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