J segment positions bp 500 000 600 000 700Figure 1. (a) TCR a (TRA) and (b) TCR b (TRB) FD Olmutinib cancer calculated for each variable and joining segment (equation (3.1)). Values at each point are plotted along the nucleotide positions on the locus. Inset in each figure shows the values for the J segments in comparison with the entire locus. Note scale difference of approximately 1 log. TCR d region on the TRA locus is excluded, as are the D and C segments for the TRB locus.figure are similar in appearance and are symmetric, except for the spacing between TRA-J segments being an order of magnitude lower when compared with TRA-V segments. This implies that there exists spatial symmetry in the TCR loci bearing different T-cell gene segments (V and J specifically), evident in the proportionality of the size and distribution of the gene segments. It may be hypothesized that this phenomenon exerts an influence on the order of TCR gene rearrangement, such as the Db to Jb and DJb or Ja to Vb or Va recombination. In calculating FD-TCR, the D and C segments for TRA and TRB and the V30 segment of TRB were not considered because of their infrequent and non-periodic occurrence, as well as being interspersed between other loci. However, notably their size followed fixed proportion to the sizes of the J and V segments, respectively, such that D segments were approximately 1/3 to 1/4 the size of J, and the C segments were approximately three times the length of the V segments. Further, the TRB V30 segment did follow similar rules in terms of magnitude and intergenic space length (from the adjacent C segment located 50 of V30) as previously recorded for other V segments. Similarly, the TCR-g locus was also not evaluated because of the small number of gene segments, however, it is to be noted that the gene segment and intergenic lengths are similar to the TRA and TRB loci. During TCR recombination, the J segments in the TRA locus and the D segments in the TRB locus, are recombined with the V segments. The spatial distribution of V segments in the TRA and TRB loci was therefore examined relative to the position of the J and the D loci, respectively, to determine the spatial relationship between the recombining loci. The relative position of V loci was calculated with respect to the two D segments for TRB, and the 50 -, mid-point and 30 -J segments for TRA, by a formula considering the 50 -initial nucleotide positions (xi) of the D or J gene segments, and the final, 30 nucleotide position of the V segments (xf ) from the origin of the locus relative HM61713, BI 1482694 site recombination distance Vn ?xi ?D or J segment : xf nth Vsegment ?:2?Relative recombination distance (RRD) demonstrated a logarithmic decline as more telomeric V segments were considered across both TRA and TRB loci. When RRD for successive TRB V loci was plotted in order of occurrence on the locus, the value declined as a logarithmic function of V segment position, with a slope of 1.6 for the TRB locus (electronic supplementary material, figure S2a) and approximately 1.3 for119 117 115 113 111 109 107 1051 125 123 1 0005 7 9 11 13 15rsif.royalsocietypublishing.org100101923J. R. Soc. Interface 13:100 101 99 97 95 93 91 89 87 85 83 81 79 77 75 73 71 J segments 69 67 65 63 61 59 57 V segments 55 53 51 49 47 45 43 1 10 27 29 31 33 35 37 39Figure 2. Relative position of the first nucleotide of each TRA gene segment from the 30 end (blue) of the locus plotted against spacing (red) following that TCR gene segments (y-axis, log10-s.J segment positions bp 500 000 600 000 700Figure 1. (a) TCR a (TRA) and (b) TCR b (TRB) FD calculated for each variable and joining segment (equation (3.1)). Values at each point are plotted along the nucleotide positions on the locus. Inset in each figure shows the values for the J segments in comparison with the entire locus. Note scale difference of approximately 1 log. TCR d region on the TRA locus is excluded, as are the D and C segments for the TRB locus.figure are similar in appearance and are symmetric, except for the spacing between TRA-J segments being an order of magnitude lower when compared with TRA-V segments. This implies that there exists spatial symmetry in the TCR loci bearing different T-cell gene segments (V and J specifically), evident in the proportionality of the size and distribution of the gene segments. It may be hypothesized that this phenomenon exerts an influence on the order of TCR gene rearrangement, such as the Db to Jb and DJb or Ja to Vb or Va recombination. In calculating FD-TCR, the D and C segments for TRA and TRB and the V30 segment of TRB were not considered because of their infrequent and non-periodic occurrence, as well as being interspersed between other loci. However, notably their size followed fixed proportion to the sizes of the J and V segments, respectively, such that D segments were approximately 1/3 to 1/4 the size of J, and the C segments were approximately three times the length of the V segments. Further, the TRB V30 segment did follow similar rules in terms of magnitude and intergenic space length (from the adjacent C segment located 50 of V30) as previously recorded for other V segments. Similarly, the TCR-g locus was also not evaluated because of the small number of gene segments, however, it is to be noted that the gene segment and intergenic lengths are similar to the TRA and TRB loci. During TCR recombination, the J segments in the TRA locus and the D segments in the TRB locus, are recombined with the V segments. The spatial distribution of V segments in the TRA and TRB loci was therefore examined relative to the position of the J and the D loci, respectively, to determine the spatial relationship between the recombining loci. The relative position of V loci was calculated with respect to the two D segments for TRB, and the 50 -, mid-point and 30 -J segments for TRA, by a formula considering the 50 -initial nucleotide positions (xi) of the D or J gene segments, and the final, 30 nucleotide position of the V segments (xf ) from the origin of the locus relative recombination distance Vn ?xi ?D or J segment : xf nth Vsegment ?:2?Relative recombination distance (RRD) demonstrated a logarithmic decline as more telomeric V segments were considered across both TRA and TRB loci. When RRD for successive TRB V loci was plotted in order of occurrence on the locus, the value declined as a logarithmic function of V segment position, with a slope of 1.6 for the TRB locus (electronic supplementary material, figure S2a) and approximately 1.3 for119 117 115 113 111 109 107 1051 125 123 1 0005 7 9 11 13 15rsif.royalsocietypublishing.org100101923J. R. Soc. Interface 13:100 101 99 97 95 93 91 89 87 85 83 81 79 77 75 73 71 J segments 69 67 65 63 61 59 57 V segments 55 53 51 49 47 45 43 1 10 27 29 31 33 35 37 39Figure 2. Relative position of the first nucleotide of each TRA gene segment from the 30 end (blue) of the locus plotted against spacing (red) following that TCR gene segments (y-axis, log10-s.
