Biology subjects

Su, C.

Publications and source records attributed to Su, C..

At least 73 records · Page 4Linked to original sources

bioRxiv2022

Genomic perspectives on the emerging SARS-CoV-2 Omicron variant

A new variant of concern for SARS-CoV-2, Omicron (B.1.1.529), was designated by the World Health Organization on November 26, 2021. This study analyzed the viral genome sequencing data of 108 samples collected from patients infected with Omicron. First, we found that the enrichment efficiency of viral nucleic acids was reduced due to mutations in the region where the primers anneal to. Second, the Omicron variant possesses an excessive number of mutations compared to other variants circulating at the same time (62 vs. 45), especially in the Spike gene. Mutations in the Spike gene confer alterations in 32 amino acid residues, which was more than those observed in other SARS-CoV-2 variants. Moreover, a large number of nonsynonymous mutations occur in the codons for the amino acid residues located on the surface of the Spike protein, which could potentially affect the replication, infectivity, and antigenicity of SARS-CoV-2. Third, there are 53 mutations between the Omicron variant and its closest sequences available in public databases. Many of those mutations were rarely observed in the public database and had a low mutation rate. In addition, the linkage disequilibrium between these mutations were low, with a limited number of mutations (6) concurrently observed in the same genome, suggesting that the Omicron variant would be in a different evolutionary branch from the currently prevalent variants. To improve our ability to detect and track the source of new variants rapidly, it is imperative to further strengthen genomic surveillance and data sharing globally in a timely manner.

genomics↗

bioRxiv2021

A spatiotemporal steroidogenic regulatory network in human fetal adrenal glands and gonads

Human fetal adrenal glands produce substantial amounts of dehydroepiandrosterone (DHEA), which is one of the most important precursors of sex hormones. However, the underlying biological mechanism remains largely unknown. Herein, we sequenced human fetal adrenal glands and gonads from 7 to 14 GW via the 10x Genomics single-cell transcriptome techniques and reconstructed their location information by Spatial Transcriptome, conducted COOL-seq for the MC2R+ inner zone steroidogenic cells during the time window of sex differentiation (8-12GW). We found that relative to gonads, adrenal glands begin to synthesize steroids early. The coordination among steroidogenic cells and multiple nonsteroidogenic cells promotes adrenal cortex construction and steroid synthesis. Notably, during the time window of sex differentiation (8-12 GW), key enzyme gene expression shifts to accelerate DHEA synthesis in males and cortisol synthesis in females. Furthermore, high SST+ expressions in the adrenal gland and testis amplify androgen synthesis in males. Our research highlights the robustness of the action of fetal adrenal glands on gonads to modify the process of sexual differentiation.

systems biology↗

bioRxiv2021

Profiling the Landscape of Drug Resistance Mutations in Neosubstrates to Molecular Glue Degraders

Targeted protein degradation (TPD) holds immense promise for drug discovery but mechanisms of acquired resistance to degraders remain to be fully identified. Here we used CRISPR-suppressor scanning to identify mechanistic classes of drug resistance mutations to molecular glue degraders in GSPT1 and RBM39, neosubstrates targeted by E3 ligase substrate receptors cereblon and DCAF15, respectively. While many mutations directly alter the ternary complex heterodimerization surface, distal resistance sites were also identified. Several distal mutations in RBM39 led to modest decreases in degradation yet can enable cell survival, underscoring how small differences in degradation can lead to resistance. Integrative analysis of resistance sites across GSPT1 and RBM39 revealed varying levels of sequence conservation and mutational constraint that control the emergence of different resistance mechanisms, highlighting that many regions co-opted by TPD are inessential. Altogether, our study identifies common resistance mechanisms for molecular glue degraders and outlines a general approach to survey neosubstrate requirements necessary for effective degradation.

molecular biology↗

bioRxiv2021

CSNet: Estimating cell-type-specific gene co-expression networks from bulk gene expression data

Inferring and characterizing gene co-expression networks has led to important insights on the molecular mechanisms of complex diseases. Most co-expression analyses to date have been performed on gene expression data collected from bulk tissues with different cell type compositions across samples. As a result, the co-expression estimates only offer an aggregate view of the underlying gene regulations and can be confounded by heterogeneity in cell type compositions, failing to reveal gene coordination that may be distinct across different cell types. In this paper, we describe a flexible framework for estimating cell-type-specific gene co-expression networks from bulk sample data, without making specific assumptions on the distributions of gene expression profiles in different cell types. We develop a novel sparse least squares estimator, referred to as CSNet, that is efficient to implement and has good theoretical properties. Using CSNet, we analyzed the bulk gene expression data from a cohort study on Alzheimers disease and identified previously unknown cell-type-specific co-expressions among Alzheimers disease risk genes, suggesting cell-type-specific disease pathology for Alzheimers disease.

bioinformatics↗

bioRxiv2021

Evidence for a Potential Pre-Pandemic SARS-like Coronavirus Among Animals in North America

In late 2019, a novel coronavirus began circulating within humans in central China. It was designated SARS-CoV-2 because of its genetic similarities to the 2003 SARS coronavirus (SARS-CoV). Now that SARS-CoV-2 has spread worldwide, there is a risk of it establishing new animal reservoirs and recombination with native circulating coronaviruses. To screen local animal populations in the United States for exposure to SARS-like coronaviruses, we developed a serological assay using the receptor binding domain (RBD) from SARS-CoV-2. SARS-CoV-2s RBD is antigenically distinct from common human and animal coronaviruses allowing us to identify animals previously infected with SARS-CoV or SARS-CoV-2. Using an indirect ELISA for SARS-CoV-2s RBD, we screened serum from wild and domestic animals for the presence of antibodies against SARS-CoV-2s RBD. Surprisingly pre-pandemic feline serum samples submitted to the University of Tennessee Veterinary Hospital were [~]50% positive for anti-SARS RBD antibodies. Some of these samples were serologically negative for feline coronavirus (FCoV), raising the question of the etiological agent generating anti-SARS-CoV-2 RBD cross-reactivity. We also identified several white-tailed deer from South Carolina with anti-SARS-CoV-2 antibodies. These results are intriguing as cross-reactive antibodies towards SARS-CoV-2 RBD have not been reported to date. The etiological agent responsible for seropositivity was not readily apparent, but finding seropositive cats prior to the current SARS-CoV-2 pandemic highlights our lack of information about circulating coronaviruses in other species. ImportanceWe report cross-reactive antibodies from pre-pandemic cats and post-pandemic South Carolina white-tailed deer that are specific for that SARS-CoV RBD. There are several potential explanations for this cross-reactivity, each with important implications to coronavirus disease surveillance. Perhaps the most intriguing possibility is the existence and transmission of an etiological agent (such as another coronavirus) with similarity to SARS-CoV-2s RBD region. However, we lack conclusive evidence of pre-pandemic transmission of a SARS-like virus. Our findings provide impetus for the adoption of a One Health Initiative focusing on infectious disease surveillance of multiple animal species to predict the next zoonotic transmission to humans and future pandemics.

immunology↗

bioRxiv2021

Projecting genetic associations through gene expression patterns highlights disease etiology and drug mechanisms

Genes act in concert with each other in specific contexts to perform their functions. Determining how these genes influence complex traits requires a mechanistic understanding of expression regulation across different conditions. It has been shown that this insight is critical for developing new therapies. In this regard, the role of individual genes in disease-relevant mechanisms can be hypothesized with transcriptome-wide association studies (TWAS), which have represented a significant step forward in testing the mediating role of gene expression in GWAS associations. However, modern models of the architecture of complex traits predict that gene-gene interactions play a crucial role in disease origin and progression. Here we introduce PhenoPLIER, a computational approach that maps gene-trait associations and pharmacological perturbation data into a common latent representation for a joint analysis. This representation is based on modules of genes with similar expression patterns across the same conditions. We observed that diseases were significantly associated with gene modules expressed in relevant cell types, and our approach was accurate in predicting known drug-disease pairs and inferring mechanisms of action. Furthermore, using a CRISPR screen to analyze lipid regulation, we found that functionally important players lacked TWAS associations but were prioritized in trait-associated modules by PhenoPLIER. By incorporating groups of co-expressed genes, PhenoPLIER can contextualize genetic associations and reveal potential targets missed by single-gene strategies.

bioinformatics↗

bioRxiv2021

Multiple levels of triggered factors and positive effect of cell-to-cell bottleneck in mutation repair of RNA viruses

Debilitating mutation in RNA viruses can be repaired via different mechanisms, while triggering factors of mutation repair were poorly understood. In this study, multiple levels of triggering factors of mutation repair was identified based on genetic damage of tRNA-like structure (TLS) in cucumber mosaic virus (CMV). TLS mutation in different RNAs of CMV distinctively impacted the pathogenicity and mutation repair. Relative quantity defect of RNA2 or quality defect of RNA3 resulting from TLS mutation was correlated with high rate of mutation repair, and TLS mutation of RNA1 failed to be repaired. However, TLS mutation of RNA1 can be repaired in the mixed inoculation with RNA2 having pre-termination mutation of 2b or at the low dose of original inoculation, especially around dilution end-point. Taken together, TLS mutation resulting into quality or quantity defect of viral genome or TLS mutation at low dose around dilution end-point was inclined to be repaired. In addition, different levels of mutation repair of TLS necessarily required the cell-to-cell movement, which implied the positive effect of cell-to-cell bottleneck on evolution of low-fitness virus, a phenomenon opposite to the Muller ratchet. This study provided important revelations on virus evolution and application of viral mild vaccine. Author summaryDue to the low-fidelity of replicase, debilitating RNA viruses can be repaired through different mechanisms, which implied the resilience of RNA viruses. In this study, we identified multiple levels of triggered factors and occurrence occasion of mutation repair using the divided genome of CMV, which contained conserved cis-element tRNA-like structure (TLS) at the 3end. TLS mutation of different RNA in CMV presented different rate of mutation repair from 0-80%. TLS mutation resulting into genomic quality or quantity defect or at low dose around dilution end-point was inclined to be repaired. However, all above types of mutation repair necessarily required cell-to-cell movement, which presented the positive effect of cell-to-cell bottleneck on virus evolution and increased fitness of low-fitness RNA viruses. It is an opposite phenomenon to the Muller ratchet, in which bottleneck always decreased the fitness of viruses. Except to identify the triggering factors of mutation repair in RNA viruses, this study also provided important revelations on creation and application of mild vaccine based on RNA viruses.

pathology↗

bioRxiv2021

Spatially coordinated heterochromatinization of distal short tandem repeats in fragile X syndrome

Short tandem repeat (STR) instability is causally linked to pathologic transcriptional silencing in a subset of repeat expansion disorders. In fragile X syndrome (FXS), instability of a single CGG STR tract is thought to repress FMR1 via local DNA methylation. Here, we report the acquisition of more than ten Megabase-sized H3K9me3 domains in FXS, including a 5-8 Megabase block around FMR1. Distal H3K9me3 domains encompass synaptic genes with STR instability, and spatially co-localize in trans concurrently with FMR1 CGG expansion and the dissolution of TADs. CRISPR engineering of mutation-length FMR1 CGG to normal-length preserves heterochromatin, whereas cut-out to pre-mutation-length attenuates a subset of H3K9me3 domains. Overexpression of a pre-mutation-length CGG de-represses both FMR1 and distal heterochromatinized genes, indicating that long-range H3K9me3-mediated silencing is exquisitely sensitive to STR length. Together, our data uncover a genome-wide surveillance mechanism by which STR tracts spatially communicate over vast distances to heterochromatinize the pathologically unstable genome in FXS. One-Sentence SummaryHeterochromatinization of distal synaptic genes with repeat instability in fragile X is reversible by overexpression of a pre-mutation length CGG tract.

genomics↗

bioRxiv2021

Atrx deletion impairs cGAS-STING signaling and increases response to radiation and oncolytic herpesvirus in sarcoma

ATRX is one of the most frequently altered genes in solid tumors, and mutation is especially frequent in soft tissue sarcomas. However, the role of ATRX in tumor development and response to cancer therapies remains poorly understood. Here, we developed a primary mouse model of soft tissue sarcoma and showed that Atrx deleted tumors are more sensitive to radiation therapy. In the absence of Atrx, irradiated sarcomas have increased persistent DNA damage, telomere dysfunction, and mitotic catastrophe. We find that Atrx deleted sarcomas have a reduced adaptive immune response, impaired cGAS-STING signaling, and increased sensitivity to an oncolytic herpesvirus therapy. Translation of these results to patients with ATRX mutant cancers could enable genomically-guided cancer therapeutic approaches that improve patient outcomes.

cancer biology↗

bioRxiv2021

Cryo-EM study on the homo-oligomeric ring formation of yeast TRiC/CCT subunits reveals TRiC ring assembly mechanism

The complex eukaryotic chaperonin TRiC/CCT helps maintain cellular protein homeostasis, however, its assembly mechanism remains largely unknown. To address the subunit specificity in TRiC assembly, we express each of the individual yeast TRiC subunit in E. coli. Our cryo-EM structural study and biochemical analyses demonstrate that CCT1/2/6 can form TRiC-like homo-oligomeric double ring (HR) complex, however ATP-hydrolysis cannot trigger their ring closure; after deletion of the long N-terminal extension, CCT5 can form the closed double-ring structure; while CCT3/4/7/8 cannot form the HRs. It appears that CCT1 forms a HR in a unique spiral configuration, and ATP-hydrolysis can drive it to re-assemble with an inserted extra subunit-pair. Our data suggest that CCT5 could be the leading subunit in ATP-hydrolysis-driven TRiC ring closure. Moreover, we demonstrate that ADP is sufficient to trigger the assembly of the HRs and TRiC from the assembly intermediate micro-complex form. Our study reveals that through evolution, the more ancestral subunits may have evolved to take more responsibilities in TRiC ring assembly, and we propose a possible assembly mechanism of TRiC involving subunit-pair insertion. Collectively, our study gives hints on the structural basis of subunit specificity in TRiC assembly and cooperativity, beneficial for future TRiC-related therapeutic strategy development.

biochemistry↗

bioRxiv2020

Identification of COVID-19-relevant transcriptional regulatory networks and associated kinases as potential therapeutic targets

Identification of transcriptional regulatory mechanisms and signaling networks involved in the response of host to infection by SARS-CoV-2 is a powerful approach that provides a systems biology view of gene expression programs involved in COVID-19 and may enable identification of novel therapeutic targets and strategies to mitigate the impact of this disease. In this study, we combined a series of recently developed computational tools to identify transcriptional regulatory networks involved in the response of epithelial cells to infection by SARS-CoV-2, and particularly regulatory mechanisms that are specific to this virus. In addition, using network-guided analyses, we identified signaling pathways that are associated with these networks and kinases that may regulate them. The results identified classical antiviral response pathways including Interferon response factors (IRFs), interferons (IFNs), and JAK-STAT signaling as key elements upregulated by SARS-CoV-2 in comparison to mock-treated cells. In addition, comparing SARS-Cov-2 infection of airway epithelial cells to other respiratory viruses identified pathways associated with regulation of inflammation (MAPK14) and immunity (BTK, MBX) that may contribute to exacerbate organ damage linked with complications of COVID-19. The regulatory networks identified herein reflect a combination of experimentally validated hits and novel pathways supporting the computational pipeline to quickly narrow down promising avenue of investigations when facing an emerging and novel disease such as COVID-19.

systems biology↗

bioRxiv2020

Restriction enzyme selection dictates detection range sensitivity in chromatin conformation capture-based variant-to-gene mapping approaches

Promoter-focused chromatin conformation techniques directly detect interactions between gene promoters and distal genomic sequences, providing structural information relevant to gene regulation without the excessive non-genic architectural data generated by full scale Hi-C. 3D promoter interactome maps are crucial for understanding how epigenomic features like histone modifications and open chromatin, or genetic variants identified in genome wide association studies (GWAS), contribute to biological function. However, variation in sensitivity between such promoter-focused methods, principally due to restriction enzyme selection, has not been systematically assessed. Here, we performed a head-to-head comparison between promoter capture C (PCC) and promoter capture Hi-C (PCHiC) with the respective 4 cutters DpnII and MboI versus 6 cutter HindIII datasets from the same five cell types. While PCHiC generally produces a higher signal to noise ratio for significant interactions in comparison to PCC, we show that DpnII/MboI detects more proximal interactions and shows little overlap with the HindIII detection range. Promoter-interacting genomic regions mapped by 4-cutters are more enriched for regulatory features and disease-associated genetic variation than 6-cutters maps, suggesting that high-resolution maps better capture gene regulatory architectures than do lower resolution approaches.

genomics↗

bioRxiv2020

Integrative genomics identifies lncRNA regulatory networks across 1,044 pediatric leukemias and solid tumors

Long non-coding RNAs (lncRNAs) play an important role in gene regulation and contribute to tumorigenesis. While pan-cancer studies of lncRNA expression have been performed for adult malignancies, the lncRNA landscape across pediatric cancers remains largely uncharted. Here, we curate RNA sequencing data for 1,044 pediatric leukemia and solid tumors and integrate paired tumor whole genome sequencing and epigenetic data in relevant cell line models to explore lncRNA expression, regulation, and association with cancer. We report a total of 2,657 robustly expressed lncRNAs across six pediatric cancers, including 1,142 exhibiting histotype-specific expression. DNA copy number alterations contributed to lncRNA dysregulation at a proportion comparable to protein coding genes. Application of a multi-dimensional framework to identify and prioritize lncRNAs impacting gene networks revealed that lncRNAs dysregulated in pediatric cancer are associated with proliferation, metabolism, and DNA damage hallmarks. Analysis of upstream regulation via cell-type specific transcription factors further implicated distinct histotype-specific and developmental lncRNAs. We integrated our analyses to prioritize lncRNAs for experimental validation and showed that silencing of TBX2-AS1, our top-prioritized neuroblastoma-specific lncRNA, resulted in significant growth inhibition of neuroblastoma cells, confirming our computational predictions. Taken together, these data provide a comprehensive characterization of lncRNA regulation and function in pediatric cancers and pave the way for future mechanistic studies.

cancer biology↗

bioRxiv2020

CBX1 mutations cause a neurodevelopmental syndrome due to heterochromatin organizational alterations

PurposeThis study aimed to establish variants in CBX1, encoding heterochromatin protein 1{beta} (HP1{beta}), as a cause of a novel syndromic neurodevelopmental disorder. MethodsPatients with CBX1 variants were identified, and clinician researchers were connected using GeneMatcher and physician referrals. Clinical histories were collected from each patient. To investigate the pathogenicity of identified variants, we performed in vitro cellular assays, neurobehavioral and cytological analyses of neuronal cells obtained from newly generated Cbx1 mutant mouse lines. ResultsIn three unrelated individuals with developmental delay, hypotonia, and autistic features, we identified heterozygous de novo variants in CBX1. The identified variants were in the chromodomain, the functional domain of HP1 {beta}, which mediates interactions with chromatin. Cbx1 chromodomain mutant mice displayed increased latency-to-peak response, suggesting the possibility of synaptic delay or myelination deficits. Cytological and chromatin immunoprecipitation experiments confirmed the reduction of mutant HP1{beta} binding to heterochromatin, while HP1{beta} interactome analysis demonstrated that the majority of HP1{beta}-interacting proteins remained unchanged between the wild-type and mutant HP1{beta}. ConclusionThese collective findings confirm the role of CBX1 in developmental disabilities through the disruption of HP1{beta} chromatin binding during neurocognitive development. As HP1{beta} forms homodimers and heterodimers, mutant HP1{beta} likely sequesters wild-type HP1{beta} and other HP1 proteins, exerting dominant-negative effects.

genetics↗

bioRxiv2020

Dynamics and functional roles of splicing factor autoregulation

Non-spliceosomal splicing factors are essential, conserved regulators of alternative splicing. They provide concentration-dependent control of diverse pre-mRNAs. Many splicing factors direct unproductive splicing of their own pre-mRNAs through negative autoregulation. However, the impact of such feedback loops on splicing dynamics at the single cell level remains unclear. We developed a system to dynamically, quantitatively analyze negative autoregulatory splicing by the SF2 splicing factor in response to perturbations in single HEK293 cells. Here, we show that negative autoregulatory splicing provides critical functions for gene regulation, establishing a ceiling of SF2 protein concentration, reducing cell-cell heterogeneity in SF2 levels, and buffering variation in SF2 transcription. Most importantly, it adapts SF2 splicing activity to variations in demand from other pre-mRNA substrates. A minimal mathematical model of autoregulatory splicing explains these experimentally observed features, and provides values for effective biochemical parameters. These results reveal the unique functional roles that splicing negative autoregulation plays in homeostatically regulating transcriptional programs.

systems biology↗

bioRxiv2020

Cis-regulatory architecture of human ESC-derived hypothalamic neuron differentiation aids in variant-to-gene mapping of relevant common complex traits

SummaryThe hypothalamus regulates metabolic homeostasis by influencing behavior, energy utilization and endocrine systems. Given its role governing health-relevant traits, such as body weight and reproductive timing, understanding the genetic regulation of hypothalamic development and function should yield insights into these traits and diseases. However, given its inaccessibility, studying human hypothalamic gene regulation has proven challenging. To address this gap, we generated a chromatin architecture atlas of an established embryonic stem cell (ESC)-derived hypothalamic-like neuron (HN) model across three stages of in vitro differentiation. We profiled accessible chromatin and identified physically interacting contacts between gene promoters and their putative cis-regulatory elements (cREs) to characterize changes in the gene regulatory landscape during hypothalamic differentiation. Next, we integrated these data with GWAS loci for multiple traits and diseases enriched for heritability in these cells, identifying candidate effector genes and cREs impacting transcription factor binding. Our results reveal common target genes for these traits, potentially identifying core hypothalamic developmental pathways. Our atlas will enable future efforts to determine precise mechanisms underlying hypothalamic development with respect to specific disease pathogenesis.Competing Interest StatementThe authors have declared no competing interest.View Full Text

genomics↗

bioRxiv2020

Medial Prefrontal Cortex Interacts with the Anteromedial Thalamus in Motivation and Dopaminergic Activity

How does the prefrontal cortex (PFC) regulate motivated behavior? Our experiments characterize the circuits of the PFC regulating motivation, reinforcement and dopamine activity, revealing a novel cortico-thalamic loop. The stimulation of medial PFC (mPFC) neurons activated many downstream regions, as shown by functional MRI. Axonal terminal stimulation of mPFC neurons in downstream regions, including the anteromedial thalamic nucleus (AM), reinforced behavior and activated midbrain dopaminergic neurons. The stimulation of AM neurons projecting to the mPFC also reinforced behavior and activated dopamine neurons, and mPFC and AM showed a positive-feedback loop organization. Reciprocal excitatory functional connectivity, as well as co-activation of the two regions, was found in human participants who watched reinforcing videos. Our results suggest that this cortico-thalamic loop regulates motivation, reinforcement and dopaminergic neuron activity.

neuroscience↗

bioRxiv2019

Human follicular helper T cell promoter connectomes reveal novel genes and regulatory elements at SLE GWAS loci

Systemic lupus erythematosus (SLE) is a complex inflammatory disease mediated by autoreactive antibodies that damages multiple tissues in children and adults. Genome-wide association studies (GWAS) have statistically implicated hundreds of loci in the susceptibility to human disease, including SLE, but the majority have failed to identify the causal variants or the effector genes. As a physicochemical approach to detecting functional variants and connecting them to target genes, we generated comprehensive, high-resolution maps of SLE variant accessibility and gene connectivity in the context of the three-dimensional chromosomal architecture of human tonsillar follicular helper T cells (TFH), a cell type required for the production of anti-nuclear antibodies characteristic of SLE. These spatial epigenomic maps identified a shortlist of over 400 potentially functional variants across 48 GWAS-implicated SLE loci. Twenty percent of these variants were located in open promoters of highly-expressed TFH genes, while 80% reside in non-promoter genomic regions that are connected in 3D to genes that likewise tend to be highly expressed in TFH. Importantly, we find that 90% of SLE-associated variants exhibit spatial proximity to genes that are not nearby in the 1D sequence of the genome, and over 60% of variants skip the nearest gene to physically interact only with the promoters of distant genes. Gene ontology confirmed that genes in spatial proximity to SLE variants reside in highly SLE-relevant networks, including accessible variants that loop 200-1000 kb to interact with the promoters of the canonical TFH genes BCL6 and CXCR5. CRISPR-Cas9 genome editing confirmed that these variants reside in novel, distal regulatory elements required for normal BCL6 and CXCR5 expression by T cells. Furthermore, SLE-associated SNP-promoter interactomes implicated a set of novel genes with no known role in TFH or SLE disease biology, including the homeobox-interacting protein kinase HIPK1 and the Ste kinase homolog MINK1. Targeting these kinases in primary human TFH cells inhibited production of IL-21, a requisite cytokine for production of class-switched antibodies by B cells. This 3D-variant-to-gene mapping approach gives mechanistic insight into the SLE-associated regulatory architecture of the human genome.

genomics↗