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Cantsilieris, Stuart; Nelson, Bradley J.; Huddleston, John; Baker, Carl; Harshman, Lana; Penewit, Kelsi; Munson, Katherine M.; Sorensen, Melanie; Welch, AnneMarie E.; Dang, Vy; Grassmann, Felix; Richardson, Andrea J.; Guymer, Robyn H.; Graves-Lindsay, Tina A.; Wilson, Richard K.; Weber, Bernhard H. F.; Baird, Paul N.; Allikmets, Rando; Eichler, Evan E.
Proceedings of the National Academy of Sciences - PNAS, 05/2018, Letnik: 115, Številka: 19Journal Article
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.
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