Perturb-seq screen implicates transcriptional adaptation in buffering essential paralog gene families

Genetic buffering among paralogs — where the loss of one member of a gene family is partially compensated by related genes sharing similar functions — is a well-established source of genetic robustness. The molecular mechanisms underlying this compensation, however, are incompletely understood. Transcriptional adaptation is one proposed mechanism: the sequence similarity between paralogous genes may allow the transcriptional machinery to upregulate family members when one is inactivated, possibly through recognition of the degraded mRNA or related sequence features.

A preprint posted to bioRxiv on 29 September 2026 describes a systematic Perturb-seq screen — combining CRISPR-based perturbation with single-cell RNA sequencing readout — targeting 110 paralog gene knockouts. The authors assess compensatory expression changes both within paralog families and across the whole transcriptome, finding evidence that transcriptional adaptation contributes to paralog buffering in a subset of cases. The magnitude and directionality of compensation varied by gene family, and the study begins to map the features of paralog pairs where adaptation is most pronounced.

The findings have implications for understanding why loss-of-function variants in some essential genes produce surprisingly mild phenotypes, and for the interpretation of functional genomics screens that rely on complete gene inactivation. This is a preprint and has not yet been peer reviewed (bioRxiv doi: 10.64898/2026.09.24.754217).