Journal article

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

Stuart Cantsilieris, Bradley J Nelson, John Huddleston, Carl Baker, Lana Harshman, Kelsi Penewit, Katherine M Munson, Melanie Sorensen, AnneMarie E Welch, Vy Dang, Felix Grassmann, Andrea J Richardson, Robyn H Guymer, Tina A Graves-Lindsay, Richard K Wilson, Bernhard HF Weber, Paul N Baird, Rando Allikmets, Evan E Eichler

Proceedings of the National Academy of Sciences of the United States of America | NATL ACAD SCIENCES | Published : 2018


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 a..

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Awarded by US NIH

Awarded by National Health and Medical Research Council (NHMRC) C. J. Martin Biomedical Fellowship

Awarded by NHMRC Senior Research Fellowship

Awarded by NIH



Funding Acknowledgements

We thank T. Brown for assistance with manuscript preparation. This work was supported, in part, by grants from the US NIH (Grant R01HG002385 to E.E.E. and Grant U41HG007635 to R.K.W. and E.E.E.). S.C. was supported by a National Health and Medical Research Council (NHMRC) C. J. Martin Biomedical Fellowship (1073726). P.N.B. was supported by an NHMRC Senior Research Fellowship (APP1138585). The Centre for Eye Research Australia receives operational infrastructure support from the Victorian Government. R.A. was supported, in part, by NIH Grants R01-EY013435 and P30-EY019007 and by an unrestricted grant from Research to Prevent Blindness to the Department of Ophthalmology, Columbia University. E.E.E. is an Investigator of the Howard Hughes Medical Institute.