Developmentally Regulated and Strain - Specific Expression of Murine Vh Gene Families by George D . Yancopoulos Barbara A

The genes that encode the antigen-binding portions (variable regions) of mam-malian Ig heavy (H) and light (L) chains are assembled from multiple germline DNA elements (1). Precursor B (pre-B) lymphocytes in "primary" B cell differentiation organs (the fetal liver and adult marrow) assemble and express first H and subsequently L chain genes in an ordered process that culminates in the generation of primary B-lymphocytes that express complete Ig molecules on their surface (2). Primary B lymphocytes then migrate to "peripheral" lymphoid organs, such as the spleen and lymph nodes, where they mature into Ig-secreting cells (plasma cells) after interaction with cognate antigens or nonspecific activators (3). Different populations of B-lineage cells may express distinct sets ofvariable regions (variable region "reper-toires") (4). Newly generated B cells express a primary repertoire; this primary repertoire may reflect constraints of the Ig gene assembly process, and presumably has not yet been perturbed by external selective forces. The repertoire of peripheral B-lineage cells, on the other hand, may be molded by positive or negative selective forces (4). The H chain variable region gene (VHDJ) is assembled from three germline DNA elements denoted V for variable, D for diversity, and JH for joining (reviewed in Reference 1). 12 D segments lie within the 80 kb immediately upstream of the JH cluster and 100-1000 or more V segments lie upstream of the D and JH clusters ; in BALB/c mice the most proximal VH segments are found within 200 kb of the D locus (Morrow, M., and F Alt, manuscript in preparation). Murine VH segments have been divided into nine families based on amino acid or nucleotide sequence homology (5-8), with the size of these families varying from a few (eg. Reference 9) to as many as hundreds of members (10, 11; see Fig. 1 A). Individual members of a VH family are usually grouped together on the chromosome (5, 12); the relative positions of the VH families were initially determined by deletion and recom-binant inbred strain analyses (5, 12; see Fig. 1 A). Modifications of this order, including some interspersion of the VH families, have been suggested (13, 14, 15). The assembly of V, D and JH segments follows an ordered two-step process in