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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.

Author information

1
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195.
2
Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195.
3
Institute of Human Genetics, University of Regensburg, 93053 Regensburg, Germany.
4
Centre for Eye Research Australia, Department of Surgery (Ophthalmology), University of Melbourne, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia.
5
McDonnell Genome Institute at Washington University, St. Louis, MO 63108.
6
Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH 43205.
7
Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 93053.
8
Department of Ophthalmology, Columbia University, New York, NY 10027.
9
Department of Pathology and Cell Biology, Columbia University, New York, NY 10027.
10
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195; eee@gs.washington.edu.

Abstract

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.

KEYWORDS:

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

PMID:
29686068
PMCID:
PMC5948961
DOI:
10.1073/pnas.1717600115
[Indexed for MEDLINE]
Free PMC Article

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