14 research outputs found
Segmental duplication as one of the driving forces underlying the diversity of the human immunoglobulin heavy chain variable gene region
Background: Segmental duplication and deletion were implicated for a region containing the human
immunoglobulin heavy chain variable (IGHV) gene segments, 1.9III/hv3005 (possible allelic variants of IGHV3-30) and
hv3019b9 (a possible allelic variant of IGHV3-33). 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 IGHV 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 nucleotide
sequence level using sequences from the three human 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 IGHV 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 nucleotide sequence level and in IGHV 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 IGHV gene segments in this region are functionally important.
Conclusions: Non-reciprocal genetic rearrangements associated with large duplicate sequence blocks could
substantially contribute to the IGHV 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 IGHV gene segment repertoire, antibody diversity, and therefore, the immune system. Because one of the
gene segments, 3-30 (1.9III), is associated with autoimmune diseases, 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 regio
The global burden of iron overload
There have been major developments in the field of iron metabolism in the past decade following the identification of the HFE gene and the mutation responsible for the C282Y substitution in the HFE protein. While HFE-associated hemochromatosis occurs predominantly in people of northern European extraction, other less-common mutations can lead to the same clinical syndrome and these may occur in other populations in the Asian-Pacific region. The most common of these is the mutation that leads to changes in the ferroportin molecule, the protein responsible for the transport of iron across the basolateral membrane of the enterocyte and from macrophages. Recent research has unraveled the molecular processes of iron transport and regulation of how these are disturbed in hemochromatosis and other iron-loading disorders. At the same time, at least one new oral iron chelating agent has been developed that shows promise in the therapy of hemochromatosis as well as thalassemia and other secondary causes of iron overload. It is pertinent therefore to examine the developments in the global field of iron overload that have provided insights into the pathogenesis, disease penetrance, comorbid factors, and management