Biology subjects

Tian, X.

Publications and source records attributed to Tian, X..

At least 199 records · Page 11Linked to original sources

bioRxiv2019

Evolutionary genomics of structural variation in Asian rice (Oryza sativa) and its wild progenitor (O. rufipogon)

Structural variants (SVs) are a largely unstudied feature of plant genome evolution, despite the fact that SVs contribute substantially to phenotypes. In this study, we discovered structural variants (SVs) across a population sample of 358 high-coverage, resequenced genomes of Asian rice (Oryza sativa) and its wild ancestor (O. rufipogon). In addition to this short-read dataset, we also inferred SVs from whole-genome assemblies and long-read data. Comparisons among datasets revealed different features of genome variability. For example, genome alignment identified a large (~4.3 Mb) inversion in indica rice varieties relative to an outgroup, and long-read analyses suggest that ~9% of genes from this outgroup are hemizygous. We focused, however, on the resequencing sample to investigate the population genomics of SVs. Clustering analyses with SVs recapitulated the rice cultivar groups that were also inferred from SNPs. However, the site-frequency spectrum of each SV type -- which included inversions, duplications, deletions, translocations and mobile element insertions -- was skewed toward lower frequency variants than synonymous SNPs, suggesting that SVs are predominantly deleterious. The strength of these deleterious effects varied among SV types, with inversions especially deleterious, and across transposable element (TE) families. Among TEs SINE and mariner insertions were especially deleterious, due to stronger selection against their insertions. We also used SVs to study domestication by contrasting between rice and O. rufipogon. Cultivated genomes contained ~25% more derived SVs than O. rufipogon, suggesting these deleterious SVs contribute to the cost of domestication. We also used SVs to study the effects of positive selection on the rice genome. Generally, the search for domestication genes were enriched for known candidates, suggesting some utility for SVs towards this purpose. More importantly, we detected hundreds to thousands of genes gained and lost during domestication, many of which are predicted to contribute to traits of agronomic interest.

evolutionary biology↗

bioRxiv2019

Elucidation of the determinant for orchestration of solo unisexual cycle in an important human fungal pathogen

In fungi, the sex-determination program universally directs sexual development and syngamy (the fusion of gametes) that underlies pre-meiotic diploidization. However, the contribution of sex-determination to syngamy-independent sexual cycle, which requires autopolyploidization as an alternative approach to elevate ploidy before meiosis, remains unclear in fungi and other eukaryotes. The human fungal pathogen Cryptococcus neoformans, as a model organism for studying fungal sexual reproduction, can undergo syngamy-dependent bisexual and syngamy-independent solo unisexual reproduction, in which endoreplication is considered to enable pre-meiotic self-diploidization. Here, by characterizing a mutant lacking all the core sex-determination factors, we show that sex-determination plays a central role in bisexual syngamy but is not strictly required for unisexual development and self-diploidization. This implies an unknown circuit, rather than the sex-determination program, for specifically coordinating Cryptococcus unisexual cycle. We reveal that syngamy and self-diploidization are both governed by the Qsp1-directed paracrine system via two regulatory branches, Vea2 and Cqs2. Vea2 directs bisexual syngamy through the sex-determination program; conversely, Cqs2 is dispensable for bisexual syngamy but activates unisexual endoreplication. Through functional profiling of 41 transcription factors documented to regulate Cryptococcus sexual development, we reveal that only Cqs2 can drive and integrate all unisexual phases and ensure the production of meiospore progenies. Furthermore, ChIP-seq analysis together with genetic evaluation indicate that Cqs2 induces unisexual self-diploidization through its direct control of PUM1, whose expression is sufficient to drive autopolyploidization. Therefore, Cqs2 serves as the critical determinant that orchestrates Cryptococcus multistage unisexual cycle that does not strictly require the sexual-determination program.

microbiology↗

bioRxiv2019

Can computers understand word meanings like the human brain does? Comparable semantic representation in neural and computer systems

Semantic representation has been studied independently in neuroscience and computer science. A deep understanding of human neural computations and the revolution to strong artificial intelligence appeal for a joint force in the language domain. We investigated comparable representational formats of lexical semantics between these two complex systems with fine temporal resolution neural recordings. We found semantic representations generated from computational models significantly correlated with EEG responses at an early stage of a typical semantic processing time window in a two-word semantic priming paradigm. Moreover, three representative computational models differentially predicted EEG responses along the dynamics of word processing. Our study provided a finer-grained understanding of the neural dynamics underlying semantic processing and developed an objective biomarker for assessing human-like computation in computational models. Our novel framework trailblazed a promising way to bridge across disciplines in the investigation of higher-order cognitive functions in human and artificial intelligence.

neuroscience↗

bioRxiv2019

A Plausible Accelerating Function of Intermediate States in Cancer Metastasis

Epithelial-to-mesenchymal transition (EMT) is a fundamental cellular process and plays an essential role in development, tissue regeneration, and cancer metastasis. Interestingly, EMT is not a binary process but instead proceeds with multiple partial intermediate states. However, the functions of these intermediate states are not fully understood. Here, we focus on a general question about how the number of partial EMT states affects cell transformation. First, by fitting a hidden Markov model of EMT with experimental data, we propose a statistical mechanism for EMT in which many unobservable microstates may exist within one of the observable macrostates. Furthermore, we find that increasing the number of intermediate states can accelerate the EMT process and that adding parallel paths or transition layers accelerates the process even further. Last, a stabilized intermediate state traps cells in one partial EMT state. This work advances our understanding of the dynamics and functions of EMT plasticity during cancer metastasis.

systems biology↗

bioRxiv2019

Learning Your Heart Actions From Pulse: ECG Waveform Reconstruction From PPG

This paper studies the relation between electrocardiogram (ECG) and photoplethysmogram (PPG) and infers the waveform of ECG via the PPG signals that can be obtained from affordable wearable Internet-of-Things (IoT) devices for mobile health. In order to address this inverse problem, a transform is proposed to map the discrete cosine transform (DCT) coefficients of each PPG cycle to those of the corresponding ECG cycle based on our proposed cardiovascular signal model. The proposed method is evaluated with different morphologies of the PPG and ECG signals on three benchmark datasets with a variety of combinations of age, weight, and health conditions using different training setups. Experimental results show that the proposed method can achieve a high prediction accuracy greater than 0.92 in averaged correlation for each dataset when the model is trained subject-wise. With a signal processing and learning system that is designed synergistically, we are able to reconstruct ECG signals by exploiting the relation of these two types of cardiovascular measurement. The reconstruction capability of the proposed method can enable low-cost ECG screening from affordable wearable IoT devices for continuous and long-term monitoring. This work may open up a new research direction to transfer the understanding of the clinical ECG knowledge base to build a knowledge base for PPG and data from wearable devices.

bioinformatics↗

bioRxiv2019

How do we segment text? Two-stage chunking operation in reading

Chunking in language comprehension is a process that segments continuous linguistic input into smaller chunks that are in readers mental lexicon. Effective chunking during reading facilitates disambiguation and enhances efficiency for comprehension. However, the mechanisms of chunking remain elusive, especially in reading given that information arrives simultaneously yet the written systems may not have explicit cues for labeling boundaries such as Chinese. What are the mechanisms of chunking operation that mediates the reading of the text that normally contains hierarchical information? We investigated this question by manipulating the lexical status of the chunks at distinct levels of grain-size in four-character Chinese strings, including the two-character local chunk and four-character global chunk. Participants were asked to make lexical decision on these strings in a behavioral experiment, followed by a passive reading task when their electroencephalography (EEG) were recorded. The behavioral results showed that the lexical decision time of lexicalized two-character local chunks was influenced by the lexical status of four-character global chunk, but not vice versa, which indicated that the processing of global chunks possessed priority over the local chunks. The EEG results revealed that familiar lexical chunks were detected simultaneously at both levels and further processed in a different temporal order -- the onset of lexical access for the global chunks was earlier than that of local chunks. These consistent behavioral and EEG results suggest that chunking in reading occurs at multiple levels via a two-stage operation -- simultaneous detection and global-first recognition.\n\nSignificance StatementThe learners of a new language often read word by word. But why can proficient readers read multiple words at a time? The current study investigates how we efficiently segment a complicate text into smaller pieces and how we process these pieces. Participants read Chinese strings with different structures while their key-press responses and brain EEG signals were recorded. We found that texts were quickly (about 100 ms from their occurrences) segmented to varied sizes of pieces, and larger pieces were then processed earlier than small pieces. Our results suggest that readers can use existing knowledge to efficiently segment and process written information.

animal behavior and cognition↗

bioRxiv2019

Zonation-dependent single-endothelial cell transcriptomic changes in the aged brain

With advances in single-cell genomics, molecular signatures of cells comprising the brain vasculature are revealed in unprecedented detail1,2, yet the ageing-associated cell subtype transcriptomic changes which may contribute to neurovascular dysfunction in neurodegenerative diseases3-7 remain elusive. Here, we performed single-cell transcriptomic profiling of brain endothelial cells (EC) in young adult and aged mice to characterize their ageing-associated genome-wide expression changes. We identified zonation-dependent transcriptomic changes in aged brain EC subtypes, with capillary ECs exhibiting the most transcriptomic alterations. Pathway enrichment analysis revealed altered immune/cytokine signaling in ECs of all vascular segments, while functional changes impacting the blood-brain barrier (BBB) and glucose/energy metabolism were most prominently implicated in ECs of the capillary bed - the primary site where ECs and other neurovascular unit (NVU) cell types closely interact and coordinate to regulate BBB and cerebral blood flow in health and diseased conditions8-17. Furthermore, an overrepresentation of Alzheimers disease (AD)-associated genes identified from GWAS studies was evident among the human orthologs of differentially expressed genes of aged capillary ECs but not other EC subtypes. Importantly, for numerous EC-enriched differentially expressed genes with important functional roles at the BBB and/or association with AD, we found concordant expression changes in human aged or AD brains. Finally, we demonstrated that treatment with exenatide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, strongly reverses transcriptomic changes in ECs and largely reduces BBB leakage in the aged brain. Thus, our study provides insights into detailed transcriptomic alterations underlying brain EC ageing that are complex with subtype specificity yet amenable to pharmacological interventions.

neuroscience↗

bioRxiv2019

Revealing the Temporal Dynamics in Non-invasive Electrophysiological recordings with Topography-based Analyses

The fine temporal resolution of electroencephalography (EEG) makes it one of the most widely used non-invasive electrophysiological recording methods in cognitive neuroscience research. One of the common ways to explore the neural dynamics is to create event-related potentials (ERPs) by averaging trials, followed by the examination of the response magnitude at peak latencies. However, a complete profile of neural dynamics, including temporal indices of onset time, offset time, duration, and processing speed, is needed to investigate cognitive neural mechanisms. Based on the multivariate topographic analysis, we developed an analytical framework that included two methods to explore neural dynamics in ERPs. The first method separates continuous ERP waveforms into distinct components based on their topographic patterns. Crucial temporal indices such as the peak latency, onset and offset times can be automatically identified and indices about processing speed such as duration, rise, and fall speed can be derived. The second method scrutinizes the temporal dynamics of identified components by reducing the temporal variance among trials. The response peaks of signal trials are identified based on a target topographic template, and temporal-variance-free ERPs are obtained after aligning individual trials. This method quantifies the temporal variance as a new measure of cognitive noise, as well as increases both the accuracy of temporal dynamics estimation and the signal-to-noise ratio (SNR) of the ERP responses. The validity and reliability of these methods were tested with simulation as well as empirical datasets from an attention study and a semantic priming (N400) study. Together, we offer an analytical framework in a data-driven, bias-free manner to investigate neural dynamics in non-invasive scalp recordings. These methods are implemented in the Python-based open-source package TTT (Topography-based Temporal-analysis Toolbox).

neuroscience↗

bioRxiv2019

Verbal thinking in rhythm: motor-to-sensory transformation network mediates imagined singing

What enables our mental activities for thinking verbally or humming in our mind? We hypothesized that the interaction between motor and sensory systems induces speech and melodic mental representations, and this motor-to-sensory transformation forms the neural basis that enables our verbal thinking and covert singing. Analogous with the neural entrainment to auditory stimuli, participants imagined singing lyrics of well-known songs rhythmically while their neural electromagnetic signals were recorded using magnetoencephalography (MEG). We found that when participants imagined singing the same song in similar durations across trials, the delta frequency band (1-3 Hz, similar to the rhythm of the songs) showed more consistent phase coherence across trials. This neural phase tracking of imagined singing was observed in a frontal-parietal-temporal network - the proposed motor-to-sensory transformation pathway, including the inferior frontal gyrus (IFG), insula, premotor, intra-parietal sulcus (IPS), the temporal-parietal junction (TPJ), primary auditory cortex (HG), and superior temporal gyrus and sulcus (STG & STS). These results suggest that neural responses can entrain the rhythm of mental activity. Moreover, the theta band (4-8 Hz) phase coherence was localized in the auditory cortices. The mu (9-12 Hz) and beta (17-20 Hz) bands were observed in the right-lateralized sensorimotor systems that were consistent with the singing context. The gamma band was broadly manifested in the observed network. The coherent activation in the motor-to-sensory transformation network as well as the frequency-specific activation in the motor, somatosensory, and auditory cortices mediate the internal construction of perceptual representations and form the foundation of neural computations for mental operations.

neuroscience↗

bioRxiv2019

Screening and identification of MicroRNAs expressed in perirenal adipose tissue during rabbit growth

MiRNAs regulate adipose tissue development, which are closely related to subcutaneous and intramuscular fat deposition and adipocyte differentiation. As an important economic and agricultural animal, rabbits have low adipose tissue deposition and are an ideal model to study adipose regulation. However, the miRNAs related to fat deposition during the growth and development of rabbits are poorly defined. In this study, miRNA-sequencing and bioinformatics analyses were used to profile the miRNAs in rabbit perirenal adipose tissue at 35, 85 and 120 days post-birth. Differentially expressed (DE) miRNAs between different stages were identified by DEseq in R. Target genes of DE miRNAs were predicted by TargetScan and miRanda. To explore the functions of identified miRNAs, Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. Approximately 1.6 GB of data was obtained by miRNA-seq. A total of 987 miRNAs (780 known and 207 newly predicted) and 174 DE miRNAs were identified. The miRNAs ranged from 18nt to 26nt. GO enrichment and KEGG pathway analyses revealed that the target genes of the DE miRNAs were mainly involved in zinc ion binding, regulation of cell growth, MAPK signaling pathway, and other adipose hypertrophy-related pathways. Six DE miRNAs were randomly selected and their expression profiles were validated by q-PCR. In summary, we provide the first report of the miRNA profiles of rabbit adipose tissue during different growth stages. Our data provide a theoretical reference for subsequent studies on rabbit genetics, breeding and the regulatory mechanisms of adipose development.

developmental biology↗

bioRxiv2019

Reversal of ageing- and injury-induced vision loss by Tet-dependent epigenetic reprogramming

Ageing is a degenerative process leading to tissue dysfunction and death. A proposed cause of ageing is the accumulation of epigenetic noise, which disrupts youthful gene expression patterns that are required for cells to function optimally and recover from damage1-3. Changes to DNA methylation patterns over time form the basis of an ageing clock4, 5, but whether old individuals retain information to reset the clock and, if so, whether this would improve tissue function is not known. Of all the tissues in the body, the central nervous system (CNS) is one of the first to lose regenerative capacity6, 7. Using the eye as a model tissue, we show that expression of Oct4, Sox2, and Klf4 genes (OSK) in mice resets youthful gene expression patterns and the DNA methylation age of retinal ganglion cells, promotes axon regeneration after optic nerve crush injury, and restores vision in a mouse model of glaucoma and in normal old mice. This process, which we call recovery of information via epigenetic reprogramming or REVIVER, requires the DNA demethylases Tet1 and Tet2, indicating that DNA methylation patterns dont just indicate age, they participate in ageing. Thus, old tissues retain a faithful record of youthful epigenetic information that can be accessed for functional age reversal.

molecular biology↗

bioRxiv2019

Discovery of powdery mildew resistance gene candidates from Aegilops biuncialis chromosome 2Mb based on transcriptome sequencing

Powdery mildew is one of the most widespread diseases of wheat. Breeding resistant varieties by utilization of resistance genes is considered as the most economic and effective method of controlling this disease. Previous study showed that the gene(s) at 2Mb in Chinese Spring (CS)-Aegilops biuncialis 2Mb disomic addition line TA7733 conferred high resistance to powdery mildew. In this study, 15 Bgt isolates prevalent in different regions of China were used to further test the resistance spectrum of TA7733. As a result, TA7733 was high resistance to all tested isolates, indicating that the gene(s) on chromosome 2Mb was broad-spectrum powdery mildew resistance. In order to mine resistance gene candidates and develop 2Mb-specific molecular markers to assist the transfer resistance gene(s) at chromosome 2Mb, RNA-seq of TA7733 and CS was conducted before and after Bgt-infection, generating a total of 158,953 unigenes. Of which, 7,278 unigenes were TA7733-specific which were not expressed in CS, and 295 out of these 7,278 unigenes were annotated as R genes. Based on Blastn against with CS Ref Seq v1.0, 61 R genes were further mapped to homoeologous group 2. Analysis of R gene-specific molecular markers designed from R gene sequences verified 40 out of 61 R genes to be 2Mb specific. Annotation of these 40 R genes showed most genes encoded nucleotide binding leucine rich repeat (NLR) protein, being most likely resistance gene candidates. The broad-spectrum powdery mildew resistance gene(s), disease resistance gene candidates, and functional molecular markers of 2Mb-specific in present study will not only lay foundations for transferring disease resistance gene(s) from 2Mb to common wheat by inducing CS-Ae. biuncialis homoeologous recombination, but also provide useful candidates for isolating and cloning resistance gene(s) and dissecting molecular and genetic mechanisms of disease resistance from 2Mb.

genetics↗

bioRxiv2019

CDK1 phosphorylates ULK1-ATG13 complex to regulate mitotic autophagy and Taxol chemosensitivity

ULK1-ATG13 is the most upstream autophagy initiation complex that is phosphorylated by mTORC1 and AMPK to induce autophagy in asynchronous conditions. However, the phospho-regulation and function of ULK1-ATG13 in mitosis and cell cycle remains unknown. Here we show that ULK1-ATG13 complex is differentially regulated throughout the cell cycle. Notably, in mitosis, both ULK1 and ATG13 are highly phosphorylated by CDK1/cyclin B, the key cell cycle machinery. Combining mass spectrometry and site-directed mutagenesis, we found that CDK1-induced ULK1-ATG13 phosphorylation positively regulates mitotic autophagy and Taxol chemosensitivity, and some phosphorylation sites occur in cancer patients. Moreover, double knockout of ULK1 and ATG13 could block cell cycle progression and significantly decrease cancer cell proliferation in cell line and mouse models. Our results not only bridge the mutual regulation between the core machineries of autophagy and mitosis, illustrate the mitotic autophagy regulation mechanism, but also provide ULK1-ATG13 as potential targets for cancer therapy.

cell biology↗

bioRxiv2019

Extension of the in vivo haploid induction system from diploid maize to hexaploid wheat

Doubled haploid breeding technology has been one of the most important techniques for accelerating crop breeding. In compare to in vivo haploid induction in maize, which is efficient and background independent, wheat haploid production by interspecific hybridization pollinated with maize is influenced by genetic background and requires rescue of young embryos. Here, we analyzed the homologues of maize haploid induction gene MTL/ZmPLA1/NLD in several crop species systematically, the homologues are highly conserved in sorghum, millet and wheat etc. Since wheat is a very important polyploidy crop, as a proof of concept, we demonstrated that the in vivo haploid induction method could be extended from diploid maize to hexaploid wheat by knocking out the wheat homologues (TaPLAs). Result showed that double knock-out mutation could trigger wheat haploid induction at ~ 2%-3%, accompanied by 30% - 60% seed setting rate. The performance of haploid wheat individual showed shorter plant, narrower leaves and male sterile. Our results also revealed that knockout of TaPLA-A and TaPLA-D do not affect pollen viability. This study not only confirmed the function of the induction gene and explored a new approach for haploid production in wheat, but also provided an example that the in vivo haploid induction could be applied in more crop species with different ploidy levels. Furthermore, by combining with gene editing, it would be a fast and powerful platform for traits improvement in polyploidy crops breeding.

plant biology↗

bioRxiv2019

Dynamics of soil nematode communities revealed significant variation in greenhouse with different continuous cropping years

Continuous cropping usually resulted in a series of soil problems, especially root knot nematode disaster in greenhouse because of imbalance in soil nematode community. However, the dynamic change in soil nematode community in greenhouse with various continuous cropping years during plant growing season is unclear. Here, soil nematode communities in greenhouse after 2 and 10 years of continuous cropping were comparatively analyzed using 18S rDNA high-throughput sequencing to reveal the changing processes in soil nematode communities. Compared to the 2-year greenhouse, soil in the 10-year greenhouse showed soil acidification, nutrients accumulation, salinization. In term of -diversity, Bacterial-feeding nematodes (BF) were dominant in the 2-year greenhouse over the whole growing season, but plant-parasitic nematodes (PP) became the dominant group in the 10-year greenhouse in the late growing season. Meloidogyne gradually became the dominant group (Relative abundance 70.9%) in the 10-year greenhouse, while Rhabditidae (Relative abundance from 99.8% to 26.8%) was the predominant members in the 2-year greenhouse. For {beta}-diversity, hierarchical clustering analysis, unWeighted UniFrac principal component analysis (PCA) and principal co-ordinates analysis (PCoA) all revealed that soil nematode communities in the two types of greenhouses exhibited significant differences. Redundancy analysis (RDA) showed that soil nematode communities in the 10-year greenhouse were related to high soil organic material, total nitrogen, electrical conductivity and disease index of root knot nematode. Fisher exact test and Pearson correlation coefficients revealed that Meloidogyne caused main differences in soil nematode communities between the two types of greenhouses. Meanwhile, population dynamics of Meloidogyne were divided into dormant phase, low-level increasing phase and exponential phase during the whole season. In total, the significant variation led different dynamics of soil nematode communities in the 2-year and 10-year greenhouse.

ecology↗

bioRxiv2019

The complete chloroplast genome of Chinese medicine (Psoralea corylifolia Linn): Molecular Structures, Barcoding analysis, and Phylogenetic Analysis

Psoralea corylifolia is one kind of traditional Chinese medicine used in China widely. In this study, we sequence the complete chloroplast genome of P. corylifolia, which is 153,114 bp in size and includes a pair of inverted repeats regions of 25,557 bp interspersed by a small single copy of 17,885 bp and a large single copy of 84,115 bp region. Approximately 98 simple sequence repeats, 14 forward, 2 reverse, 2 complement, 32 palindromic and 49 tandem repeats are identified in the P. corylifolia chloroplast genome. The chloroplast genomes of P. corylifolia and three Glycine species are conserved in gene order and content, but show high diversity within intergenic spacers. P. corylifolia with three Glycine species in Papilionoideae fall into the same clade based on 75 conserved coding-protein genes phylogenomic analysis. Moreover, four chloroplast DNA regions (ycf1, matK, accD, ndhF) can serve as the barcodes. In general, our findings will dedicate to better comprehension of the genome aspect as well as evolutionary status of P. corylifolia.

genomics↗

bioRxiv2019

Infection of Plasmodiophora brassicae changes the fungal endophyte community of tumourous stem mustard roots as revealed by high-throughput sequencing and culture-dependent methods

Diverse fungal endophytes live in plants and are shaped by some abiotic and biotic stresses. Plant disease as particular biotic stress possibly gives an impact on the communities of fungal endophytes. In this study, clubroot disease caused by an obligate biotroph protist, Plasmodiophora brassicae, was considered to analyze its influence on the fungal endophyte community using an internal transcribed spacer (ITS) through high-throughput sequencing and culture-dependent methods. The results show that the diversity of the endophyte community in the healthy roots was much higher than the clubroots. Ascomycota was the dominant group of endophytes (including Phoma, Mortierella, Penicillium, etc.) in the healthy roots while P. brassicae was the dominant taxon in the clubroots. Hierarchical clustering, principal component analysis (PCA) and principal coordinates analysis (PCoA) indicated significant differences between the endophyte communities in the healthy roots and clubroots. Linear discriminant analysis effect size (LefSe) analysis showed that the dominant genera could be regarded as potential biomarkers. The endophyte community in the healthy roots had a more complex network compared with the clubroots. Also, many plant pathogenic Fusarium were isolated from the clubroots by the culture-dependent method. The outcome of this study illustrates that P. brassicae infection may change the fungal endophyte community associated with the roots of tumourous stem mustard and facilitates the entry of soil pathogen into the roots.

microbiology↗

bioRxiv2019

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program

Summary paragraphThe Trans-Omics for Precision Medicine (TOPMed) program seeks to elucidate the genetic architecture and disease biology of heart, lung, blood, and sleep disorders, with the ultimate goal of improving diagnosis, treatment, and prevention. The initial phases of the program focus on whole genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here, we describe TOPMed goals and design as well as resources and early insights from the sequence data. The resources include a variant browser, a genotype imputation panel, and sharing of genomic and phenotypic data via dbGaP. In 53,581 TOPMed samples, >400 million single-nucleotide and insertion/deletion variants were detected by alignment with the reference genome. Additional novel variants are detectable through assembly of unmapped reads and customized analysis in highly variable loci. Among the >400 million variants detected, 97% have frequency <1% and 46% are singletons. These rare variants provide insights into mutational processes and recent human evolutionary history. The nearly complete catalog of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and non-coding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and extends the reach of nearly all genome-wide association studies to include variants down to ~0.01% in frequency.

genomics↗