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; Anne Marie E. Welch; Vy Dang; Felix Grassmann; Andrea J. Richardson; Robyn H. Guymer; Tina A. Graves-Lindsay; Richard K. Wilson; Bernhard H.F. Weber; Paul N. Baird; Rando Allikmets; Evan E. Eichler

doi:10.1073/pnas.1717600115

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, Anne Marie E. Welch, Vy Dang, Felix Grassmann, Andrea J. Richardson, Robyn H. Guymer, Tina A. Graves-Lindsay, Richard K. Wilson, Bernhard H.F. Weber, Paul N. Baird, Rando Allikmets, Evan E. Eichler^*

^*Corresponding author for this work

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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.

Original language	English
Pages (from-to)	E4433-E4442
Number of pages	10
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	115
Issue number	19
Early online date	23 Apr 2018
DOIs	https://doi.org/10.1073/pnas.1717600115
Publication status	Published - 8 May 2018

Bibliographical note

Data deposition: The data reported in this paper have been deposited as a National Center for Biotechnology Information BioProject (accession no. PRJNA401648).

Author contributions: S.C. and E.E.E. designed research; S.C., C.B., L.H., K.P., K.M.M., M.S., A.E.W., V.D., T.A.G.-L., and R.K.W. performed research; S.C., J.H., C.B., L.H., K.P., K.M.M., M.S., A.E.W., V.D., F.G., A.J.R., R.H.G., T.A.G.-L., R.K.W., B.H.F.W., P.N.B., R.A., and E.E.E. contributed new reagents/analytic tools; S.C., B.J.N., J.H., and E.E.E. analyzed data; and S.C., B.J.N., and E.E.E. wrote the paper.

Keywords

Age-related macular degeneration
AMD
CFH gene family
Natural selection
Structural variation

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cantsilieris, S., Nelson, B. J., Huddleston, J., Baker, C., Harshman, L., Penewit, K., Munson, K. M., Sorensen, M., Welch, A. M. E., Dang, V., Grassmann, F., Richardson, A. J., Guymer, R. H., Graves-Lindsay, T. A., Wilson, R. K., Weber, B. H. F., Baird, P. N., Allikmets, R., & Eichler, E. 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. https://doi.org/10.1073/pnas.1717600115

Recurrent structural variation, clustered sites of selection, and disease risk for the complement factor H (CFH) gene family. / Cantsilieris, Stuart; Nelson, Bradley J.; Huddleston, John et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 19, 08.05.2018, p. E4433-E4442.

Research output: Contribution to journal › Article › peer-review

Cantsilieris, S, Nelson, BJ, Huddleston, J, Baker, C, Harshman, L, Penewit, K, Munson, KM, Sorensen, M, Welch, AME, Dang, V, Grassmann, F, Richardson, AJ, Guymer, RH, Graves-Lindsay, TA, Wilson, RK, Weber, BHF, Baird, PN, Allikmets, R & Eichler, EE 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, vol. 115, no. 19, pp. E4433-E4442. https://doi.org/10.1073/pnas.1717600115

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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.",

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note = "Data deposition: The data reported in this paper have been deposited as a National Center for Biotechnology Information BioProject (accession no. PRJNA401648). Author contributions: S.C. and E.E.E. designed research; S.C., C.B., L.H., K.P., K.M.M., M.S., A.E.W., V.D., T.A.G.-L., and R.K.W. performed research; S.C., J.H., C.B., L.H., K.P., K.M.M., M.S., A.E.W., V.D., F.G., A.J.R., R.H.G., T.A.G.-L., R.K.W., B.H.F.W., P.N.B., R.A., and E.E.E. contributed new reagents/analytic tools; S.C., B.J.N., J.H., and E.E.E. analyzed data; and S.C., B.J.N., and E.E.E. wrote the paper. ",

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AU - Baker, Carl

AU - Harshman, Lana

AU - Penewit, Kelsi

AU - Munson, Katherine M.

AU - Sorensen, Melanie

AU - Welch, Anne Marie E.

AU - Dang, Vy

AU - Grassmann, Felix

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N2 - 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.

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

Abstract

Bibliographical note

Keywords

UN SDGs

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