Complement factor H: sequence analysis of 221 kb of human genomic DNA containing the entire fH, fHR-1 and fHR-3 genes

Complement factor H (fH) is a member of a family of proteins involved in th e regulation of complement activation (RCA). These proteins share a common structural motif, the Short Consensus Repeat (SCR), which is structurally c onserved among related genes and between phylogenetically divergent species . fH is composed of 20 such SCRs and a variety of biological functions have been localised to specific SCR domains. The majority of individual SCRs id entified are encoded by single exons, and processes such as gene conversion , duplication and exon shuffling have been implicated in the evolution and genomic radiation of SCR-encoding genes. We have analysed two GenBank seque nce entries relating to two overlapping PAC clones sequenced at the Sanger Centre which contain the entire human DI gene and two adjacent DI-related ( MR) genes, fHR-1 and fHR-3. Here, we report the detailed analysis of the as sembled 221 kb of contiguous, ungapped genomic sequence from human chromoso me 1q32, in part employing the RUMMAGE-DP automated annotation tool. Genomi c duplications involving fH and MR exons were identified and Alu/L1 repeat dating established that the duplications occurred after the separation of r odent and primate lineages. The analysis indicates that retrotransposition as well as single and multiple exon duplication events are likely to have b een involved in SCR radiation and RCA gene evolution, facilitated by conser vation of splice-phasing and the single-exon, single-SCR nature of the enco ded domains. (C) 2000 Elsevier Science Ltd. All rights reserved.