Homologies in Valpha and Vdelta genes of the T cell receptor: a statistical analysis. (Abstract/Poster in atti di convegno)

Type
Label
  • Homologies in Valpha and Vdelta genes of the T cell receptor: a statistical analysis. (Abstract/Poster in atti di convegno) (literal)
Anno
  • 1993-01-01T00:00:00+01:00 (literal)
Alternative label
  • Lisa A, Migone N, Zappador C, Matessi C. (1993)
    Homologies in Valpha and Vdelta genes of the T cell receptor: a statistical analysis.
    in XXXIX Congresso dell'Associazione Genetica Italiana, Senigallia (AN), 29/9-1/10 1993
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Lisa A, Migone N, Zappador C, Matessi C. (literal)
Pagina inizio
  • 227 (literal)
Pagina fine
  • 228 (literal)
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  • Atti Associazione Genetica Italiana (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroVolume
  • XXXIX (literal)
Note
  • Poster (literal)
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  • IGM-CNR; Centro di Immunogenetica ed istocompatibilità, CNR and Dip. di Genetica, Biologia e Chimica Medica, Un. Torino (literal)
Titolo
  • Homologies in Valpha and Vdelta genes of the T cell receptor: a statistical analysis. (literal)
Abstract
  • The functions of the gamma/delta T cell receptor (TCR) are much less understood than those of alpha/gamma TCR. There is however a growing consensus that gamma/delta T lymphocytes operate in distinct manners, and at different levels than alpha/beta T cells. gamma/delta T cells appear to belong to a separate cell lineage, which tends to differentiate at earlier stages of development than apha/beta lineages. Several results suggest that gamma/delta cells do not normally interact with B cells in the characteristic helper role of alpha/beta T lymphocytes. The gamma/delta receptor does not show the strong specificity (restriction) for MHC proteins of class I or II, typical of the alpha/beta receptor. Hence, some authors believe that the main function of this receptor could be to recognize antigenic fragments attached to monomorphic, MHC like antigen presenting proteins. In man and mouse the TCR alpha and delta genes are confined together in a narrow region, bounded by the Calpha gene segment at the 3' end and by the mixed array of Valpha and Vdelta elements at the 5' end. It is therefore most likely that the alpha and delta genes were originated by duplications of the appropriate elements of a single ancestral gene. If the functional roles of the alpha/beta and gamma/delta receptors are indeed as distinct as they are thought to be, the evolutionary divergence of the alpha and deltagenes could have had pronounced effects on the repertoire of Valpha and Vdelta peptidic domains since the bulk of the TCR V-domain, according to several authors, is responsible for contacts with the antigen presenting protein. It is then possible that evidence in support of a functional divergence of the alpha/beta and alpha/delta receptors is revealed by careful analysis of the pattern of sequence similarities between the various Valpha and Vdelta elements. We have considered the nucleotide sequences of 59 Valpha/delta elements for man, distributed in 33 families, and of 101 Valpha/delta elements for mouse, covering 21 families. Among the human sequences, 8 correspond nominally to Vdelta elements but 4 of them (Vdelta 4-7) very rarely are used in mature 8 genes, being normally expressed in a chains. The normal VS human repertoire consists of the remaining elements (Vdelta 1,2,3,8). In the mouse sequences, 11 nominal Vdelta elements are represented. Of these, 7 cover the normal repertoire (Vdelta 1-7, with 7 close variants of Vdelta 6), while the others (Vdelta 8-11) are very rarely used in delta chains. For man and mouse separately, we have aligned the inferred aminoacld sequences pairwise, using the Needleman-Wunsch algorithm with standard scoring parameters. We measured the similarity Sij between sequences i and j, of respective length Ni and Nj, by the quantity Sij = Qij/max{Ni , Nj}, where Qij is the total score achieved by the alignment of Ii and j. In this way, any two identical sequences would have maximum similarity irrespective of their length, while a sequence j identical to a subsequence of i would have a similarity to i smaller than maximum. This is justified whenever we are confident that all loci of interest are represented by essentially complete sequences. A similarity measure of this type, among others, has been used in other articles. Distances Dij between any two sequences i and j were calculated from the matrix of similarities {Sij} using the standard conversion formula: Dij = sqrt(Sii + Sjj)-2Sij). The two distance matrices {Dij}, calculated for man and mouse respectively, provided the basic data for the two statistical methods by which we analyzed the pattern of sequence similarities between Valpha and Vdelta elements: (i) Principal Coordinate Analysis (PCA) and (ii) Average Linkage Cluster Analysis (CLA). PCA tries to represent each sequence as a point in a multidimensional euclidean space, in such a way that the metric distance between any two such points I and J matches as closely as possible the actual distance Dij between the corresponding sequences. In this way the coordinates of point i provide a quantitative representation of the qualitative properties of the primary structure of sequence I, in ihe sense that the similarity relations within a set of sequences can be visualized by 2- or 3-dimensional scatterplots based on Principal Coordinates (PC) [4,5]. Usually the most informative scatterplots are based on the first 2 or 3 PC, the coordinates that individually account for the greatest fraction of overall variability. CLA is a classical method to estimate phylogenetic trees. It Is most reliable when rates of evolution are uniform in the different lineages, while it can produce distortions If evolutionary rates are too heterogeneous [6], a point that we have not yet analyzed. Thus, our preliminary results with this method should be considered with caution. The first 2 PC account for 23% of total variation between sequences in man, and 31% In mouse. The plots of these 2 PC give essentially the same picture in both species. The sequences are neatly subdivided in 4 groups, one of which occupies a central position and is surrounded by the others with approximate symmetry. All Vdelta elements of the normal repertoire, with the sole exception of mouse Vdelta7, are in the central group, while the majority of Valpha elements (83% of Valpha families in man, 63% in mouse) is distributed in the 3 peripheral groups. This picture, though suggestive, does not allow by itself a firm inference concerning functional divergence between alpha and delta chains. In fact, we might interpret these results as showing a major ancient radiation of 4 ancestral sequences, followed by minor recent radiations within each lineage. Since neutral evolution is often a dominant factor of molecular phylogenies, the ciustering together of Vdelta elements away from Valpha sequences might be functionally irrelevant and simply reflect common descent from a recent ancestor. However, a more reliable estimate of true phylogeny can be obtained by CLA, which accounts fully for the overall diversity, while the 2 first PC only reflect a partial aspect of it. Again, the results of CLA are homogeneous for the 2 species, in both of which it turns out that the 3 peripheral groups of PCA indeed correspond to monophyletic clusters while, quite surprisingly, the central group is an aggregate of independent lineages, which are as distant from each other as they are from the peripheral clusters. In particular, human Vdelta2, Vdelta3 and mouse Vdelta1, Vdelta2, Vdelta5 represent each a lineage by itself. In spite of their distant relation and great overall divergence, all sequences of the central group have in common the features reflected by the 2 first PC. A most natural interpretation of this outcome Is that either they have independently acquired the common features through directional evolution, or they all share certain primitive properties of a distant ancestor, which have been conserved against diversifying pressure from neutral evolution. Out of parsimony, we should of course prefer the- second interpretation; but |n either case we have a significant indication that the pronounced differences in the first 2 PC between the central group, dominated by Vdelta elements, and the 3 peripheral groups of Valpha elements are a consequence of natural selection, which obviously would imply the functional relevance of these differences and support the hypothesis of distinct biological roles of gamma/delta and alfa/beta TCR. Furthermore, if indeed the first 2 PC represent axes along which Valpha and Vdelta elements are functionally differentiated, our PC plots would suggest the following additional hypotheses: (i) the bulk of Valpha elements is subdivided in 3 functionally distinct classes, represented by the 3 peripheral groups; (ii) a few Valpha elements have strong functional analogies with the Vdelta elements, as indicated by their location in the central group. II would be quite interesting to see if any Immunological evidence could be brought in support of these hypotheses. (literal)
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