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

<p>Lymphocytes of vertebrate adaptive immune systems acquired the capability to</p> <p>assemble, from split genes in the germline, billions of functional antigen receptors.</p> <p>These receptors show specificity; unlike the broadly tuned receptors of the innate</p> <p>system, antibodies (Ig) expressed by B lymphocytes, for instance, can faithfully</p> <p>distinguish between the two enantiomers of organic acids4 whereas T cell receptors</p> <p>(TCRs) reliably recognize single amino acid replacements in their peptide antigens5.</p> <p>In developing lymphocytes, antigen receptor genes (AgRs) are assembled from a</p> <p>comparatively small set of germline-encoded genetic elements in a process referred</p> <p>to as V(D)J recombination6,7. Potential self-reactivity of some AgRs arising from the</p> <p>quasi-random somatic diversification is suppressed by several robust control</p> <p>mechanisms. For decades, scientists have puzzled over the evolutionary origin of</p> <p>somatically diversifying antigen receptors. It has remained unclear how, at the</p> <p>inception of this mechanism, immunologically beneficial expanded receptor diversity</p> <p>was traded against the emerging risk of destructive self-recognition. Here, we explore</p> <p>the hypothesis that sequence microhomologies marking the ends of recombining</p> <p>elements are the crucial targets of selection determining the outcome of nonhomologous</p> <p>end joining-based repair of DNA double-strand breaks generated during</p> <p>RAG-mediated recombination in early vertebrates. We find that, across the main clades</p> <p>of jawed vertebrates, TCR &alpha; repertoire diversity is best explained by species-specific</p> <p>extents of such sequence microhomologies. Thus, selection of germline sequence</p> <p>composition of rearranging elements emerges as a major factor determining the</p> <p>degree of diversity of somatically generated AgRs.</p>