Homology-directed recombination in IgH variable region genes from human neonates, infants and adults: Implications for junctional diversity

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• 作者：Karl Bauer ; Michael Hummel ; Claudia Berek ; Catherine Paar ; Claudia Rosenberger ; Sebastian Kerzel ; Hans Versmold ; Michael Zemlin
• 关键词：Human ; B cells ; Gene rearrangement ; Repertoire development
• 刊名：Molecular Immunology
• 出版年：2007
• 出版时间：April 2007
• 年：2007
• 卷：44
• 期：11
• 页码：2969-2977
• 全文大小：590 K

文摘

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.