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. 1998 Dec 7;188(11):2151-62.
doi: 10.1084/jem.188.11.2151.

The complete nucleotide sequence of the human immunoglobulin heavy chain variable region locus

F Matsuda  1 , K Ishii, P Bourvagnet, K i Kuma, H Hayashida, T Miyata, T Honjo
Affiliations

The complete nucleotide sequence of the human immunoglobulin heavy chain variable region locus

F Matsuda et al. J Exp Med. .

Abstract

The complete nucleotide sequence of the 957-kb DNA of the human immunoglobulin heavy chain variable (VH) region locus was determined and 43 novel VH segments were identified. The region contains 123 VH segments classifiable into seven different families, of which 79 are pseudogenes. Of the 44 VH segments with an open reading frame, 39 are expressed as heavy chain proteins and 1 as mRNA, while the remaining 4 are not found in immunoglobulin cDNAs. Combinatorial diversity of VH region was calculated to be approximately 6,000. Conservation of the promoter and recombination signal sequences was observed to be higher in functional VH segments than in pseudogenes. Phylogenetic analysis of 114 VH segments clearly showed clustering of the VH segments of each family. However, an independent branch in the tree contained a single VH, V4-44.1P, sharing similar levels of homology to human VH families and to those of other vertebrates. Comparison between different copies of homologous units that appear repeatedly across the locus clearly demonstrates that dynamic DNA reorganization of the locus took place at least eight times between 133 and 10 million years ago. One nonimmunoglobulin gene of unknown function was identified in the intergenic region.

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Figures

Figure 1
Figure 1
Organization of the human immunoglobulin VH locus. The 957-kb DNA is represented by the four collections of thick horizontal lines with the 3′ end at the bottom right corner. VH segments belonging to different VH families are indicated by vertical lines of different colors with their names on the upper row. Pseudogenes and newly identified VH segments are indicated with a P and an asterisk at the end of the name, respectively. Full height vertical lines represent VH segments without truncation while those containing truncation at the 5′-, 3′-, and both 5′- and 3′-portions are indicated by half-height upper, lower, and middle lines, respectively. An enlarged physical map of the 39-kb DNA of the human D gene cluster is also shown. Locations of D segments of six families are shown by diamonds of different colors with their names. Eight nonimmunoglobulin genes are shown with their names by short arrows of different colors indicating the transcriptional orientation. 13 locus-specific homology units are indicated by boxes of different colors in the middle row. Different classes of sequences are shown in the lower row: (a) Alu (red), MIR (magenta); (b) LINE1 (green), LINE2 (dark green); (c) retrotransposons (yellow), retroviral and other LTRs (blue); (d) DNA transposons (black); (e) medium reiteration frequency repetitive sequences (purple); and (f) simple repeats (cyan). DNA clones covering the locus are shown at the bottom. The YAC clone Y13.3, cosmid clones M146, U22-1, U22, and M83, as well as P1 clones H10 and A1 were newly isolated in this study whereas the others have been described previously (8). The nucleotide sequence was deposited in DDBJ/GenBank/EMBL database under the accession number AB019437-AB019441.
Figure 2
Figure 2
(A) A phylogenetic tree of the human VH segments based on their nucleotide sequence alignment. Three distinct sets of the VH segments that correspond to VHI, VHII, and VHIII subgroups (39) are separated by broken lines and indicated by Roman numerals. The seven VH families are indicated by different colors. Groups of the VH3 and VH4 segments containing the 5′-truncation are circled. (B) Estimation of divergence time between 10 homologous units containing a pair of the VH3 and VH4 segments. The human/mouse divergence time (vertical line) is indicated in million years ago (Myr).
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