Extensive genomic and functional polymorphism of the complement control proteins

Abstract

Using combinations of genomic markers, we describe more than 20 distinct ancestral haplotypes (AH) of complement control proteins (CCPs), located within the regulators of complement activation (RCA) alpha block at 1q32. This extensive polymorphism, including functional sites, is important because CCPs are involved in the regulation of complement activation whilst also serving as self and viral receptors. To identify haplotypes, we used the genomic matching technique (GMT) based on the pragmatic observation that extreme nucleotide polymorphism is packaged with duplicated sequences as polymorphic frozen blocks (PFB). At each PFB, there are many alternative sequences (haplotypes) which are inherited faithfully from very remote ancestors. We have compared frequencies of RCA haplotypes and report differences in recurrent spontaneous abortion (RSA) and psoriasis vulgaris (PV).

Genesis of ancestral haplotypes: RNA modifications and reverse transcription–mediated polymorphisms

“…Spanning approximately 4Mb of DNA at chromosome band 6p 21.3 these strong linkage disequilibrium (LD) patterns among polymorphic alleles have been confirmed in many studies by these groups [5,6] and others [7,8]. The concept has been extended to the conserved polymorphic blocks of functionally related genes on other chromosomes, such as the genes encoding the proteins regulating complement activation in the RCA complex on chromosome 1 [9,10 ] as well as other mammalian species, such as the dog MHC [11]. In the 1990s these studies led to the development of the Genomic Matching Technique (GMT) to match donor and recipients at the MHC in bone marrow transplantation [12,13].…”

Novel sequence elements define ancestral haplotypes of the region encompassing complement factor H

“…We also show, for the first time, that useful markers can be discovered by identifying a new class of haplospecific sequence elements [33,38,40].…”

“…coriell.org); (b) two local families (CYO1 and CYO2), as previously described [38]; and (c) three families (GEMF 046, 206 and 251) provided by the Centre for Eye Research Australia, University of Melbourne. All samples were collected after ethics approval, which included obtaining informed consent after the nature and possible consequences of the studies were explained.…”

“…The strategy of the GMT and the majority of the materials and methods used have been described previously [38]. Specific exceptions relating to the RCA beta complex are described below.…”

“…After extensive experience in assigning MHC haplotypes for transplant matching [34 -37], GMT has been applied to the RCA alpha region and demonstrated at least 20 distinct haplotypes within the region encoding CR1 [38]. Some RCA haplotypes have epistatic interactions with MHC haplotypes [39].…”