Homology-directed recombination in IgH variable region genes from human neonates, infants and adults: implications for junctional diversity.
Homology-directed recombination, i.e. the preferential joining of gene segments at short sequence homologies, is found in 80% of IgH variable region genes from neonatal mice and causes a marked uniformity of their VH-DH- and DH-JH-junctions, which are predominated by one to three junctional sequences. To analyze the impact of homology-directed recombination on IgH gene diversity in humans, IgH rearrangements from fetuses and neonates (gestational age 20-42 weeks), infants (age 1-27 months) and adults were cloned and sequenced. As a marker of homology-directed recombination the VH-DH- and DH-JH-junctions were searched for nucleotides that could have been encoded by each of the two adjacent gene segments. Such overlapping sequences were rare (<3%) in VH-DH-junctions from newborns, infants, and adults. In contrast, overlapping sequences were found in 30% of the DH-JH-junctions from preterm neonates. Their frequency decreased with age to 19% in term neonates, 12% in infants and 4% in adults (p<0.001). Our analysis of the five most common DH-JH-combinations in neonates demonstrated that overlapping nucleotides reduced diversity: only 48% of junctions with overlapping nucleotides were different compared to 99% of junctions with N-insertions between DH and JH (p<0.001). However, homology-directed recombination had a much smaller effect on overall junctional diversity in human neonates than in neonatal mice because it rarely occurred in VH-DH-junctions and affected only 19% (term neonates) to 30% (preterm neonates) of the DH-JH-junctions. Therefore, unlike in mice, homology-directed recombination does not cause junctional uniformity in human neonates.
Bauer
Karl
K
Department of Pediatrics, JW Goethe University, Frankfurt, Germany.
Hummel
Michael
M
Berek
Claudia
C
Paar
Catherine
C
Rosenberger
Claudia
C
Kerzel
Sebastian
S
Versmold
Hans
H
Zemlin
Michael
M
D000328:Adult; D000367:Age Factors; D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology; D002675:Child, Preschool; D015322:Gene Rearrangement, B-Lymphocyte; D050438:Genes, Immunoglobulin Heavy Chain; D006801:Humans; D007133:Immunoglobulin Joining Region / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D051379:Mice; D008807:Mice, Inbred BALB C; D005810:Multigene Family; D011995:Recombination, Genetic; D012689:Sequence Homology, Nucleic Acid
D007133:Immunoglobulin Joining Region; D007135:Immunoglobulin Variable Region