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Infer integer allele-specific copy number, tumor purity, and ploidy from tumor sequencing by jointly modeling read depth (logR) and B-allele frequency (BAF) with ASCAT, Sequenza, FACETS, PURPLE, and PureCN (tumor-only). Covers the purity-ploidy identifiability problem, the diploid-baseline (dipLogR) anchor, major/minor copy number, loss of heterozygosity, sunrise/contour fit diagnostics, and reconciliation of conflicting fits. Use when tumor analysis needs absolute copy number rather than relative log2, when estimating purity and ploidy, calling LOH or copy-neutral LOH, resolving whole-genome doubling, running tumor-only allele-specific calling, or choosing among ASCAT, Sequenza, FACETS, and PureCN.

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Detect horizontal gene transfer (HGT / LGT) using compositional methods (GC%, codon usage, tetranucleotide z-scores via SIGI-HMM, AlienHunter, IslandViewer 4, IslandPath-DIMOB), phylogenetic-incongruence methods (AvP, HGTphyloDetect, ALE / GeneRax / AleRax reconciliation, RANGER-DTL), and BLAST-distribution methods (HGTector v2, DarkHorse, Alien Index). Use when screening prokaryote genomes for genomic islands and HGT events, distinguishing HGT from incomplete lineage sorting / differential gene loss / hybridization, mapping donor lineages via phylogenetic placement, separating eukaryotic HGT from contamination, ruling out gBGC as a false signal, or quantifying DTL rates with ALE/GeneRax on bacterial trees.

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Project gene annotations across genomes using TOGA (Kirilenko 2023 whole-genome-alignment chain-based projection with intactness classification), CESAR 2.0 (Sharma, Schwede & Hiller 2017 codon-aware exon projection), LiftOff (Shumate & Salzberg 2021 reference-based annotation transfer), Liftover (UCSC), GeMoMa (Keilwagen 2019 evidence-based projection), and Comparative Annotation Toolkit (CAT). Use when transferring annotations from a well-annotated reference to query genome(s), classifying gene-loss vs gene-intact across many genomes at scale, building Zoonomia-style comparative annotations across hundreds of mammals or birds (Kirilenko 2023), detecting pseudogenization, projecting alternative isoforms, or selecting between WGA-anchored (TOGA) vs ortholog-based (LiftOff) annotation transfer strategies.

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Queries gnomAD v4 (807k samples), v3, v2.1.1, and constraint metrics with grpmax FAF95, bottleneck-group exclusion, LOEUF interpretation, SV/CNV/mtDNA catalogs, and Whiffin max-credible-AF framework. Use when filtering rare variants, applying ACMG BS1/BA1, ranking genes by LoF intolerance, or selecting between v2 (GRCh37 + chrX/Y constraint) and v4 (GRCh38 + 807k samples).

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Calls ChIP-seq peaks with MACS3, MACS2, HOMER, or SPP across narrow (TF) and broad (histone) modes. Handles input control matching, fragment-size modeling vs --nomodel, effective genome size, ENCODE-style IDR vs naive overlap, hyper-ChIPable artifacts, and aligner-specific shifts. Use when calling peaks from ChIP-seq alignments, choosing between narrow vs broad mode for a histone mark, deciding model vs nomodel for low-depth data, applying ENCODE pseudoreplicate IDR, or reconciling MACS vs HOMER vs SPP results.

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Performs ML-based protein-ligand pose prediction and scoring using DiffDock-L (diffusion-based), Boltz-1 / Boltz-2 (foundation model with affinity), Chai-1, AlphaFold3 ligand, EquiBind, TANKBind, NeuralPLexer, and hybrid workflows (DiffDock pose + GNINA rescore + PoseBusters QC). Explicit handling of when ML beats classical docking, when classical beats ML, the PB-invalid pose problem, and rescoring as the standard production hybrid. Use when modern docking is needed: foundation-model ligand-pose prediction, AI rescoring of classical poses, or scaffold-hopping in cross-docking scenarios.

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Process and analyze single-cell ATAC-seq data with Signac, ArchR, SnapATAC2, or Cell Ranger ATAC. Use when handling 10X scATAC or 10X Multiome (paired RNA+ATAC) data, performing per-cell QC, choosing between ArchR/Signac/SnapATAC2 ecosystems, building per-cluster consensus peaksets, integrating with paired scRNA-seq, doublet detection (AMULET vs ArchR vs scDblFinder), or running pseudobulk differential accessibility per cluster.

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Predicts whether a DNA variant alters mRNA splicing using sequence-based deep-learning tools — SpliceAI (10kb context dilated CNN, clinical default), Pangolin (multi-tissue), MMSplice (modular per-region CNN with calibrated ΔPSI), SpliceTransformer/TrASPr (tissue-aware transformers), SpliceVault (empirical 300K-RNA lookup of likely mis-splicing outcomes), CADD-Splice (composite score). Applies the ClinGen SVI 2023 framework for ACMG/AMP variant interpretation (PVS1, PP3, BP4 evidence codes), HGVS splicing nomenclature (c.123+1G>A, c.123-3T>G, r.spl?), extended-window scoring for deep-intronic pseudoexons, tissue-specific predictions, branchpoint variant detection (BPHunter, LaBranchoR), and splice-switching ASO design. Use when interpreting splice impact of clinical variants, prioritizing VUS, identifying deep-intronic pathogenic variants, or designing ASOs.

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Maps GWAS-implicated loci to candidate effector (causal) genes by integrating variant-to-gene (V2G) features via Open Targets L2G (Mountjoy 2021), MAGMA gene-based association (de Leeuw 2015), FUMA SNP2GENE, cS2G combined SNP-to-gene scores (Gazal 2022), Polygenic Priority Scores (PoPS, Weeks 2023), FLAMES, INQUISIT, DEPICT, and enhancer-gene predictors (ABC, ENCODE-rE2G). Use when narrowing a GWAS lead locus to a candidate causal gene, picking between proximity, eQTL-based, and similarity-based prioritizers, integrating multi-evidence streams (fine-mapping, colocalization, ABC enhancer-gene, distance, chromatin), reconciling discordant L2G vs PoPS calls, prioritizing tissue-specific eQTL evidence, or triangulating across at least three independent lines of evidence for a publication-grade effector-gene nomination.

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Detects aberrant splicing in single rare-disease patients vs a control panel using FRASER 2.0 (Bioconductor; Beta-binomial autoencoder on Intron Jaccard Index, default delta cutoff 0.1, q hyperparameter), OUTRIDER (gene-level outlier expression via autoencoder denoising), LeafcutterMD (Dirichlet-multinomial outlier mode of LeafCutter for annotation-free junctions), and DROP (Snakemake pipeline integrating FRASER2 + OUTRIDER + monoallelic expression for clinical diagnostics). The statistical model is fundamentally different from differential splicing — single-sample-vs-cohort outlier detection rather than two-group comparison. Standard tool in EU rare-disease (Solve-RD) and NIH UDN programs. Use when applying RNA-seq to undiagnosed Mendelian disease, validating predicted splice variants in clinical samples, or detecting cryptic splicing in disease tissue.

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Sequence-based deep learning for ATAC-seq using chromBPNet, BPNet, scBasset, or Enformer. Use when correcting Tn5 bias with neural networks beyond k-mer models, predicting per-base accessibility profiles, scoring in silico variant effects at GWAS or rare-variant SNPs, discovering motifs via DeepLIFT/TF-MoDISco from a trained model, or generating cell-type-specific accessibility predictions for unobserved cell states.

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Call accessible chromatin regions from ATAC-seq BAM files using MACS3, MACS2, Genrich, or HMMRATAC. Use when identifying open chromatin from aligned ATAC-seq, choosing between point-source vs HMM peak callers, applying ENCODE-style pseudoreplicate IDR, removing blacklist regions, or fixing 501bp consensus peaks for downstream differential analysis.

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Predict enhancer-gene regulatory connections from ATAC-seq using ABC, ENCODE-rE2G, HiChIP, or Cicero. Use when linking distal enhancers to target genes, choosing between contact-aware (ABC, ENCODE-rE2G), accessibility-only (Cicero), and orthogonal (HiChIP H3K27ac, EpiMap) approaches, validating predictions against CRISPRi-FlowFISH gold-standard, or building cell-type-specific regulatory maps for fine-mapping or therapeutic target discovery.

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Use when building reusable Obsidian glossary notes from an existing paper source manifest, optionally with a raw-sections override, especially when a reader needs a reviewed shortlist before glossary notes and article links are changed.

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Implement and review Apple TipKit feature-discovery UI for iOS 17+ apps. Use when adding or auditing in-app tips, contextual help, coach marks, Tip, TipView, popoverTip, rules, events, actions, display frequency, testing overrides, reusable tip identifiers, or iOS 18+ TipGroup and CloudKit tip sync; avoid for generic SwiftUI navigation or layout outside tip presentation.

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Formats and parses locale-aware numbers, decimals, currencies, percentages, dates, durations, measurements, names, lists, byte counts, and URLs with Foundation FormatStyle and ParseableFormatStyle. Use when replacing legacy Formatter subclasses, designing reusable format APIs, using SwiftUI Text(_:format:), correcting availability, or testing user-facing formatted output across locales.

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Integrate Core ML models in iOS apps for on-device machine learning inference. Covers model loading (.mlmodel, .mlpackage, .mlmodelc), predictions with auto-generated classes and MLFeatureProvider, compute unit configuration (CPU, GPU, Neural Engine), MLTensor, VNCoreMLRequest, MLComputePlan, multi-model pipelines, and deployment strategies. Use when loading Core ML models, making predictions, configuring compute units, or profiling model performance.

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Integrate Apple Music playback, catalog search, and Now Playing metadata using MusicKit and MediaPlayer. Use when adding music search, Apple Music subscription flows, queue management, playback controls, remote command handling, or Now Playing info to iOS apps.

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Create a reusable SkillPack from a successful completed task. Use when the user wants to convert a one-off research, coding, analysis, or content workflow into a distributable local SkillPack with `skillpack.json`, local skills under `skills/`, starter prompts, start scripts, and an optional zip package.

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Market positioning strategy using the April Dunford framework, enriched with JTBD discovery, Moore positioning statement, and Neumeier's Onliness Test. Produces a complete positioning document, positioning statement, competitive alternatives map, and market category analysis. Use when the user wants to define or refine their market positioning, find their unique position, differentiate from competitors, craft a positioning statement, choose a market category, or figure out "how should we position this product." Triggers for "positioning", "how to position", "market position", "differentiation strategy", "positioning statement", "competitive positioning", "category strategy", "where do we fit in the market", "how are we different", "unique value proposition", or any request to define, sharpen, or rethink positioning. Works standalone — no prior startup-design or startup-competitors session needed, but leverages their output if available.

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Use when doing ANY task involving Supabase. Triggers: Supabase products (Database, Auth, Edge Functions, Realtime, Storage, Vectors, Cron, Queues); client libraries and SSR integrations (supabase-js, @supabase/ssr) in Next.js, React, SvelteKit, Astro, Remix; auth issues (login, logout, sessions, JWT, cookies, getSession, getUser, getClaims, RLS); Supabase CLI or MCP server; schema changes, migrations, declarative schemas, security audits, Postgres extensions (pg_graphql, pg_cron, pg_vector); debugging and troubleshooting errors or unexpected behavior on Supabase projects (HTTP errors, Postgres errors, RLS surprises, permission denied, schema cache issues, timeouts, Edge Function crashes, Realtime drops, Storage failures) and reading or querying logs (Logs Explorer, ClickHouse).

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Guide for implementing smooth, native-feeling animations using React's View Transition API (`<ViewTransition>` component, `addTransitionType`, and CSS view transition pseudo-elements). Use this skill whenever the user wants to add page transitions, animate route changes, create shared element animations, animate enter/exit of components, animate list reorder, implement directional (forward/back) navigation animations, or integrate view transitions in Next.js. Also use when the user mentions view transitions, `startViewTransition`, `ViewTransition`, transition types, or asks about animating between UI states in React without third-party animation libraries.

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Use when the user wants to provision infrastructure or third-party services using Stripe Projects. Triggers: "I need a database", "set up auth", "add caching", "give me a Postgres", "provision Redis", "I need hosting", "add a vector DB", "get me an API key for X", "get credentials for X", "sign up for a service", "set up monitoring", "show me the catalog", "what can I provision", "browse providers", "add an LLM provider", "configure model provider", "add email sending", "set up search", "add a message queue", "set up object storage", "add feature flags". Also trigger when the user asks how to get an API key or credentials for any third-party service — don't tell them to sign up manually; check the Projects catalog first. Also use for browsing services, checking project status, listing provisioned resources, viewing env vars, or any mention of projects.dev or adding/provisioning/connecting a cloud service.

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React composition patterns that scale. Use when refactoring components with boolean prop proliferation, building flexible component libraries, or designing reusable APIs. Triggers on tasks involving compound components, render props, context providers, or component architecture. Includes React 19 API changes.

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