On the organization of human T-cell receptor loci: log-periodic distribution of T-cell receptor gene segments

Abstract

We dedicate this work to Mr Omair Ahmed Toor and other people with Down's Syndrome and patients with congenital neurological disorders from around the world, whose constant struggle to overcome the challenges of everyday life and better themselves are an inspiration to all.On the organization of human T-cell receptor loci: log-periodic distribution of T-cell receptor gene segments School of Engineering, Virginia Commonwealth University, Richmond, VA, USAThe human T-cell repertoire is complex and is generated by the rearrangement of variable (V), diversity (D) and joining (J) segments on the T-cell receptor (TCR) loci. The T-cell repertoire demonstrates self-similarity in terms clonal frequencies when defined by V, D and J gene segment usage; therefore to determine whether the structural ordering of these gene segments on the TCR loci contributes to the observed clonal frequencies, the TCR loci were examined for self-similarity and periodicity in terms of gene segment organization. Logarithmic transformation of numeric sequence order demonstrated that the V and J gene segments for both T-cell receptor a (TRA) and b (TRB) loci are arranged in a self-similar manner when the spacing between the adjacent segments was considered as a function of the size of the neighbouring gene segment, with an average fractal dimension of approximately 1.5. Accounting for the gene segments occurring on helical DNA molecules with a logarithmic distribution, sine and cosine functions of the log-transformed angular coordinates of the start and stop nucleotides of successive TCR gene segments showed an ordered progression from the 5 0 to the 3 0 end of the locus, supporting a log-periodic organization. T-cell clonal frequency estimates, based on V and J segment usage, from normal stem cell donors were plotted against the V and J segment on TRB locus and demonstrated a periodic distribution. We hypothesize that this quasi-periodic variation in genesegment representation in the T-cell clonal repertoire may be influenced by the location of the gene segments on the periodic-logarithmically scaled TCR loci. Interactions between the two strands of DNA in the double helix may influence the probability of gene segment usage by means of either constructive or destructive interference resulting from the superposition of the two helices.

T Cell Repertoire Evolution After Allogeneic Bone Marrow Transplantation: An Organizational Perspective

“…22 Briefly, total counts for unique VJ recombinations were analyzed with V and J segments organized according to their position along the genome at the TCR β locus relative to the 5¢ centromeric end of the TRB gene. 9 Pseudogenes were included in the analysis bringing the total number of possible V segments to sixty-five with the potential to recombine with any of the thirteen J segments found at the TCR β locus. Data were visualized using Microsoft Excel and represent all TCR β recombinations for that particular sample.…”

“…This may be accomplished by accounting for the helical nature of DNA molecules and calculating the angular coordinates of each TRB segment as previously described. 9 Briefly, DNA is considered as a propagating wave with each turn of the DNA helix corresponding with 2π radians in terms of angular distance across the TRB locus. Given that there are 10.4 nucleotides per turn of DNA, 27…”

“…Instead, it has been hypothesized that the position of the gene segment on the TRB locus determines the probability of each TCR β V segment to recombine with each of the J segments, to form unique TCR bearing clones. 9 To investigate this, the average recombination potential for individual J ( Figure 2B Supplementary Figure 2A), the complexity of the repertoire still doesn't recover to that of the donor even three years out post-transplant ( Supplementary Figures 2B and 2C). This is also reflected in the total unique productive sequences (Supplementary Figure 2E) for the recipients, despite no significant differences in sequencing reads from these samples as compared to donor (Supplementary Figure 2D).…”

“…These unique TCR subunits are generated by the recombination of gene segments on a and b T cell receptor loci, termed TRA and TRB, and located on chromosomes 14q and 7q respectively. 9,10 Each of the TCR loci has variable (V), joining (J) and constant (C) gene segments, and in the case of TRB, there are diversity (D) segments as well. One each of the V and J, and if present, D gene segments on these loci are recombined during T cell ontogeny to yield unique VDJ rearranged, T cell receptor a and b subunits ( Supplementary Figure 1).…”

“…When evaluating the organization of the repertoire in terms of T cell clones containing various TRB V and J segments, it was noted that the T cell repertoire was self-similar, hence fractal in nature in BMT donors, and tended to be restored to this state with time after BMT suggestive of an inherent order to determining TCR usage. 22 This order may in fact derive from the organization of the gene segments along the DNA molecules, 9,23 which would allow for some level of predictability in terms of T cell reconstitution.…”