Ru. Chukwuocha et Aj. Feeney, ROLE OF HOMOLOGY-DIRECTED RECOMBINATION - PREDOMINANTLY PRODUCTIVE REARRANGEMENTS OF V(H)81X IN NEWBORNS BUT NOT IN ADULTS, Molecular immunology, 30(16), 1993, pp. 1473-1479
In the neonate, Ig V-D-J junctions often occur at regions of short seq
uence homology, resulting in one to two predominant junctional sequenc
es for most-V-D and D-J recombinations. We have proposed that this mec
hanism of homology-directed recombination may play a role in the non-r
andom usage of V(H) genes observed in fetal and neonatal life, since u
se of the short homologies at V-D junctions would preferentially make
productive rearrangements for the overutilized 7183 and Q52 V(H) genes
, and would make predominantly non-productive rearrangements for the u
nderutilized V(H)J558 gene family. Here we test this hypothesis for th
e 81X gene from the V(H)7183 family. Since pre-B cells which have rear
ranged the 81X gene do not appear to undergo the normal clonal prolife
ration before light chain rearrangement, analysis of the percentage of
productive versus non-productive rearrangements for this V(H) gene is
not skewed by the expansion of pre-B cells with productively rearrang
ed IgH alleles. If V-D-J rearrangements were random, one would predict
that only one-third of the rearrangements would be in-frame. This is
close to what we observed for the 81X gene in adult bone marrow. In co
ntrast, we show that 62% of all 81X rearrangements in fetal/newborn pr
e-B cells were productive. Forty-one percent of all the neonatal pre-B
sequences containing DFL16 or DSP2 used homology-directed recombinati
on to create the predominantly observed V-D junctional sequences, and
93% of those sequences were productive. This is consistent with our hy
pothesis that the mechanism of homology-directed recombination would r
esult in an increased proportion of productive 81X rearrangements in t
he newborn. Therefore, we suggest that in fetal and neonatal life, whe
n N regions are lacking, V(H)7183 and V(H)Q52 genes are more likely to
undergo productive rearrangements than other V(H) families and thus a
re much more likely to contribute to the early B cell repertoire.