High-throughput sequencing (HTS) of human T cell receptors has revealed a high level of complexity in the T cell repertoire, which makes it difficult to correlate T cell reconstitution with clinical outcomes. The associations identified thus far are of a broadly statistical nature, precluding precise modeling of outcomes based on T cell repertoire development following bone marrow transplantation (BMT). Previous work has demonstrated an inherent, mathematically definable order observed in the T cells from a diverse group of donors, which is perturbed in recipients following BMT. In this study, T cell receptor (TCR)-b sequences from HLA-matched related donor and recipient pairs are analyzed to further develop this methodology. TCR-b sequencing from unsorted and sorted T cell subsets isolated from the peripheral blood samples of BMT donors and recipients show conservation and symmetry of VJ segment usage in the clonal frequencies, linked to the organization of the gene segments along the TCR locus. This TCR-b VJ segment translational symmetry is preserved post-transplantation and even in cases of acute graft-versus-host disease (aGVHD), suggesting that GVHD occurrence represents a polyclonal donor T cell response to recipient antigens. The complexity of the repertoire is significantly diminished after BMT, and the T cell clonal hierarchy is altered post-transplantation. Low-frequency donor clones tended to take on a higher rank in the recipients following BMT, especially in patients with aGVHD. Over time, the repertoire evolves to a more donor-like state in the recipients who did not develop GVHD as opposed to those who did. The results presented here support new methods of quantifying and characterizing post-transplantation T cell repertoire reconstitution.

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.

SummaryBackgroundThe large-scale pattern of distribution of genes on the chromosomes in the known animal genomes is not well characterized. We hypothesized that individual genes will be distributed on chromosomes in a mathematically ordered manner across the animal kingdom.ResultsTwenty-one animal genomes reported in the NCBI database were examined. Numerically, there was a trend towards increasing overall gene content with increasing size of the genome as reflected by the chromosomal complement. Gene frequency on individual chromosomes in each animal genome was analyzed and demonstrated uniformity of proportions within each animal with respect to both average gene frequency on individual chromosomes and gene distribution across the unique genomes. Further, average gene distribution across animal species followed a relationship whereby it was, approximately, inversely proportional to the square root of the number of chromosomes in the unique animal genomes, consistent with the notion that there is an ordered increase in gene dispersion as the complexity of the genome increased. To further corroborate these findings a derived measure, termed gene spacing on chromosomes correlated with gene frequency and gene distribution.ConclusionAs animal species have evolved, the distribution of their genes on individual chromosomes and within their genomes, when viewed on a large scale is not random, but follows a mathematically ordered process, such that as the complexity of the organism increases, the genes become less densely distributed on the chromosomes and more dispersed across the genome.

The 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 selfsimilarity 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 α (TRA) and β (TRB) loci were arranged in a selfsimilar manner when the spacing between the adjacent segments was considered as a function of the size of the neighboring gene segment, with an average fractal dimension of ͠1.5. The ratio of genomic distance between either the J (in TRA) or D (in TRB) segments and successive V segments on these loci declined logarithmically with a slope of similar magnitude. Accounting for the gene segments occurring on helical DNA molecules in 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’ to the 3’ end of the locus, supporting a log-periodic organization. T cell clonal frequencies, based on V and J segment usage, from three 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 gene-segment 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.

The 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 selfsimilarity 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 α (TRA) and β (TRB) loci were arranged in a selfsimilar manner when the spacing between the adjacent segments was considered as a function of the size of the neighboring gene segment, with an average fractal dimension of ~1.5. The ratio of genomic distance between either the J (in TRA) or D (in TRB) segments and successive V segments on these loci declined logarithmically with a slope of similar magnitude. Accounting for the gene segments occurring on helical DNA molecules in 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' to the 3' end of the locus, supporting a log-periodic organization. T cell clonal frequencies, based on V and J segment usage, from three 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 gene-segment 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.On the organization of T cell receptor loci. Toor A, Toor A, Manjili M.