Analysis of Ig H chain gene segment utilization in human fetal liver. Revisiting the "proximal utilization hypothesis".

The utilization of Ig H chain gene segments during ontogeny is postulated to result from an immature recombination machinery that preferentially rearranges genes according to chromosomal position. We have tested the "proximal utilization hypothesis" using the two functional members of the VH5 family as a model. Nucleotide sequence analyses of transcripts involving these VH gene segments in 11- to 12-wk fetal liver samples revealed that they were utilized frequently, even though they are 500 kb apart. Although 50% of the H chain rearrangements in our study use the DQ52 gene segment, the most 3' end proximal human D segment, the preference for rearranging D gene segments based on 3' end proximity does not apply to other D segments because different members of the DLR family that are interspersed throughout the D locus are equally rearranged in our sample. The recurrent utilization of the DQ52 and JH4 gene segments and a propensity to preserve the two nucleotides flanking the 3' end of the VH gene segment to generate the amino acid residue at the V-D junction appear to be the major biases in the generation of an otherwise diverse fetal repertoire.