Assignment of the structural gene for the third component of human complement to chromosome 19.

Abstract

The third component of complement (C3) is synthesized and secreted by cultured human primary fibroblasts. A monoclonal antibody having specificity for an antigenic determinant carried by human but not mouse C3 was used to study the continued expression of human C3 in three panels of independently derived human-mouse somatic cell hybrids. Expression of the human product was shown to segregate with human chromosome 19 and with no other chromosome or group of chromosomes. A unique-sequence human genomic C3 DNA clone was isolated and used as a probe in DNA hybridization experiments with DNA prepared from appropriate human-mouse somatic cell hybrids to confirm assignment of the human C3 gene to chromosome 19.The complement system has two independent means of activation, which give rise to the classical and alternative pathways. In each pathway, activation of the third component (C3) is the central event.The genetics of complement has been extensively investigated in man (1), with particular success having been derived from the study of deficiencies of individual components and of polymorphic variants, which may be identified electrophoretically, in families and populations. To date, the structural loci for three complement components, factor B (2, 3), C2 (4-6), and C4 (7,8), have been closely linked to the HLA-B locus on chromosome 6 by such studies.Although allotypic variants of several other complement components have been described, none of these have been mapped to particular human chromosomes. In the case of C3, neither the electrophoretic variants (9, 10) nor the inherited deficiencies (11) are linked to HLA.An alternative approach to family and population studies for human gene mapping is the use of somatic cell genetics. Assignments of particular human functions to individual chromosomes are dependent on (i) accurate assessment ofthe human chromosome content of the interspecies somatic cell hybrids under study and (ii) a means whereby the human gene products or human gene DNA sequences can be distinguished from those of the other species. We have assigned the human C3 gene to chromosome 19 by using a monoclonal antibody having specificity for human C3 to study the expression of this complement component in appropriate somatic cell hybrids. We have confirmed this assignment by using a human C3 genomic DNA clone to identify human C3 gene sequences in DNA samples prepared from the same somatic cell hybrids. MATERIALS AND METHODSCell Lines and Monoclonal Antibodies. The human fibroblast, 10FDF, was grown from a newborn foreskin explant. RAG (12) and 1R (13) are mouse renal adenocarcinoma and Lcell lines, respectively. Both are hypoxanthine phosphoribosyltransferase negative. The somatic cell hybrid MOG2 (14) is constructed from a human fibroblast and RAG, and the somatic cell hybrids SIR7 and SIR1l are constructed from human fibroblasts and IR. All cells were maintained in bicarbonate-buffered RPMI 1640 medium/10% fetal calf serum supplemented with penicillin at 100 units/ml, streptomycin at 100 pqg/ml ...

Nucleotide sequence of cDNA encoding human alpha 2-macroglobulin and assignment of the chromosomal locus.

“…3 The a2M gene belongs in a gene family together with the complement C3, C4, and C5 genes. In mice, the C3 and C4 genes reside on the same chromosome, chromosome 17 (54); in humans they reside on different chromosomes: C3 on chromosome 19 (23) and C4 on chromosome 6 (24). Thus, no selective pressure is apparent to maintain these loci on the same chromosome after duplication and divergence.…”

“…Comparison of human a2M with murine C3 revealed a 25% overall sequence homology (17,18,22), supporting the proposal of their common evolutionary origin. The human C3 gene is located on chromosome 19 (23), and the human C4 genes map to the histocompatibility complex on chromosome 6 (24).…”

Human apolipoprotein A-I--C-III gene complex is located on chromosome 11.

“…33 Another group has studied two families in which polymorphic forms of apo E demonstrated linkage with electrophoretic variants of the third component of complement in males. 34 Since the latter has been mapped to chromosome 1 d, 35 apo E may reside on this chromosome and therefore would not be linked to the apo A-l-apo C-lll gene complex. Thus, although two of the apolipoprotein genes, apo A-l and apo C-lll, are closely linked in the genome, it appears that at least some of the apolipoprotein genes, apo A-ll and apo E, are dispersed.…”

Fecondite et mortalite infantile dans la dystrophie myotonique au Saguenay-Lac-St-Jean (Quebec Canada)

“…Ce n'est qu'en 1983 que la liaison du gène de la DM à d'autres loci (C3, PEPD) fut décrite, ce qui permit la localisation du gène de la DM sur le chromosome 19 ( McAlpine et al 1976;Whitehead et al 1982;O'Brien et al 1983;Eiberg et al 1983). …”