# Cell atlases and the developmental foundations of the phenotype

## TL;DR

This paper introduces a framework linking gene expression during development to organismal phenotypes using C. elegans, showing that similar gene activity patterns often lead to similar traits.

## Contribution

The paper introduces the 𝒟–𝒫 rule, a novel framework connecting developmental gene expression to phenotypic outcomes using single-cell atlases and ontologies.

## Key findings

- Genes with similar developmental expression patterns tend to produce similar phenotypic outcomes on average.
- Strong adherence to the 𝒟–𝒫 rule is associated with broad gene expression and systemic phenotypes.
- Specific cell types, like ASK neurons, mediate phenotype-specific gene contributions.

## Abstract

It is widely acknowledged that development shapes phenotypes, yet the extent to which genes with similar expression patterns during development lead to equivalent organismal phenotypes when mutated remains unclear. Here, we propose addressing this issue, which we term the 𝒟evelopment–to–𝒫henotype, or 𝒟–𝒫, rule, by leveraging single-cell gene expression atlases and phenotypic ontologies, using Caenorhabditis elegans as a model system. This framework quantifies the proportionality between developmental expression and phenotypic similarities, demonstrating that the relationship holds on average. Genes that strongly fulfill the rule exhibit broad “housekeeping” expression and are associated with systemic phenotypes, whereas weak similarities correspond to specific expression patterns and specialized phenotypes. Deviations from the 𝒟–𝒫 rule provide insights into developmental divergence and phenotypic degeneracy, highlighting genes with narrow functional roles but systemic phenotypic impact. Furthermore, genes that closely adhere to the rule exhibit the highest pleiotropic impact on organismal traits. Our analysis also identifies cell types, such as ASK neurons, as key mediators of phenotype-specific gene contributions, exemplified by their association with chemosensory behavior and chemotaxis. These findings validate the 𝒟–𝒫 rule and underscore the role of cells as critical mediators of the genotype-phenotype map, offering a unified framework to understand the developmental origins of phenotypic complexity.

Single-cell sequencing technologies now allow us to map gene activity during embryonic development, revealing how different cell types emerge over time. Yet a major question remains: how does this developmental gene activity relate to organismal phenotypes? Here, we introduce the 𝒟evelopment-to-𝒫henotype (𝒟–𝒫) rule, which posits that genes with similar developmental expression patterns tend to produce similar phenotypic outcomes. Using Caenorhabditis elegans, we integrate a detailed single-cell developmental atlas with a structured phenotype ontology to quantify this relationship. We define developmental and phenotypic similarity scores for thousands of genes and find a positive correlation between them, supporting the rule. We also investigate exceptions, such as developmental divergence and phenotypic degeneracy, and identify specific cell types that disproportionately influence phenotypic outcomes. Our work provides a quantitative framework linking gene expression during development to organismal traits.