Organization and Expression of Human VH Genes

The variable regions of immunoglobulin heavy chains are encoded by the three germline gene segments: V(ariable), D(iversity) and J(oining). These segments are joined during precursor B cell differentiation to form a functional VHDJH variable region gene. In the mouse there are hundreds of different VH gene segments that can be subdivided into families based on nucleotide sequence homology (reviewed in Alt, et al., 1987). Various studies of transformed and normal murine B lineage cells have shown that chromosomal position of VH segments is a major determinant of their rearrangement frequency, resulting in a preferential rearrangement of VH segments proximal to the cluster of JH elements (Yancopoulos, et al., 1984, 1988; Reth, et al., 1986; Perlmutter, et al., 1985). This preferential rearrangement phenomenon leads to the biased expression of JH-proximal VH segments in primary B cell repertoires; for example, these gene segments are the major contributors to the Ig heavy chain mRNA produced by B lineage cells of the fetal liver (Yancopoulos, et al., 1988). In contrast, B cells in peripheral lymphoid organs of adult mice appear to utilize most VH segments at equal frequency; that is the representation of different families in the peripheral Ig heavy chain mRNA repertoire correlates with the complexity of each family and is not related to chromosomal position (Yancopoulos, et al., 1988; Dildrop, et al., 1985). These findings led to the proposal that an initially biased repertoire is randomized, probably by cellular mechanisms, in the transition from primary to peripheral lymphoid tissues (Yancopoulos, et al., 1988).