellular binding partners, including SAMHD1, STING and the HUSH complex. We found that Vpx co-immunoprecipitated with canonical NF-{kappa}B transcription factor p65 and not NF-{kappa}B transcription factor proteins p50 or p100, preventing nuclear translocation of p65, a novel mechanism of NF-{kappa}B antagonism by lentiviruses. We found that broad antagonism of NF-{kappa}B activation by Vpx was conserved across distantly related lentiviruses as well as for Vpr from SIV Mona monkey (SIVmon), which has Vpx-like SAMHD1-degradation activity. ImportanceBroad antagonism of NF-{kappa}B activation has been described for HIV-1, but not for Vpx-encoding lentiviruses such as HIV-2. Here we extend our understanding of lentiviral antagonism by identifying an interaction between Vpx and transcription factor NF-{kappa}B p65, leading to inhibition of its nuclear translocation and broad NF-{kappa}B antagonism. This further evidences a requirement for lentiviruses to target universal regulators of immunity, including NF-{kappa}B, to avoid the anti-viral sequelae of pro-inflammatory gene expression stimulated by both viral and extra-viral agonists, such as lipopolysaccharide translocation, during disruption of the gut microbiome barrier during HIV-1 infection. Further structural studies of p65 targeting by Vpx may yield translational insights in the form of novel pan-NF-{kappa}B inhibitors for pathologies characterised by excessive NF-{kappa}B activity. Our findings are also relevant to the gene therapy field where virus-like particle associated Vpx is routinely used to enhance vector transduction through antagonism of SAMHD1, and perhaps also through manipulation of other pathways such as NF-{kappa}B.

molecular biology↗

bioRxiv2021

Genome-wide admixture mapping of eGFR and CKD identify European and African ancestry-of-origin loci in U.S. Hispanics/Latinos

BackgroundAdmixture mapping is a powerful approach for gene mapping of complex traits that leverages the diverse genetic ancestry in populations with recent admixture such as U.S. Hispanics/Latinos (HL), who have increased risk of chronic kidney disease (CKD). MethodsGenome-wide admixture mapping was performed for CKD and estimated glomerular filtration rate (eGFR) in a sample of 12,601 participants from the Hispanic Community Health Study/Study of Latinos, with validation in a sample of 8191 African Americans from the Womens Health Initiative (WHI). ResultsThree novel ancestry-of-origin loci were identified on chromosomes 2, 14 and 15 for CKD and eGFR. The chromosome 2 locus (2p16.3) consisted of two European ancestry regions encompassing the FSHR and NRXN1 genes, with European ancestry at this locus associated with increased risk for CKD. The chromosome 14 locus (14q32.2) located within the DLK1-DIO3 imprinted domain was driven by European ancestry, and was associated with lower eGFR. The chromosome 15 locus (15q13.3-14) included intronic variants of RYR3 and was within an African-specific genomic region that was associated with higher eGFR. These findings were compared to the conventional genome-wide association study that failed to identify significant associations in these regions. We validated the chromosome 14 and 15 loci for eGFR in the WHI African Americans. ConclusionsThis study provides evidence of shared ancestry-specific genomic regions influencing eGFR in HL and African Americans, and illustrates the potential for leveraging genetic ancestry in recently admixed populations for novel discovery of kidney trait loci.

genetics↗