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Proc Natl Acad Sci U S A. 2018 May 8;115(19):E4433-E4442. doi: 10.1073/pnas.1717600115. Epub 2018 Apr 23.

Recurrent structural variation, clustered sites of selection, and disease risk for the complement factor H (CFH) gene family.

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Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195.
Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195.
Institute of Human Genetics, University of Regensburg, 93053 Regensburg, Germany.
Centre for Eye Research Australia, Department of Surgery (Ophthalmology), University of Melbourne, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia.
McDonnell Genome Institute at Washington University, St. Louis, MO 63108.
Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH 43205.
Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 93053.
Department of Ophthalmology, Columbia University, New York, NY 10027.
Department of Pathology and Cell Biology, Columbia University, New York, NY 10027.
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195;


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 four CFH-related (CFHR) gene paralogs (CFHR2 and CFHR4 ∼25-35 Mya and CFHR1 and CFHR3 ∼7-13 Mya). Remarkably, all evolutionary breakpoints share a common ∼4.8-kbp segment corresponding to an ancestral CFHR gene 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 ancestral CFH, creating four CFHR fusion 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 of CFH [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 new CFHR genes but also in the predisposition to complex human genetic disease phenotypes.


AMD; CFH gene family; age-related macular degeneration; natural selection; structural variation

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