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Functional Architecture of Deleterious Genetic Variants in the Genome of a Wrangel Island Mammoth

Fry, Erin, Kim, Sun K, Chigurapti, Sravanthi, Mika, Katelyn M, Ratan, Aakrosh, Dammermann, Alexander, Mitchell, Brian J, Miller, Webb, Lynch, Vincent J·2020·Genome Biology and Evolution
DOI 10.1093/gbe/evz279PMC PMC7094797

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Abstract

Woolly mammoths were among the most abundant cold-adapted species during the Pleistocene. Their once-large populations went extinct in two waves, an end-Pleistocene extinction of continental populations followed by the mid-Holocene extinction of relict populations on St. Paul Island ∼5,600 years ago and Wrangel Island ∼4,000 years ago. Wrangel Island mammoths experienced an episode of rapid demographic decline coincident with their isolation, leading to a small population, reduced genetic diversity, and the fixation of putatively deleterious alleles, but the functional consequences of these processes are unclear. Here, we show that a Wrangel Island mammoth genome had many putative deleterious mutations that are predicted to cause diverse behavioral and developmental defects. Resurrection and functional characterization of several genes from the Wrangel Island mammoth carrying putatively deleterious substitutions identified both loss and gain of function mutations in genes associated with developmental defects (HYLS1), oligozoospermia and reduced male fertility (NKD1), diabetes (NEUROG3), and the ability to detect floral scents (OR5A1). These data suggest that at least one Wrangel Island mammoth may have suffered adverse consequences from reduced population size and isolation.

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Fig. 1. —Functional architecture of deleterious variants in the Wrangel Island mammoth genome. (A) Violin plot of PolyPhen-2 scores for derived, homozygous variants in each mammoth and Asian elephant. Phylogenetic relationships are shown at the bottom and the ancestral Yakut (AncYakut) node is indicated with a blue circle. Green, light purple, and dark purple backgrounds indicate variants that are predicted to be benign, possibly damaging, and probably damaging, respectively. (B) Word Cloud showing mouse KO phenotypes in which homozygous probably damaging amino acid substitutions in the Wrangel Island mammoth are enriched. In this figure, the size of each phenotype is drawn proportional to the −log(10)P value of that terms enrichment. Inset scale shows word size for phenotypes with a −log(10)P value of 2.
Fig. 1. —Functional architecture of deleterious variants in the Wrangel Island mammoth genome. (A) Violin plot of PolyPhen-2 scores for derived, homozygous variants in each mammoth and Asian elephant. Phylogenetic relationships are shown at the bottom and the ancestral Yakut (AncYakut) node is indicated with a blue circle. Green, light purple, and dark purple backgrounds indicate variants that are predicted to be benign, possibly damaging, and probably damaging, respectively. (B) Word Cloud showing mouse KO phenotypes in which homozygous probably damaging amino acid substitutions in the Wrangel Island mammoth are enriched. In this figure, the size of each phenotype is drawn proportional to the −log(10)P value of that terms enrichment. Inset scale shows word size for phenotypes with a −log(10)P value of 2.CC BY · PubMed Central
Fig. 2 —The Wrangel Island mammoth HYLS1 P119L mutant is dysfunctional. (A) Sequence logo showing conservation of HYLS1 around the Wrangel Island mammoth P119L mutation. Upper, logo from 100 vertebrates. Lower, logo from mammoths (Oimyakon, M4, and Wrangel Island). Note that the maximum information (conservation) of an amino acid site is log 2 20 = 4.3 bits. (B–E) Representative images of Xenopus multiciliated cells from embryos injected with Control MO (B), HYLS1 MO (C), HYLS1 MO and WT XHYLS1 (D), and HYLS1 MO and XHYLS1-S186L; note that S186L is the equivalent of the Wrangel Island mammoth genome P119L in Xenopus HYLS1 (E) stained with acetylated tubulin to mark cilia (green) and phalloidin to mark cell boundaries (red). Note: arrows identify cells with defective ciliogenesis (scale bars = 10 μm). (F, G) Multiciliated cell from a Xenopus embryo injected with mRNA encoding XHYLS1-S186L-GFP shows proper localization to the centrioles (green) and proper formation of cilia marked with acetylated tubulin (red) with cell boundaries marked with phalloidin (purple) (scale bar = 10 μm). (H) Quantification of ciliogenesis defect scoring cells with >25 cilia (Wilcox test P values are shown).
Fig. 2 —The Wrangel Island mammoth HYLS1 P119L mutant is dysfunctional. (A) Sequence logo showing conservation of HYLS1 around the Wrangel Island mammoth P119L mutation. Upper, logo from 100 vertebrates. Lower, logo from mammoths (Oimyakon, M4, and Wrangel Island). Note that the maximum information (conservation) of an amino acid site is log 2 20 = 4.3 bits. (B–E) Representative images of Xenopus multiciliated cells from embryos injected with Control MO (B), HYLS1 MO (C), HYLS1 MO and WT XHYLS1 (D), and HYLS1 MO and XHYLS1-S186L; note that S186L is the equivalent of the Wrangel Island mammoth genome P119L in Xenopus HYLS1 (E) stained with acetylated tubulin to mark cilia (green) and phalloidin to mark cell boundaries (red). Note: arrows identify cells with defective ciliogenesis (scale bars = 10 μm). (F, G) Multiciliated cell from a Xenopus embryo injected with mRNA encoding XHYLS1-S186L-GFP shows proper localization to the centrioles (green) and proper formation of cilia marked with acetylated tubulin (red) with cell boundaries marked with phalloidin (purple) (scale bar = 10 μm). (H) Quantification of ciliogenesis defect scoring cells with >25 cilia (Wilcox test P values are shown).CC BY · PubMed Central
Fig. 3 —The Wrangel Island mammoth NKD1 A88V substitution is a loss of function mutation. (A) The Wrangel Island mammoth A88V mutation is located near the EF-hand domain (dark blue), the calcium binding motif is shown in yellow. (B) Sequence logo showing conservation of NKD1 around the Wrangel Island A88V mutation. Upper, logo from 100 vertebrates. Lower, logo from mammoths (Oimyakon, M4, and Wrangel Island). (C) Luciferase expression from the pGL4.49[luc2P/TCF-LEF/Hygro] reporter vector in elephant fibroblasts transfected with control vector, AncYakut NKD1, or Wrangel Island (WI) Mammoth NKD1, and treated with the WNT-signaling agonist CHIR99021. Background luminescence of nontransfected cells (NTC).
Fig. 3 —The Wrangel Island mammoth NKD1 A88V substitution is a loss of function mutation. (A) The Wrangel Island mammoth A88V mutation is located near the EF-hand domain (dark blue), the calcium binding motif is shown in yellow. (B) Sequence logo showing conservation of NKD1 around the Wrangel Island A88V mutation. Upper, logo from 100 vertebrates. Lower, logo from mammoths (Oimyakon, M4, and Wrangel Island). (C) Luciferase expression from the pGL4.49[luc2P/TCF-LEF/Hygro] reporter vector in elephant fibroblasts transfected with control vector, AncYakut NKD1, or Wrangel Island (WI) Mammoth NKD1, and treated with the WNT-signaling agonist CHIR99021. Background luminescence of nontransfected cells (NTC).CC BY · PubMed Central
Fig. 4 —The Wrangel Island mammoth NEUROG3 is a hypermorph. (A) The Wrangel Island mammoth G195E mutation is located in the C-terminal transactivation domain of NEUROG3; location of mutations associated with human disease is shown in red. (B) Sequence logo showing conservation of NEUROG3 transactivation domain in mammals (upper) and mammoths (lower; Oimyakon, M4, and Wrangel Island). The location of ΦXXΦΦ cofactor interaction motifs are shown (Φ, any hydrophobic amino acid; X, any amino acid). (C) Relative luciferase expression from the pGL3[luc/6x-PAX4E/minP] reporter vector in elephant fibroblasts transfected with control vector, AncYakut NEUROG3, or Wrangel Island mammoth NEUROG3.
Fig. 4 —The Wrangel Island mammoth NEUROG3 is a hypermorph. (A) The Wrangel Island mammoth G195E mutation is located in the C-terminal transactivation domain of NEUROG3; location of mutations associated with human disease is shown in red. (B) Sequence logo showing conservation of NEUROG3 transactivation domain in mammals (upper) and mammoths (lower; Oimyakon, M4, and Wrangel Island). The location of ΦXXΦΦ cofactor interaction motifs are shown (Φ, any hydrophobic amino acid; X, any amino acid). (C) Relative luciferase expression from the pGL3[luc/6x-PAX4E/minP] reporter vector in elephant fibroblasts transfected with control vector, AncYakut NEUROG3, or Wrangel Island mammoth NEUROG3.CC BY · PubMed Central
Fig. 5 —The Wrangel Island mammoth β-ionone sensor OR5A1 is nonfunctional. (A) Snake diagram of the Wrangel Island mammoth OR5A1 protein. The locations of cysteine residues and disulfide bonds are shown as yellow circles and lines, respectively. The locations of residues previously shown by high throughput mutagenesis to affect receptor function are shown as brown circles (Mainland et al. 2014). The locations of the Wrangel Island mammoth S193F substitution and the human D183N polymorphism are also shown. (B) Sequence logo showing conservation of OR5A1 AAs 180-195 from 5,000 randomly selected odorant receptors (upper) and mammals (lower). Locations of the S193F substitution and the D183N polymorphism are shown. (C) Dose–response curve showing normalized activity of the AncYakut and Wrangel Island mammoth OR5A1 odorant receptors to β-ionone. Data shown are standardized to nontransfected Hana3a cells and no β-ionone, n = 6.
Fig. 5 —The Wrangel Island mammoth β-ionone sensor OR5A1 is nonfunctional. (A) Snake diagram of the Wrangel Island mammoth OR5A1 protein. The locations of cysteine residues and disulfide bonds are shown as yellow circles and lines, respectively. The locations of residues previously shown by high throughput mutagenesis to affect receptor function are shown as brown circles (Mainland et al. 2014). The locations of the Wrangel Island mammoth S193F substitution and the human D183N polymorphism are also shown. (B) Sequence logo showing conservation of OR5A1 AAs 180-195 from 5,000 randomly selected odorant receptors (upper) and mammals (lower). Locations of the S193F substitution and the D183N polymorphism are shown. (C) Dose–response curve showing normalized activity of the AncYakut and Wrangel Island mammoth OR5A1 odorant receptors to β-ionone. Data shown are standardized to nontransfected Hana3a cells and no β-ionone, n = 6.CC BY · PubMed Central

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Metadata

Authors
Fry, E., Kim, S. K., Chigurapti, S., Mika, K. M., Ratan, A., Dammermann, A., Mitchell, B. J., Miller, W., & Lynch, V. J.
Affiliations
  • Department of Human Genetics, The University of Chicago
  • Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University
  • Center for Public Health Genomics, University of Virginia
  • Max Perutz Labs, Vienna Biocenter (VBC), University of Vienna, Austria
  • Center for Comparative Genomics and Bioinformatics, Pennsylvania State University
  • Department of Biological Sciences, University at Buffalo, SUNY
ORCID
Lynch, Vincent J
Venue
Genome Biology and Evolution
Publisher
Oxford University Press (OUP)
Published
2020-02-07
Volume
12
Issue
3
Pages
48-58
ISSN
1759-6653
DOI
10.1093/gbe/evz279
PMC
PMC7094797
Cited by
12
References
0
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)

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