Distinct evolution at TCRα and TCRβ loci in the genusMus

Abstract T cells recognize an immense spectrum of pathogens to initiate immune responses by means of a large repertoire of T cell receptors (TCRs) that arise from somatic rearrangements of variable , diversity and joining gene segments at the TCR loci. These gene segments have emerged from a limited number of ancestral genes through a series of gene duplication events, resulting in a greatly variable number of such genes across different species. Apart from the complete V(D)J gene annotations in the human and mouse reference assemblies, little is known about the structure of TCR loci in other species. Here, we performed a comprehensive comparison of the TCRα and TCRβ gene segment clusters in mice and three of its closely related sister species. We show that the TCRα variable gene cluster is frequently rearranged, leading to deletions and sequence inversions in this region. The resulting complexity of TCR loci severely complicates the assembly of these loci and the annotation of gene segments. By jointly utilizing genomic and transcriptomic data, we show that in Mus musculus castaneus the variable gene cluster at the α locus has undergone a recent major locus contraction, leading to the loss of 74 variable gene segments. Additionally, we validated the expression of functional variable genes, including atypical ones with inverted orientation relative to other such segments. Disentangling the fine-scale structure of TCR loci in different species can provide valuable insights in the evolution and diversity of TCR repertoires.