Origin and evolutionary malleability of T cell receptor α diversity (zipped files for GitHub code)

Lymphocytes of vertebrate adaptive immune systems acquired the capability to

assemble, from split genes in the germline, billions of functional antigen receptors.

These receptors show specificity; unlike the broadly tuned receptors of the innate

system, antibodies (Ig) expressed by B lymphocytes, for instance, can faithfully

distinguish between the two enantiomers of organic acids4 whereas T cell receptors

(TCRs) reliably recognize single amino acid replacements in their peptide antigens5.

In developing lymphocytes, antigen receptor genes (AgRs) are assembled from a

comparatively small set of germline-encoded genetic elements in a process referred

to as V(D)J recombination6,7. Potential self-reactivity of some AgRs arising from the

quasi-random somatic diversification is suppressed by several robust control

mechanisms. For decades, scientists have puzzled over the evolutionary origin of

somatically diversifying antigen receptors. It has remained unclear how, at the

inception of this mechanism, immunologically beneficial expanded receptor diversity

was traded against the emerging risk of destructive self-recognition. Here, we explore

the hypothesis that sequence microhomologies marking the ends of recombining

elements are the crucial targets of selection determining the outcome of nonhomologous

end joining-based repair of DNA double-strand breaks generated during

RAG-mediated recombination in early vertebrates. We find that, across the main clades

of jawed vertebrates, TCR α repertoire diversity is best explained by species-specific

extents of such sequence microhomologies. Thus, selection of germline sequence

composition of rearranging elements emerges as a major factor determining the

degree of diversity of somatically generated AgRs.