Publication Date:
2018-04-23
Description:
Structural variation and single-nucleotide variation of the complement factor H (CFH) gene family underlie several complex genetic diseases, including age-related macular degeneration (AMD) and atypical hemolytic uremic syndrome (AHUS). To understand its diversity and evolution, we performed high-quality sequencing of this ∼360-kbp locus in six primate lineages, including multiple human haplotypes. Comparative sequence analyses reveal two distinct periods of gene duplication leading to the emergence of fourCFH-related (CFHR) gene paralogs (CFHR2andCFHR4∼25–35 Mya andCFHR1andCFHR3∼7–13 Mya). Remarkably, all evolutionary breakpoints share a common ∼4.8-kbp segment corresponding to an ancestralCFHRgene promoter that has expanded independently throughout primate evolution. This segment is recurrently reused and juxtaposed with a donor duplication containing exons 8 and 9 from ancestralCFH, creating fourCFHRfusion genes that include lineage-specific members of the gene family. Combined analysis of 〉5,000 AMD cases and controls identifies a significant burden of a rare missense mutation that clusters at the N terminus ofCFH[P= 5.81 × 10−8, odds ratio (OR) = 9.8 (3.67-Infinity)]. A bipolar clustering pattern of rare nonsynonymous mutations in patients with AMD (P〈 10−3) and AHUS (P= 0.0079) maps to functional domains that show evidence of positive selection during primate evolution. Our structural variation analysis in 〉2,400 individuals reveals five recurrent rearrangement breakpoints that show variable frequency among AMD cases and controls. These data suggest a dynamic and recurrent pattern of mutation critical to the emergence of newCFHRgenes but also in the predisposition to complex human genetic disease phenotypes.
Print ISSN:
0027-8424
Electronic ISSN:
1091-6490
Topics:
Biology
,
Medicine
,
Natural Sciences in General
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