Architecture of a multi-cellular polygenic network governing immune homeostasis

Dubovik, Tania; Starosvetsky, Elina; LeRoy, Benjamin; Normand, Rachelly; Admon, Yasmin; Alpert, Ayelet; Ofran, Yishai; G’Sell, Max; Shen-Orr, Shai S.

doi:10.1101/256073

Cited by 1 publication

(2 citation statements)

References 42 publications

(46 reference statements)

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“…In KRAS, the high-dimensional, continuous, and high-resolution profiles identified a continuum from neutral to highly impactful variants and categorized this continuum into variant classes, each distributing differently along a broad phenotypic space, and associated with specific gene expression programs which shift gradually. Such quantitative shifts of the cellular landscape at the single cell level are consistent with studies on the effects of variants affecting cellular compositions (Brodin et al, 2015; Dubovik et al, 2018; Li et al, 2018).…”

Section: Discussionsupporting

confidence: 87%

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Massively parallel phenotyping of variant impact in cancer with Perturb-seq reveals a shift in the spectrum of cell states induced by somatic mutations

Ursu

Neal

Shea

et al. 2020

Preprint

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Genome sequencing studies have identified millions of somatic variants in cancer, but their phenotypic impact remains challenging to predict. Current experimental approaches to distinguish between functionally impactful and neutral variants require customized phenotypic assays that often report on average effects, and are not easily scaled. Here, we develop a generalizable, high-dimensional, and scalable approach to functionally assess variant impact in single cells by pooled Perturb-seq. Specifically, we assessed the impact of 200 TP53 and KRAS variants in >300,000 single lung cancer cells, and used the profiles to categorize variants into phenotypic subsets to distinguish gain-of-function, loss-of-function and dominant negative variants, which we validated by comparison to orthogonal assays. Surprisingly, KRAS variants did not merely fit into discrete functional categories, but rather spanned a continuum of gain-of-function phenotypes driven by quantitative shifts in cell composition at the single cell level. We further discovered novel gain-of-function KRAS variants whose impact could not have been predicted solely by their occurrence in patient samples. Our work provides a scalable, gene-agnostic method for coding variant impact phenotyping, which can be applied in cancer and other diseases driven by somatic or germline coding mutations.

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Section: Discussionsupporting

confidence: 87%

“…Such quantitative shifts of the cellular landscape at the single cell level are consistent with studies on the effects of variants affecting cellular compositions (Brodin et al, 2015;Dubovik et al, 2018;Li et al, 2018).…”

Section: Discussionsupporting

confidence: 83%