Conserved exchange of paralog proteins during neuronal differentiation.

Domenico Di Fraia,Manuela Helmer Citterich,Marie-Therese Mackmull,Mihaela Anitei,Luca Parca,Amparo Andres-Pons,Laura Behrendt,Martin Beck,Christoph Kaether,Alessandro Ori‬‬,Darren Gilmour

doi:10.26508/lsa.202201397

Abstract

Gene duplication enables the emergence of new functions by lowering the evolutionary pressure that is posed on the ancestral genes. Previous studies have highlighted the role of specific paralog genes during cell differentiation, for example, in chromatin remodeling complexes. It remains unexplored whether similar mechanisms extend to other biological functions and whether the regulation of paralog genes is conserved across species. Here, we analyze the expression of paralogs across human tissues, during development and neuronal differentiation in fish, rodents and humans. Whereas ∼80% of paralog genes are co-regulated, a subset of paralogs shows divergent expression profiles, contributing to variability of protein complexes. We identify 78 substitutions of paralog pairs that occur during neuronal differentiation and are conserved across species. Among these, we highlight a substitution between the paralogs SEC23A and SEC23B members of the COPII complex. Altering the ratio between these two genes via RNAi-mediated knockdown is sufficient to influence neuron differentiation. We propose that remodeling of the vesicular transport system via paralog substitutions is an evolutionary conserved mechanism enabling neuronal differentiation.

Highlights

A major evolutionary event underlying the emergence of multicellular organisms is the specialization of functions between different cell types
The detection of divergently regulated paralogs in RNA-Seq data can be challenging because of the handling of reads that map to multiple paralog genes. Given how these reads were handled in the analyzed datasets, our estimates of divergent paralogs expression could be in some cases underpowered because of the equal splitting of shared reads between paralog genes
In agreement with the theory that paralog genes are main carriers of biological variability (Ohno, 2013; Guschanski et al, 2017), we found that genes that have paralogs are more often differentially expressed across tissues, during development and neuronal differentiation, indicating that they can be used as general descriptors of these specific biological states

Summary

Introduction

A major evolutionary event underlying the emergence of multicellular organisms is the specialization of functions between different cell types. Human-specific gene duplications have been described to play a role in human brain development (Suzuki et al, 2018; Schmidt et al, 2019) Besides their modulation across cell types, an important role of paralogs is reflected by their ability to compensate for each other in maintaining the general homeostatic state of cells. Genome-wide CRISPR/Cas9-based screens have shown that paralog genes have a protective action on cell proliferation against the effect of gene loss-of-function in humans (Dandage & Landry, 2019) and cancer cell lines (De Kegel & Ryan, 2019; Thompson et al, 2021). All these observations highlight the functional impact that paralog genes have in modulating biological activity, development, and cell differentiation

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