Abstract
In this study we have used multiplex ligation-dependent probe amplification (MLPA) to measure the copy number of CFHR3 and CFHR1 in DNA samples from 238 individuals from the UK and 439 individuals from the HGDP-CEPH Human Genome Diversity Cell Line Panel. We have then calculated the allele frequency and frequency of homozygosity for the copy number polymorphism represented by the CFHR3/CFHR1 deletion. There was a highly significant difference between geographical locations in both the allele frequency (X2 = 127.7, DF = 11, P-value = 4.97x10-22) and frequency of homozygosity (X2 = 142.3, DF = 22, P-value = 1.33x10-19). The highest frequency for the deleted allele (54.7%) was seen in DNA samples from Nigeria and the lowest (0%) in samples from South America and Japan. The observed frequencies in conjunction with the known association of the deletion with AMD, SLE and IgA nephropathy is in keeping with differences in the prevalence of these diseases in African and European Americans. This emphasises the importance of identifying copy number polymorphism in disease.
Highlights
Complement genes within the RCA (Regulators of Complement Activation) cluster at chromosome 1q32 are arranged in tandem within two groups [1]
That there might be differences in the population frequency of the CFHR3/1 deletion was suggested from a study published in 2006 which showed that the prevalence of homozygous deletion in African populations was,16% [17]
In this study we have used multiplex ligation-dependent probe amplification (MLPA) to determine the copy number of CFHR3 and CFHR1 in a variety of different geographical locations derived from the HGDP-CEPH collection
Summary
Complement genes within the RCA (Regulators of Complement Activation) cluster at chromosome 1q32 are arranged in tandem within two groups [1]. SDs such as those seen in the RCA cluster are frequently associated with genomic rearrangements [5] These usually occur as a result of non-allelic homologous recombination (NAHR) between SDs but can be a result of gene conversion and microhomology mediated end joining (MMEJ) [6]. Genomic disorders at this locus have affected CFH and the CFHRs in a number of ways. Complete deficiency of factor H related proteins 1 and 3 had been found to be occur in ,4% of a European population in protein studies before DNA studies of the region [10] This DNA copy number polymorphism (CNP) has been extensively characterised in health and disease. In this study we have measured copy number of CFHR3 and CFHR1 with multiplex ligationdependent probe amplification (MLPA) [20] in a range of populations derived from the HGDP-CEPH Human Genome Diversity Panel (http://www.cephb.fr/en/hgdp/diversity.php) [21]
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