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. Author manuscript; available in PMC: 2022 Apr 24.
Published in final edited form as: Cell Syst. 2022 Jan 31;13(4):286–303.e10. doi: 10.1016/j.cels.2021.12.005

Figure 5. Gene function embeddings reflect pleiotropy between hierarchically compartmentalized functions.

Figure 5.

(A) Conceptual overview of cellular organization. After learning gene functions with Webster from cancer fitness data alone, experimentally derived subcellular localization data (Go et al., 2021) were used to annotate Webster’s functions across 20 subcellular locations within a total of 7 cellular compartments.

(B) Joint embedding of fitness effects for genes and functions inferred from DepMap data, with functions colored by their specificity for one of seven cellular compartments—mitochondria, endoplasmic reticulum (ER), recycling, membrane, nucleus, cytosol, and miscellaneous. Subcellular location data were not used during the training of the Webster model. Gene effect data from Cancer Dependency Map 19Q4v3 release (https://doi.org/10.6084/m9.figshare.11384241.v3). Functional effects inferred with Webster (this study). Subcellular location data from Human Cell Map (Go et al., 2021).

(C) Insets from (B). detailing functions within the ER, recycling and membrane compartments, capturing specific subcellular locations or protein complexes within these broad compartments. Gene effect data from Cancer Dependency Map 19Q4v3 release (https://doi.org/10.6084/m9.figshare.11384241.v3). Functional effects inferred with Webster (this study). Subcellular location data from Human Cell Map (Go et al., 2021).

(D) Insets from (C). detailing genes embedded nearby their pleiotropic gene functions. Bolded genes are mentioned in the main text. Gene effect data from Cancer Dependency Map 19Q4v3 release (https://doi.org/10.6084/m9.figshare.11384241.v3). Functional effects inferred with Webster (this study). Subcellular location data from Human Cell Map (Go et al., 2021).

(E) Pleiotropic genes bridge biological functions that are physically distinct. Left: Pleiotropic genes for peroxisome biogenesis and cholesterol biosynthesis functions, which are enriched at the peroxisome and the ER, respectively. Middle: Pleiotropic genes for the Commander/WASH, HOPS/CORVET, and amino acid activation of mTOR functions, which are enriched at the early endosome, endosomal vesicles, and lysosomes, respectively. Right: Pleiotropic genes for the SCAR/WAVE (cytosol), integrins, and focal adhesion functions.