Diverse repertoires of hypervariable immunoglobulin receptors (TCR and BCR) 14 recognize antigens in the adaptive immune system. The development of immunoglobulin receptor 15 repertoire sequencing methods makes it possible to perform repertoire-wide disease association 16 studies of antigen receptor sequences. We developed a statistical framework for associating 17 receptors to disease from only a small cohort of patients, with no need for a control cohort. Our 18 method successfully identifies

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... previously validated Cytomegalovirus and type 1 diabetes 19 responsive TCR sequences . 20 21 30 Comparison of sequenced repertoires has revealed that in any pair of individuals, large numbers 31 of TCR sequences have the same amino acid sequence Venturi et al. (2011). Several mechanisms 32 leading to the repertoire overlap have been identified so far. The first mechanism is convergent 33 recombination. Due to biases in V(D)J recombination process, the probability of generation of 34 some TCR sequences is very high, making them appear in almost every individual multiple times 35 and repeatedly sampled in repertoire profiling experiments Britanova et al. (2014). This sharing 36 does not result from a common specificity or function of T-cells corresponding to the shared TCR 37 clonotypes, and may in fact correspond to cells from the naive compartment in both donors Quigley 38 et al. (2010), or from functionally distinct subsets such as CD4 and CD8 T-cells. The second possible 39 reason for TCR sequence sharing is specific to identical twins, who may share T cell clones as a 40 1 of 12 309 Bolotin DA, Poslavsky S, Davydov AN, Frenkel FE, Fanchi L, Zolotareva OI, Hemmers S, Putintseva EV, Obraztsova 310 AS, Shugay M, Ataullakhanov RI, Rudensky AY, Schumacher TN, Chudakov DM. Antigen receptor repertoire 311 profiling from RNA-seq data. Nature Biotechnology. 2017; 35(10):908-911.