Cantsilieris, Stuart and Nelson, Bradley J. and Huddleston, John and Baker, Carl and Harshman, Lana and Penewit, Kelsi and Munson, Katherine M. and Sorensen, Melanie and Welch, AnneMarie E. and Dang, Vy and Grassmann, Felix and Richardson, Andrea J. and Guymer, Robyn H. and Graves-Lindsay, Tina A. and Wilson, Richard K. and Weber, Bernhard H. F. and Baird, Paul N. and Allikmets, Rando and Eichler, Evan E. (2018) Recurrent structural variation, clustered sites of selection, and disease risk for the complement factor H (CFH) gene family. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 115 (19). E4433-E4442. ISSN 0027-8424,
Full text not available from this repository. (Request a copy)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 similar to 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 similar to 25-35 Mya and CFHR1 and CFHR3 similar to 7-13 Mya). Remarkably, all evolutionary breakpoints share a common similar to 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 x 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HEMOLYTIC-UREMIC SYNDROME; MACULAR DEGENERATION; RARE VARIANTS; EVOLUTIONARY INSTABILITY; EARLY-ONSET; MUTATIONS; PROTEINS; DELETION; SUSCEPTIBILITY; ACTIVATION; structural variation; CFH gene family; natural selection; age-related macular degeneration; AMD |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Humangenetik |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 19 Feb 2020 12:58 |
| Last Modified: | 19 Feb 2020 12:58 |
| URI: | https://pred.uni-regensburg.de/id/eprint/14588 |
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