When few survive to tell the tale: thymus and gonad as auditioning organs: historical overview

TL;DR

This paper explores the idea that thymus and gonads may share a common mechanism of quality control through promiscuous gene expression, which could influence immune function and gamete integrity.

Contribution

It proposes a novel hypothesis that gamete quality control may operate via mechanisms similar to thymic selection, involving promiscuous gene expression and the AIRE protein.

Findings

AIRE gene is expressed in both thymus and gonads.

Promiscuous gene expression may serve as a quality control mechanism.

Implications for understanding hybrid incompatibilities and immune regulation.

Abstract

Unlike other organs, the thymus and gonads generate non-uniform cell populations, many members of which perish, and a few survive. While it is recognized that thymic cells are 'audited' to optimize an organism's immune repertoire, whether gametogenesis could be orchestrated similarly to favour high quality gametes is uncertain. Ideally, such quality would be affirmed at early stages before the commitment of extensive parental resources. A case is here made that, along the lines of a previously proposed lymphocyte quality control mechanism, gamete quality can be registered indirectly through detection of incompatibilities between proteins encoded by the grandparental DNA sequences within the parent from which haploid gametes are meiotically derived. This 'stress test' is achieved in the same way that thymic screening for potential immunological incompatibilities is achieved - by 'promiscuous' expression, under the influence of the AIRE protein, of the products of genes that are not normally specific for that organ. Consistent with this, the Aire gene is expressed in both thymus and gonads, and AIRE deficiency impedes function in both organs. While not excluding the subsequent emergence of hybrid incompatibilities due to the intermixing of genomic sequences from parents (rather than grandparents), many observations, such as the number of proteins that are aberrantly expressed during gametogenesis, can be explained on this basis. Indeed, promiscuous expression could have first evolved in gamete-forming cells where incompatible proteins would be manifest as aberrant protein aggregates that cause apoptosis. This mechanism would later have been co-opted by thymic epithelial cells which display peptides from aggregates to remove potentially autoreactive T cells.