Patterns of Coding Variation in the Complete Exomes of Three Neandertals

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2014 Apr 23

PMID 24753607

Citations 96

Authors

Sergi Castellano

Genis Parra

Federico A Sanchez-Quinto

Fernando Racimo

Martin Kuhlwilm

Martin Kircher

Susanna Sawyer

Qiaomei Fu

Anja Heinze

Birgit Nickel

Jesse Dabney

Michael Siebauer

Louise White

Hernan A Burbano

Gabriel Renaud

Udo Stenzel

Carles Lalueza-Fox

Marco de la Rasilla

Antonio Rosas

Pavao Rudan

Dejana Brajkovic

Zeljko Kucan

Ivan Gusic

Michael V Shunkov

Anatoli P Derevianko

Bence Viola

Matthias Meyer

Janet Kelso

Aida M Andres

Svante Paabo

Affiliations

Soon will be listed here.

Abstract

We present the DNA sequence of 17,367 protein-coding genes in two Neandertals from Spain and Croatia and analyze them together with the genome sequence recently determined from a Neandertal from southern Siberia. Comparisons with present-day humans from Africa, Europe, and Asia reveal that genetic diversity among Neandertals was remarkably low, and that they carried a higher proportion of amino acid-changing (nonsynonymous) alleles inferred to alter protein structure or function than present-day humans. Thus, Neandertals across Eurasia had a smaller long-term effective population than present-day humans. We also identify amino acid substitutions in Neandertals and present-day humans that may underlie phenotypic differences between the two groups. We find that genes involved in skeletal morphology have changed more in the lineage leading to Neandertals than in the ancestral lineage common to archaic and modern humans, whereas genes involved in behavior and pigmentation have changed more on the modern human lineage.

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References

Liu F, Wollstein A, Hysi P, Ankra-Badu G, Spector T, Park D . Digital quantification of human eye color highlights genetic association of three new loci. PLoS Genet. 2010; 6(5):e1000934. PMC: 2865509. DOI: 10.1371/journal.pgen.1000934. View

McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A . The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010; 20(9):1297-303. PMC: 2928508. DOI: 10.1101/gr.107524.110. View

Green R, Malaspinas A, Krause J, Briggs A, Johnson P, Uhler C . A complete Neandertal mitochondrial genome sequence determined by high-throughput sequencing. Cell. 2008; 134(3):416-26. PMC: 2602844. DOI: 10.1016/j.cell.2008.06.021. View

Prufer K, Racimo F, Patterson N, Jay F, Sankararaman S, Sawyer S . The complete genome sequence of a Neanderthal from the Altai Mountains. Nature. 2013; 505(7481):43-9. PMC: 4031459. DOI: 10.1038/nature12886. View

Rohland N, Hofreiter M . Comparison and optimization of ancient DNA extraction. Biotechniques. 2007; 42(3):343-52. DOI: 10.2144/000112383. View

Bustamante C, Fledel-Alon A, Williamson S, Nielsen R, Hubisz M, Glanowski S . Natural selection on protein-coding genes in the human genome. Nature. 2005; 437(7062):1153-7. DOI: 10.1038/nature04240. View

Fay J, Wyckoff G, Wu C . Positive and negative selection on the human genome. Genetics. 2001; 158(3):1227-34. PMC: 1461725. DOI: 10.1093/genetics/158.3.1227. View

Hider J, Gittelman R, Shah T, Edwards M, Rosenbloom A, Akey J . Exploring signatures of positive selection in pigmentation candidate genes in populations of East Asian ancestry. BMC Evol Biol. 2013; 13:150. PMC: 3727976. DOI: 10.1186/1471-2148-13-150. View

Burbano H, Hodges E, Green R, Briggs A, Krause J, Meyer M . Targeted investigation of the Neandertal genome by array-based sequence capture. Science. 2010; 328(5979):723-5. PMC: 3140021. DOI: 10.1126/science.1188046. View

10.

Li H, Durbin R . Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009; 25(14):1754-60. PMC: 2705234. DOI: 10.1093/bioinformatics/btp324. View

11.

Briggs A, Stenzel U, Meyer M, Krause J, Kircher M, Paabo S . Removal of deaminated cytosines and detection of in vivo methylation in ancient DNA. Nucleic Acids Res. 2009; 38(6):e87. PMC: 2847228. DOI: 10.1093/nar/gkp1163. View

12.

Abecasis G, Altshuler D, Auton A, Brooks L, Durbin R, Gibbs R . A map of human genome variation from population-scale sequencing. Nature. 2010; 467(7319):1061-73. PMC: 3042601. DOI: 10.1038/nature09534. View

13.

Lohmueller K, Indap A, Schmidt S, Boyko A, Hernandez R, Hubisz M . Proportionally more deleterious genetic variation in European than in African populations. Nature. 2008; 451(7181):994-7. PMC: 2923434. DOI: 10.1038/nature06611. View

14.

Ng S, Turner E, Robertson P, Flygare S, Bigham A, Lee C . Targeted capture and massively parallel sequencing of 12 human exomes. Nature. 2009; 461(7261):272-6. PMC: 2844771. DOI: 10.1038/nature08250. View

15.

Meyer M, Kircher M, Gansauge M, Li H, Racimo F, Mallick S . A high-coverage genome sequence from an archaic Denisovan individual. Science. 2012; 338(6104):222-6. PMC: 3617501. DOI: 10.1126/science.1224344. View

16.

Li Y, Vinckenbosch N, Tian G, Huerta-Sanchez E, Jiang T, Jiang H . Resequencing of 200 human exomes identifies an excess of low-frequency non-synonymous coding variants. Nat Genet. 2010; 42(11):969-72. DOI: 10.1038/ng.680. View

17.

Siepel A, Bejerano G, Pedersen J, Hinrichs A, Hou M, Rosenbloom K . Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res. 2005; 15(8):1034-50. PMC: 1182216. DOI: 10.1101/gr.3715005. View

18.

Pruitt K, Tatusova T, Klimke W, Maglott D . NCBI Reference Sequences: current status, policy and new initiatives. Nucleic Acids Res. 2008; 37(Database issue):D32-6. PMC: 2686572. DOI: 10.1093/nar/gkn721. View

19.

Pruitt K, Harrow J, Harte R, Wallin C, Diekhans M, Maglott D . The consensus coding sequence (CCDS) project: Identifying a common protein-coding gene set for the human and mouse genomes. Genome Res. 2009; 19(7):1316-23. PMC: 2704439. DOI: 10.1101/gr.080531.108. View

20.

Paten B, Herrero J, Fitzgerald S, Beal K, Flicek P, Holmes I . Genome-wide nucleotide-level mammalian ancestor reconstruction. Genome Res. 2008; 18(11):1829-43. PMC: 2577868. DOI: 10.1101/gr.076521.108. View