OLGA: fast computation of generation probabilities of B- and T-cell receptor amino acid sequences and motifs

• Published in: Bioinformatics (Oxford, England) Vol. 35; no. 17; pp. 2974 - 2981
• Main Authors: Sethna, Zachary, Elhanati, Yuval, Callan, Curtis G, Walczak, Aleksandra M, Mora, Thierry
• Format: Journal Article
• Language: English
• Published: England Oxford University Press (OUP) 01.09.2019; Oxford University Press
• Subjects: Biochemistry, Molecular Biology; Genomics; Life Sciences; Original Papers; Physics
• ISSN: 1367-4803; 1367-4811; 1367-4811
• DOI: 10.1093/bioinformatics/btz035

High-throughput sequencing of large immune repertoires has enabled the development of methods to predict the probability of generation by V(D)J recombination of T- and B-cell receptors of any specific nucleotide sequence. These generation probabilities are very non-homogeneous, ranging over 20 orders of magnitude in real repertoires. Since the function of a receptor really depends on its protein sequence, it is important to be able to predict this probability of generation at the amino acid level. However, brute-force summation over all the nucleotide sequences with the correct amino acid translation is computationally intractable. The purpose of this paper is to present a solution to this problem. We use dynamic programming to construct an efficient and flexible algorithm, called OLGA (Optimized Likelihood estimate of immunoGlobulin Amino-acid sequences), for calculating the probability of generating a given CDR3 amino acid sequence or motif, with or without V/J restriction, as a result of V(D)J recombination in B or T cells. We apply it to databases of epitope-specific T-cell receptors to evaluate the probability that a typical human subject will possess T cells responsive to specific disease-associated epitopes. The model prediction shows an excellent agreement with published data. We suggest that OLGA may be a useful tool to guide vaccine design. Source code is available at https://github.com/zsethna/OLGA. Supplementary data are available at Bioinformatics online.