UNUSUAL PATHS AND SITES OF V REGION DIVERSIFICATION

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DESCRIPTION (Adapted from the Investigator's Abstract): More than one anatomical site appears to be involved in the diversification of the bovine primary heavy chain repertoire. It has been found that although the ileal Peyer's patch (IPP) is a site of diversification in newborn and older calves, during early fetal development, spleen, but not ileum, harbors a diverse collection of heavy chain sequences. Although in cattle and sheep, immunoglobulin is not expressed in bone marrow of newborn and older calves, heavy chain expression can be readily demonstrated in early fetal bone marrow. There is also a dramatic variation in the CDR3 length noted in cattle, suggesting another unusual feature of heavy chain diversification. A knowledge of the germline is necessary to determine whether D segments of extremely variable length or the rearrangement of multiple D segments underlies CDR3 length variation. Additionally, germline data is necessary to determine whether untemplated somatic hypermutation, gene conversion or a combination of both are significant factors in generating the VH diversity found in follicles of the IPP or in early fetal spleen. To determine the mechanisms underlying bovine heavy chain diversification, the following specific aims will be pursued: 1) Determine the sites of diversification of the heavy chain primary repertoire in cattle; 2) Obtain germline heavy chain VH, DH, and JH genes; and 3) Examine the mechanism of heavy chain diversification in cattle.