Biology subjects

O'Neill, M.

Publications and source records attributed to O'Neill, M..

16 recordsLinked to original sources

bioRxiv2026

Single-cell full-length transcriptome of human lung reveals genetic effects on isoform regulation beyond gene-level expression

Genetic regulation of splicing uniquely contributes to trait-associated genome-wide association studies (GWAS) signals. However, quantitative trait loci (QTL) analysis using short-read sequencing of bulk tissues fails to capture full-length and cell-type-specific isoforms. Here, we present an isoform-level lung cell atlas from 129 never-smoking Korean women using single-cell long-read RNA-sequencing, identifying abundant unannotated and cell-type-specific isoforms. Isoform-level signatures of 37 lung cell types display a larger difference and therefore improve cell-type classification compared to gene-level expression. Notably, isoform-QTLs (isoQTLs) detect unannotated and/or cell-type-specific isoforms with independent genetic regulation from expression-QTL (eQTL), supported by enriched splicing functional elements. IsoQTLs nominate susceptibility isoforms from previously unexplained lung function and cancer GWAS loci, via eQTL-independent signals. We highlight a potentially functional novel variant of PPIL6 in multiciliated cells underlying lung cancer risk through alternative splicing. This isoform-level resource advances our understanding of cell-type-specific isoform regulation and its contribution to lung traits and diseases.

genetics↗

bioRxiv2026

Dual targeting of PDPK1 and BRAF V600E is synthetically lethal

PDPK1 functions downstream of PI3K and is essential for activating AKT and other AGC kinases. Although PDPK1 has a central role in the PI3K/AKT/mTOR signaling pathway, there has been limited evaluation of it as a target for cancer therapy. Anaplastic thyroid cancer (ATC) has one of the highest mortality rates of all human malignancies. Although combined BRAF and MEK inhibition in BRAF V600E mutant ATC (present in 45% of cases) results in response, resistance is common, and there is no curative treatment for ATC. The majority (up to 95.8%) of ATC cases have activation in the PI3K/AKT/mTOR and RAS/RAF/MEK/MAPK pathways due to genetic alterations involved in these pathways. In this study, we investigated PDPK1 as a therapeutic target for ATC. We used in vitro, ex vivo, and in vivo ATC models to evaluate the effect of targeting PDPK1 (BX795) alone and in combination with BRAF V600E inhibition (dabrafenib), and the mechanism of action that resulted in ATC cell death. BX795 monotherapy significantly reduced ATC cell proliferation, invasion, colony formation, and spheroid size. Combination BX795 and dabrafenib treatment had strong synergistic anticancer activity in BRAF V600E-mutant ATC models and led to simultaneous and sustained suppression of PDPK1/AKT and MAPK signaling, preventing the compensatory pathway reactivation observed with single-agent treatment. Mechanistically, combined inhibition induced pronounced oxidative stress, DNA damage, and G2-phase cell-cycle arrest, accompanied by mitochondrial dysfunction and robust activation of apoptosis in ATC cells. These effects resulted in marked tumor regression in in vitro, ex vivo, and in vivo ATC models. Our findings identify PDPK1 as a critical therapeutic vulnerability in ATC. Co-targeting PDPK1 and BRAF V600E produces potent synergistic anticancer activity by shutting down convergent oncogenic signaling pathways and amplifying apoptotic stress responses. These data support PDPK1 inhibition alone and in combination with BRAF blockade as a promising therapeutic strategy in BRAF V600E-mutant cancers.

cancer biology↗

bioRxiv2025

Patient-derived Cellular Models of Polygenic Scores: Application to Long QT Syndrome

Polygenic scores (PGS) have emerged as important modifiers of disease risk, drug response, and rare variant penetrance, but the biological mechanisms underlying these associations remain poorly understood. To experimentally investigate these relationships, we derived induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from individuals at the 1st, 50th, and 99th percentiles of a genome-wide QT interval polygenic score (QT-PGS). We examined baseline repolarization, drug response to the hERG inhibitor E4031, and penetrance of two KCNH2 variants (p.Arg148Trp and p.Arg823Trp) in these cellular models. While baseline field potential durations (FPDs) did not differ across PGS levels, high-PGS iPSC-CMs showed exaggerated prolongation in response to E4031 and increased phenotypic expression of both KCNH2 variants. These findings provide the first experimental demonstration that polygenic background can shape cardiac electrophysiologic phenotypes and modulate the functional impact of both pharmacologic and genetic perturbations. This work establishes a scalable platform for mechanistic studies of polygenic risk.

genetics↗

bioRxiv2025

CRISPR-Based Gene Dependency Screens reveal Mechanism of BRAF Inhibitor Resistance in Anaplastic Thyroid Cancer

Anaplastic thyroid cancer (ATC) is the most aggressive form of thyroid cancer. Despite recent advances in treating BRAFV600E-driven ATC, therapy resistance remains a significant challenge, often resulting in disease progression and death. Leveraging a focused CRISPR/KO screen in parallel with a CRISPR/activation screen, both tailored on response to BRAFV600E inhibitor treatment, we identified TAZ (encoded by the WWTR1 gene) deficiency as synthetically lethal with BRAF inhibitor in ATC. TAZ is overexpressed in ATC compared to well-differentiated thyroid tumors. We demonstrate that TAZ-deficient ATC cells display heightened sensitivity to BRAF inhibitors both in vitro and in vivo. Using gene essentiality score across a large panel of cancer cell lines, we found that BRAFV600E-driven cancers are highly sensitive to TAZ loss, unlike their counterparts with wild-type BRAF and non-BRAFV600E. Mechanistically, we demonstrate that dabrafenib triggers the Unfolded Protein Response (UPR) under ER stress and suppresses protein synthesis. TAZ loss represses the UPR, reverses the inhibition of protein synthesis, and triggers increased cell death by ferroptosis in dabrafenib-treated ATC. Collectively, our findings unveil TAZ as a new target to overcome resistance to BRAF inhibitors in undifferentiated thyroid cancer.

cancer biology↗

bioRxiv2025

Scaled multidimensional assays of variant effect identify sequence-function relationships in hypertrophic cardiomyopathy

BackgroundAn estimated 1 in 500 people live with hypertrophic cardiomyopathy (HCM), a disease for which genetic diagnosis can identify family members at risk, and increasingly guide therapy. Mutations in the myosin binding protein C3 (MYBPC3) gene account for a significant proportion of HCM cases. However, many of these variants are classified as variants of uncertain significance (VUS), complicating clinical decision-making. Scalable methods for variant interpretation in disease-specific cell types are crucial for understanding variant impact and uncovering disease mechanisms. MethodsWe developed a scaled multidimensional mapping strategy to evaluate the functional impact of variants across a critical domain of MYBPC3. We incorporate saturation base editing at the native MYBPC3 locus, a long-read RNA sequencing-enabled assay of variant splice effects, and measurements of HCM-relevant phenotypes, including MYBPC3 abundance, hypertrophic signaling, and ubiquitin-proteasome function in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). ResultsOur multidimensional mapping strategy enabled high-resolution functional analysis of MYBPC3 variants in iPSC-CMs. Targeted transient base editing generated a comprehensive variant library at the native locus, capturing diverse variant effects on cellular HCM-relevant phenotypes. Our massively parallel splicing assay identified novel splice-disrupting variants. Integration of functional assays revealed that decreased MYBPC3 abundance is a key driver of HCM-related phenotypes. In parallel, downregulation of protein degradation was observed as a compensatory response to MYBPC3 loss of function, and novel disease mechanisms were identified for missense variants near a critical binding domain, underscoring their contribution to pathogenesis. Bayesian estimates of variant effects enable the reclassification of clinical variants. ConclusionsThis work provides a platform for extending genome engineering in iPSCs to multiplexed assays of variant effects across diverse disease-relevant cellular phenotypes, enhancing the understanding of variant pathogenicity and uncovering novel biological mechanisms that could inform therapeutic strategies.

genetics↗

bioRxiv2024

PathoGD: an integrative genomics approach for CRISPR-based target design of rapid pathogen diagnostics

The design of highly specific primers and guide RNAs (gRNA) for CRISPR-based diagnostics is often a laborious process. Several tools exist for gRNA design, but most are tailored for genome editing applications. Here, we present PathoGD, an end-to-end bioinformatic pipeline comprising pangenome and k-mer modules for rapid and high-throughput design of primers and gRNAs for CRISPR-Cas12a-based pathogen detection. We validated and demonstrated high specificity of a subset of PathoGD-designed primers and gRNAs for the detection of Neisseria gonorrhoeae and Streptococcus pyogenes. PathoGD will serve as an important resource for designing CRISPR-based diagnostic assays for current and emerging pathogens.

bioinformatics↗

bioRxiv2023

Identification of a putative rhamnogalacturonan-II CMP-beta-Kdo transferase through a callus-based gene editing method which overcomes embryo lethality.

Rhamnogalacturonan II (RG-II) is a structurally complex and conserved domain of the pectin present in the primary cell walls of vascular plants. Borate crosslinking of RG-II is required for plants to grow and develop normally. Mutations that alter RG-II structure also affect crosslinking and are lethal or severely impair growth. Thus, few genes involved in RG-II synthesis have been identified. Here we developed a method using CRISPR/Cas9-mediated gene to generate callus carrying loss-of-function mutations in the MPG2 gene that encodes a putative family GT29 glycosyltransferase. Plants homozygous for this mutation do not survive. We show that in the callus mutant cell walls, RG-II does not crosslink normally because it lacks 3-deoxy-D-manno- octulosonic acid (Kdo) and thus cannot form the -L-Rhap-(1[->]5)--D-kdop-(1[->] sidechain. We suggest that MGP2 encodes an inverting CMP-{beta}-Kdo transferase (RCKT1). Our discovery provides further insight into the role of sidechains in RG-II dimerization.

plant biology↗

bioRxiv2022

Environmental and genetic drivers of population differences in SARS-CoV-2 immune responses

Humans display vast clinical variability upon SARS-CoV-2 infection1-3, partly due to genetic and immunological factors4. However, the magnitude of population differences in immune responses to SARS-CoV-2 and the mechanisms underlying such variation remain unknown. Here we report single-cell RNA-sequencing data for peripheral blood mononuclear cells from 222 healthy donors of various ancestries stimulated with SARS-CoV-2 or influenza A virus. We show that SARS-CoV-2 induces a weaker, but more heterogeneous interferon-stimulated gene activity than influenza A virus, and a unique pro-inflammatory signature in myeloid cells. We observe marked population differences in transcriptional responses to viral exposure that reflect environmentally induced cellular heterogeneity, as illustrated by higher rates of cytomegalovirus infection, affecting lymphoid cells, in African-descent individuals. Expression quantitative trait loci and mediation analyses reveal a broad effect of cell proportions on population differences in immune responses, with genetic variants having a narrower but stronger effect on specific loci. Additionally, natural selection has increased immune response differentiation across populations, particularly for variants associated with SARS-CoV-2 responses in East Asians. We document the cellular and molecular mechanisms through which Neanderthal introgression has altered immune functions, such as its impact on the myeloid response in Europeans. Finally, colocalization analyses reveal an overlap between the genetic architecture of immune responses to SARS-CoV-2 and COVID-19 severity. Collectively, these findings suggest that adaptive evolution targeting immunity has also contributed to current disparities in COVID-19 risk.

genomics↗

bioRxiv2022

Tracking subject's strategies in behavioural choice experiments at trial resolution

Investigating how, when, and what subjects learn during decision-making tasks requires tracking their choice strategies on a trial-by-trial basis. Here we present a simple but effective probabilistic approach to tracking choice strategies at trial resolution using Bayesian evidence accumulation. We show this approach identifies both successful learning and the exploratory strategies used in decision tasks performed by humans, non-human primates, rats, and synthetic agents. Both when subjects learn and when rules change the exploratory strategies of win-stay and lose-shift, often considered complementary, are consistently used independently. Indeed, we find the use of lose-shift is strong evidence that subjects have latently learnt the salient features of a new rewarded rule. Our approach can be extended to any discrete choice strategy, and its low computational cost is ideally suited for real-time analysis and closed-loop control.

neuroscience↗

bioRxiv2021

Protein complex prediction with AlphaFold-Multimer

While the vast majority of well-structured single protein chains can now be predicted to high accuracy due to the recent AlphaFold [1] model, the prediction of multi-chain protein complexes remains a challenge in many cases. In this work, we demonstrate that an AlphaFold model trained specifically for multimeric inputs of known stoichiometry, which we call AlphaFold-Multimer, significantly increases accuracy of predicted multimeric interfaces over input-adapted single-chain AlphaFold while maintaining high intra-chain accuracy. On a benchmark dataset of 17 heterodimer proteins without templates (introduced in [2]) we achieve at least medium accuracy (DockQ [3] [≥] 0.49) on 13 targets and high accuracy (DockQ [≥] 0.8) on 7 targets, compared to 9 targets of at least medium accuracy and 4 of high accuracy for the previous state of the art system (an AlphaFold-based system from [2]). We also predict structures for a large dataset of 4,446 recent protein complexes, from which we score all non-redundant interfaces with low template identity. For heteromeric interfaces we successfully predict the interface (DockQ [≥] 0.23) in 70% of cases, and produce high accuracy predictions (DockQ [≥] 0.8) in 26% of cases, an improvement of +27 and +14 percentage points over the flexible linker modification of AlphaFold [4] respectively. For homomeric inter-faces we successfully predict the interface in 72% of cases, and produce high accuracy predictions in 36% of cases, an improvement of +8 and +7 percentage points respectively.

bioinformatics↗

bioRxiv2020

Basal Expression of Interferon-Stimulated Genes Drives Population Differences in Monocyte Susceptibility to Influenza Infection

There is considerable inter-individual and inter-population variability in response to viruses. The potential of monocytes to elicit type-I interferon responses has attracted attention to their role in viral infections. Here, we use an ex vivo model to characterize the role of cellular heterogeneity in human variation of monocyte responses to influenza A virus (IAV) exposure. Using single-cell RNA-sequencing, we show widespread inter-individual variability in the percentage of IAV-infected monocytes. We show that cells escaping viral infection display increased mRNA expression of type-I interferon stimulated genes and decreased expression of ribosomal genes, relative to both infected cells and those never exposed to IAV. While this host defense strategy is shared between CD16+/CD16- monocytes, we also uncover CD16+-specific mRNA expression of IL6 and TNF in response to IAV, and a stronger resistance of CD16+ monocytes to IAV infection. Notably, individuals with high cellular susceptibility to IAV are characterized by a lower activation at basal state of an IRF/STAT-induced transcriptional network, which includes antiviral genes such as IFITM3, MX1, and OAS3. Finally, using flow cytometry and bulk RNA-sequencing across 200 individuals of African and European ancestry, we observe a higher number of CD16+ monocytes and lower susceptibility to IAV infection among monocytes from individuals of African-descent. Collectively, our results reveal the effects of IAV infection on the transcriptional landscape of human monocytes and highlight previously unappreciated differences in cellular susceptibility to IAV infection between individuals of African and European ancestry, which may account for the greater susceptibility of Africans to severe influenza. Significance StatementMonocytes may play a critical role during severe viral infections. Our study tackles how heterogeneity in monocyte subsets and activation contributes to shape individual differences in the transcriptional response to viral infections. Using single-cell RNA-sequencing, we reveal heterogeneity in monocyte susceptibility to IAV infection, both between CD16+/CD16- monocytes and across individuals, driven by differences in basal activation of an IRF/STAT-induced antiviral program. Furthermore, we show a decreased ability of IAV to infect and replicate in monocytes from African-ancestry individuals, with possible implications for antigen presentation and lymphocyte activation. These results highlight the importance of early cellular activation in determining an individuals innate immune response to viral infection.

genomics↗

bioRxiv2019

Imbalance in the response of pre- and post-synaptic components to amyloidopathy

Alzheimers disease (AD)-associated synaptic dysfunction drives the progression of pathology from its earliest stages. A{beta} species, both soluble and in plaque deposits, have been causally related to the progressive, structural and functional impairments observed in AD. It is, however, still unclear how A{beta} plaques develop over time and how they progressively affect local synapse density and turnover. Here we observed, in a mouse model of AD, that A{beta} plaques grow faster in the earlier stages of the disease and if their initial area is > 500 {micro}m2; this may be due to deposition occurring in the diffuse part of the plaque. In addition, synaptic turnover is higher in the presence of amyloid pathology and this is paralleled by a reduction in pre-but not post-synaptic densities. Plaque proximity does not appear to have an impact on synaptic dynamics. These observations indicate an imbalance in the response of the pre- and post-synaptic terminals and that therapeutics, alongside targeting the underlying pathology, need to address changes in synapse dynamics.

neuroscience↗

bioRxiv2019

Spatio-temporal distribution of Spiroplasma infections in the tsetse fly (Glossina fuscipes fuscipes) in northern Uganda

Tsetse flies (Glossina spp.) are vectors of parasitic trypanosomes, which cause human (HAT) and animal African trypanosomiasis (AAT) in sub-Saharan Africa. In Uganda, Glossina fuscipes fuscipes (Gff) is the main vector of HAT, where it transmits Gambiense disease in the northwest and Rhodesiense disease in central, southeast and western regions. Endosymbionts can influence transmission efficiency of parasites through their insect vectors via conferring a protective effect against the parasite. It is known that the bacterium Spiroplasma is capable of protecting its Drosophila host from infection with a parasitic nematode. This endosymbiont can also impact its hosts population structure via altering host reproductive traits. Here, we used field collections across 26 different Gff sampling sites in northern and western Uganda to investigate the association of Spiroplasma with geographic origin, seasonal conditions, Gff genetic background and sex, and trypanosome infection status. We also investigated the influence of Spiroplasma on Gff vector competence to trypanosome infections under laboratory conditions.\n\nGeneralized linear models (GLM) showed that Spiroplasma probability was correlated with the geographic origin of Gff host and with the season of collection, with higher prevalence found in flies within the Albert Nile (0.42 vs 0.16) and Achwa River (0.36 vs 0.08) watersheds and with higher prevalence detected in flies collected in the intermediate than wet season. In contrast, there was no significant correlation of Spiroplasma prevalence with Gff host genetic background or sex once geographic origin was accounted for in generalized linear models. Additionally, we found a potential negative correlation of Spiroplasma with trypanosome infection, with only 2% of Spiroplasma infected flies harboring trypanosome co-infections. We also found that in a laboratory line of Gff, parasitic trypanosomes are less likely to colonize the midgut in individuals that harbor Spiroplasma infection. These results indicate that Spiroplasma infections in tsetse may be maintained by not only maternal but also via horizontal transmission routes, and Spiroplasma infections may also have important effects on trypanosome transmission efficiency of the host tsetse. Potential functional effects of Spiroplasma infection in Gff could have impacts on vector control approaches to reduce trypanosome infections.\n\nAuthor SummaryWe investigated the association of symbiotic Spiroplasma with the tsetse fly host Glossina fuscipes fuscipes (Gff) to assess if Spiroplasma infections are correlated with Gff genetic background, geography, or season and its interaction with trypanosome parasites. We analyzed distribution and prevalence of Spiroplasma infections across different Gff sampling sites in northern and western Uganda, and found that the symbiont is unevenly distributed and infections have not reached fixation within these sampling sites. We tested for associations with geographic origin of the collections, seasonal environmental conditions at the time of collection, Gff host genetic background and sex, plus trypanosome co-infections. Spiroplasma prevalence was strongly correlated with geographic origin and seasonal environmental conditions. Our parasite infection data suggested a negative correlation of Spiroplasma with trypanosome infection, with only 5 out of 243 flies harboring trypanosome co-infections. We further investigated the influence of Spiroplasma on trypanosome parasite infections in the laboratory. We found that trypanosomes were less likely to establish an infection in Gff individuals that carried Spiroplasma infections. Our results provide new information on host-endosymbiont dynamics in an important human disease vector, and provide evidence that Spiroplasma may confer partial resistance to Gff trypanosome infections. These findings provide preliminary evidence that a symbiont-based control method could be successful in combating tsetse trypanosome transmission to humans and livestock in sub-Saharan Africa.

epidemiology↗

bioRxiv2018

Reporter Ion Data Analysis Reduction (R.I.D.A.R) for isobaric proteomics quantification studies

Isobaric labeling-based relative quantification techniques such as iTRAQ and TMT were introduced 15 years ago and are now nearly ubiquitous in shotgun proteomics labs around the world. The methods for data processing in these experiments has changed little since inception, with peptide database searching of all MS/MS spectra occurring concurrent or asynchronous to the quantification of the reporter fragment regions. In this study we present an alternative method for data processing whereby the reporter ion region of all MS/MS spectra are first examined and spectra that are not quantitatively interesting to the end user are discarded. The remaining MS/MS spectra that are retained can then be more rapidly searched for computationally expensive database alterations such as post-translational modifications and single amino acid variations in more practical time. We have termed this method Reporter Ion Data Analysis Reduction (RIDAR). To demonstrate the application of RIDAR, we reprocess a recent CPTAC 2 study containing approximately 7.8 million MS/MS spectra. Post RIDAR processing we can search this public dataset versus a human canonical FASTA database and a compiled proteogenomic database of over 875,000 known cancer mutations in a single day on a standard desktop computer, a time reduction of 85% compared to the conventional workflow. With the rapidly increasing size and density of shotgun proteomics data files, RIDAR facilitates rapid analysis of large proteomics datasets for researchers without access to high performance computational resources.\n\nAbstract Graphic\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=115 SRC=\"FIGDIR/small/437210_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (14K):\norg.highwire.dtl.DTLVardef@1bcf00eorg.highwire.dtl.DTLVardef@134510eorg.highwire.dtl.DTLVardef@1b594b4org.highwire.dtl.DTLVardef@35e268_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2017

A fine-tuned vector-parasite dialogue in tsetse’s cardia determines peritrophic matrix integrity and trypanosome transmission success

Arthropod vectors have multiple physical and immunological barriers that impede the development and transmission of parasites to new vertebrate hosts. These barriers include the peritrophic matrix (PM), a chitinous barrier that separates the blood bolus from the midgut epithelia and inturn, modulates vector-microbiota interactions. In tsetse flies, a sleeve-like PM is continuously produced by the cardia organ located at the fore- and midgut junction. African trypanosomes, Trypanosoma brucei, must bypass the PM twice; first to colonize the midgut and secondly to reach the salivary glands (SG), to complete their transmission cycle in tsetse. However, not all flies with midgut infections develop mammalian transmissible SG infections - the reasons for which are unclear. Here, we used transcriptomics, microscopy and functional genomics analyses to understand the factors that regulate parasite migration from midgut to SG. In flies with midgut infections only, parasites fail to cross the PM as they are eliminated from the cardia by reactive oxygen intermediates (ROIs) - albeit at the expense of collateral cytotoxic damage to the cardia. In flies with midgut and SG infections, expression of genes encoding components of the PM is reduced in the cardia, and structural integrity of the PM barrier is compromised. Under these circumstances trypanosomes traverse through the newly secreted and compromised PM. The process of PM attrition that enables the parasites to re-enter into the midgut lumen is apparently mediated by components of the parasites residing in the cardia. Thus, a fine-tuned dialogue between tsetse and trypanosomes at the cardia determines the outcome of PM integrity and trypanosome transmission success.\n\nAuthor summaryInsects are responsible for transmission of parasites that cause deadly diseases in humans and animals. Understanding the key factors that enhance or interfere with parasite transmission processes can result in new control strategies. Here, we report that a proportion of tsetse flies with African trypanosome infections in their midgut can prevent parasites from migrating to the salivary glands, albeit at the expense of collateral damage. In a subset of flies with gut infections, the parasites manipulate the integrity of a midgut barrier, called the peritrophic matrix, and reach the salivary glands for transmission to the next mammal. Either targeting parasite manipulative processes or enhancing peritrophic matrix integrity could reduce parasite transmission.

microbiology↗

bioRxiv2017

Finite-sample genome-wide regression p-values (GWRPV) with a non-normally distributed phenotype

This paper derives the exact finite-sample p-value for univariate regression of a quantitative phenotype on individual genome markers, relying on a mixture distribution for the dependent variable. The p-value estimator conventionally used in existing genome-wide association study (GWAS) regressions assumes a normally-distributed dependent variable, or relies on a central limit theorem based approximation. The central limit theorem approximation is unreliable for GWAS regression p-values, and measured phenotypes often have markedly non-normal distributions. A normal mixture distribution better fits observed phenotypic variables, and we provide exact small-sample p-values for univariate GWAS regressions under this flexible distributional assumption. We illustrate the adjustment using a years-of-education phenotypic variable.

genomics↗