Segmental duplication as one of the driving forces underlying the diversity of the XXXX immunoglobulin heavy chain variable gene region.

@entity1 @entity56917 @entity72901 @entity377 @entity792 @entity7513
BACKGROUND: Segmental duplication and deletion were implicated for a region containing the @entity1 @entity7513 ( @entity7513 ) gene segments, 1.9III/hv3005 (possible allelic variants of @entity56917 ) and hv3019b9 (a possible allelic variant of @entity72901 ). However, very little is known about the ranges of the duplication and the polymorphic region. This is mainly because of the difficulty associated with distinguishing between allelic and paralogous sequences in the @entity7513 region containing extensive repetitive sequences. Inability to separate the two parental haploid genomes in the subjects is another serious barrier. To address these issues, unique DNA sequence tags evenly distributed within and flanking the duplicated region implicated by the previous studies were selected. The selected tags in single sperm from six unrelated healthy donors were amplified by multiplex PCR followed by microarray detection. In this way, individual haplotypes of different parental origins in the sperm donors could be analyzed separately and precisely. The identified polymorphic region was further analyzed at the @entity377 sequence level using sequences from the three @entity1 genomic sequence assemblies in the database. RESULTS: A large polymorphic region was identified using the selected sequence tags. Four of the 12 haplotypes were shown to contain consecutively undetectable tags spanning in a variable range. Detailed analysis of sequences from the genomic sequence assemblies revealed two large duplicate sequence blocks of 24,696 bp and 24,387 bp, respectively, and an incomplete copy of 961 bp in this region. It contains up to 13 @entity7513 gene segments depending on haplotypes. A polymorphic region was found to be located within the duplicated blocks. The variants of this polymorphism unusually diverged at the @entity377 sequence level and in @entity7513 gene segment number, composition and organization, indicating a limited selection pressure in general. However, the divergence level within the gene segments is significantly different from that in the intergenic regions indicating that these regions may have been subject to different selection pressures and that the @entity7513 gene segments in this region are functionally important. CONCLUSIONS: Non-reciprocal genetic rearrangements associated with large duplicate sequence blocks could substantially contribute to the @entity7513 region diversity. Since the resulting polymorphisms may affect the number, composition and organization of the gene segments in this region, it may have significant impact on the function of the @entity7513 gene segment repertoire, antibody diversity, and therefore, the immune system. Because one of the gene segments, 3-30 (1.9III), is associated with @entity792 , it could be of diagnostic significance to learn about the variants in the haplotypes by using the multiplex haplotype analysis system used in the present study with DNA sequence tags specific for the variants of all gene segments in this region.
