Skip to main content
SpringerLink
Log in

A Maximum Likelihood Method for Detecting Functional Divergence at Individual Codon Sites, with Application to Gene Family Evolution

  • Published:
Journal of Molecular Evolution Aims and scope Submit manuscript

Abstract

The tailoring of existing genetic systems to new uses is called genetic co-option. Mechanisms of genetic co-option have been difficult to study because of difficulties in identifying functionally important changes. One way to study genetic co-option in protein-coding genes is to identify those amino acid sites that have experienced changes in selective pressure following a genetic co-option event. In this paper we present a maximum likelihood method useful for measuring divergent selective pressures and identifying the amino acid sites affected by divergent selection. The method is based on a codon model of evolution and uses the nonsynonymous-to-synonymous rate ratio (ω) as a measure of selection on the protein, with ω = 1, <1, and >1 indicating neutral evolution, purifying selection, and positive selection, respectively. The model allows variation in ω among sites, with a fraction of sites evolving under divergent selective pressures. Divergent selection is indicated by different ω’s between clades, such as between paralogous clades of a gene family. We applied the codon model to duplication followed by functional divergence of (i) the ε and γ globin genes and (ii) the eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN) genes. In both cases likelihood ratio tests suggested the presence of sites evolving under divergent selective pressures. Results of the ε and γ globin analysis suggested that divergent selective pressures might be a consequence of a weakened relationship between fetal hemoglobin and 2,3-diphosphoglycerate. We suggest that empirical Bayesian identification of sites evolving under divergent selective pressures, combined with structural and functional information, can provide a valuable framework for identifying and studying mechanisms of genetic co-option. Limitations of the new method are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  • M Anisimova JP Bielawski Z Yang (2001) ArticleTitleAccuracy and power of the likelihood ratio test in detecting adaptive molecular evolution Mol Biol Evol 18 1585–1592 Occurrence Handle1:CAS:528:DC%2BD3MXlslOisLw%3D Occurrence Handle11470850

    CAS  PubMed  Google Scholar 

  • M Anisimova JP Bielawski Z Yang (2002) ArticleTitleAccuracy and power of Bayesian prediction of amino acid sites under positive selection Mol Biol Evol 19 950–958 Occurrence Handle1:CAS:528:DC%2BD38Xks1Ojur8%3D Occurrence Handle12032251

    CAS  PubMed  Google Scholar 

  • E Betrán M Long (2002) ArticleTitleExpansion of genome coding regions by acquisition of new genes Genetica 115 65–80 Occurrence Handle10.1023/A:1016024131097 Occurrence Handle12188049

    Article  PubMed  Google Scholar 

  • JP Bielawski Z Yang (2003) ArticleTitleMaximum likelihood methods for detecting adaptive evolution after gene duplication J Struct Funct Genomics 3 201–212 Occurrence Handle10.1023/A:1022642807731 Occurrence Handle1:CAS:528:DC%2BD3sXhsFKqtrw%3D Occurrence Handle12836699

    Article  CAS  PubMed  Google Scholar 

  • L Chen AL DeVries CH Cheng (1997) ArticleTitleEvolution of antifreeze glycoprotein gene from a trypsinogen gene in Antarctic notothenioid fish Proc Natl Acad Sci USA 94 3811–3816 Occurrence Handle10.1073/pnas.94.8.3811 Occurrence Handle1:CAS:528:DyaK2sXis1aqsrw%3D Occurrence Handle9108060

    Article  CAS  PubMed  Google Scholar 

  • JM Claverie (2001) ArticleTitleGene number. What if there are only 30,000 human genes? Science 291 1255–1257 Occurrence Handle10.1126/science.1058969 Occurrence Handle1:CAS:528:DC%2BD3MXhtlShu7k%3D Occurrence Handle11233450

    Article  CAS  PubMed  Google Scholar 

  • JB Domachowske CA Bonville KD Dyer HF Rosenberg (1998) ArticleTitleEvolution of antiviral activity in the ribonuclease A gene superfamily: Evidence for a specific interaction between eosinophil-derived neurotoxin (EDN/RNase 2) and respiratory syncytial virus Nucleic Acids Res 26 5327–5332 Occurrence Handle10.1093/nar/26.23.5327 Occurrence Handle1:CAS:528:DyaK1MXis1Ggtw%3D%3D Occurrence Handle9826755

    Article  CAS  PubMed  Google Scholar 

  • DH Fitch WJ Bailey DA Tagle M Goodman L Sieu JL Slightom (1991) ArticleTitleDuplication of the gamma-globin gene mediated by L1 long interspersed repetitive elements in an early ancestor of simian primates Proc Natl Acad Sci USA 88 7396–7400 Occurrence Handle1:CAS:528:DyaK3MXlslKntb4%3D Occurrence Handle1908094

    CAS  PubMed  Google Scholar 

  • A Force M Lynch FB Pickett A Amores Y-I Van J Postlethwait (1999) ArticleTitlePreservation of duplicate genes by complementary, degenerative mutations Genetics 151 1531–1545 Occurrence Handle1:CAS:528:DyaK1MXisV2rs7o%3D Occurrence Handle10101175

    CAS  PubMed  Google Scholar 

  • R Forsberg FB Christiansen (2003) ArticleTitleA codon-based model of host-specific selection in parasites, with an application to the influenza A virus Mol Biol Evol 20 1252–1259 Occurrence Handle10.1093/molbev/msg149 Occurrence Handle1:CAS:528:DC%2BD3sXms1Wks7g%3D Occurrence Handle12777510

    Article  CAS  PubMed  Google Scholar 

  • EA Gaucher X Gu MM Miyamoto SA Benner (2002) ArticleTitlePredicting functional divergence in protein evolution by site-specific rate shifts Trends Biochem Sci 27 315–321 Occurrence Handle10.1016/S0968-0004(02)02094-7 Occurrence Handle1:CAS:528:DC%2BD38XksFOjurc%3D Occurrence Handle12069792

    Article  CAS  PubMed  Google Scholar 

  • JM Gibert (2002) ArticleTitleThe evolution of engrailed genes after duplication and speciation events Dev Genes Evol 212 307–318 Occurrence Handle10.1007/s00427-002-0243-2 Occurrence Handle1:CAS:528:DC%2BD38XlvFSrtrc%3D Occurrence Handle12185484

    Article  CAS  PubMed  Google Scholar 

  • N Goldman Z Yang (1994) ArticleTitleA codon based model of nucleotide substitution for protein-coding DNA sequences Mol Biol Evol 11 725–736 Occurrence Handle1:CAS:528:DyaK2cXmt1eit70%3D Occurrence Handle7968486

    CAS  PubMed  Google Scholar 

  • M Goodman (1999) ArticleTitleThe genomic record of Humankind’s evolutionary roots Am J Hum Genet 64 31–39 Occurrence Handle10.1086/302218 Occurrence Handle1:STN:280:DyaK1M7hsFSkug%3D%3D Occurrence Handle9915940

    Article  CAS  PubMed  Google Scholar 

  • M Goodman CA Porter J Czelusniak SL Page H Schneider J Shoshani G Gunnell CP Groves (1998) ArticleTitleToward a phylogenetic classification of Primates based on DNA evidence complemented by fossil evidence Mol Phylogenet Evol 9 585–598 Occurrence Handle10.1006/mpev.1998.0495 Occurrence Handle1:STN:280:DyaK1czjsVGrsQ%3D%3D Occurrence Handle9668008

    Article  CAS  PubMed  Google Scholar 

  • X Gu (2001) ArticleTitleMaximum-likelihood approach for gene family evolution under functional divergence Mol Biol Evol 18 453–464 Occurrence Handle1:CAS:528:DC%2BD3MXis1eisL4%3D Occurrence Handle11264396

    CAS  PubMed  Google Scholar 

  • KJ Hamann RM Ten DA Loegering RB Jenkins MT Heise CR Schad LR Pease GJ Gleich RL Barker (1990) ArticleTitleStructure and chromosome localization of the human eosinophil-derived neurotoxin and eosinophil cationic protein genes: Evidence for intronless coding sequences in the ribonuclease gene superfamily Genomics 7 535–546 Occurrence Handle1:CAS:528:DyaK3MXisVWmtLY%3D Occurrence Handle2387583

    CAS  PubMed  Google Scholar 

  • MP Harris JF Fallon RO Prum (2002) ArticleTitleShh-Bmp2 signalling module and the evolutionary origin and diversification of feathers J Exp Zool 294 160–176 Occurrence Handle10.1002/jez.10157 Occurrence Handle1:CAS:528:DC%2BD38Xms1Sntbw%3D Occurrence Handle12210117

    Article  CAS  PubMed  Google Scholar 

  • M Hasegawa H Kishino T Yano (1985) ArticleTitleDating of the human-ape splitting by a molecular clock of mitochondrial DNA J Mol Evol 22 160–174 Occurrence Handle1:CAS:528:DyaL2MXmtFSns7g%3D Occurrence Handle3934395

    CAS  PubMed  Google Scholar 

  • AL Hughes (1994) ArticleTitleThe evolution of functionally novel proteins after gene duplication Proc R Soc Lond B Biol Sci 256 119–124 Occurrence Handle1:CAS:528:DyaK2MXmsFSktw%3D%3D Occurrence Handle8029240

    CAS  PubMed  Google Scholar 

  • AL Hughes (2002) ArticleTitleAdaptive evolution after gene duplication Trends Genet 18 433–434 Occurrence Handle10.1016/S0168-9525(02)02755-5 Occurrence Handle1:CAS:528:DC%2BD38Xmtlelt7w%3D Occurrence Handle12175796

    Article  CAS  PubMed  Google Scholar 

  • RM Johnson S Buck C Chiu H Schneider I Sampaio DA Gage TL Shen MP Schneider JA Muniz DL Gumucio M Goodman (1996) ArticleTitleFetal globin expression in New World monkeys J Biol Chem 271 14684–14691 Occurrence Handle10.1074/jbc.271.25.14684 Occurrence Handle1:CAS:528:DyaK28XjvVWmsL8%3D Occurrence Handle8663037

    Article  CAS  PubMed  Google Scholar 

  • B Knudsen MM Miyamoto (2001) ArticleTitleA likelihood ratio test for evolutionary rate shifts and functional divergence among proteins Proc Natl Acad Sci USA 98 14512–14517 Occurrence Handle10.1073/pnas.251526398 Occurrence Handle1:CAS:528:DC%2BD3MXptFClu7c%3D Occurrence Handle11734650

    Article  CAS  PubMed  Google Scholar 

  • BF Koop M Goodman (1988) ArticleTitleEvolutionary and developmental aspects of two hemoglobin beta-chain genes (epsilon M and beta M) of opossum Proc Natl Acad Sci USA 85 3893–3897 Occurrence Handle1:CAS:528:DyaL1cXlt1ent7k%3D Occurrence Handle3375246

    CAS  PubMed  Google Scholar 

  • W-H Li (1985) Accelerated evolution following gene duplication and its implications for the neutralist-selectionist controversy T Otha K Aoki (Eds) Population genetics and molecular evolution Japan Scientific Press Tokyo 333–352

    Google Scholar 

  • M Long (2001) ArticleTitleEvolution of novel genes Curr Opin Genet Dev 11 673–680 Occurrence Handle10.1016/S0959-437X(00)00252-5 Occurrence Handle1:CAS:528:DC%2BD3MXnslajtLs%3D Occurrence Handle11682312

    Article  CAS  PubMed  Google Scholar 

  • M Long CH Langley (1993) ArticleTitleNatural selection and the origin of jingwei, a chimeric processed functional gene in Drosophila Science 260 91–95 Occurrence Handle1:CAS:528:DyaK3sXit1OnsrY%3D Occurrence Handle7682012

    CAS  PubMed  Google Scholar 

  • M Lynch JS Conery (2000) ArticleTitleThe evolutionary fate and consequences of duplicate genes Science 290 1151–1155 Occurrence Handle10.1126/science.290.5494.1151 Occurrence Handle1:CAS:528:DC%2BD3cXotVChsb8%3D Occurrence Handle11073452

    Article  CAS  PubMed  Google Scholar 

  • M Lynch A Force (2000) ArticleTitleThe probability of duplicate gene preservation by subfunctionalization Genetics 154 459–473 Occurrence Handle1:CAS:528:DC%2BD3cXms1KhsA%3D%3D Occurrence Handle10629003

    CAS  PubMed  Google Scholar 

  • T Massingham LJ Davies P Lio (2001) ArticleTitleAnalyzing gene function after duplication Bioessays 23 873–876 Occurrence Handle10.1002/bies.1128 Occurrence Handle1:CAS:528:DC%2BD3MXptVOjs7Y%3D Occurrence Handle11598954

    Article  CAS  PubMed  Google Scholar 

  • CM Meireles MP Schneider MI Sampaio H Schneider JL Slightom CH Chiu K Neiswanger DL Gumucio J Czelusniak M Goodman (1995) ArticleTitleFate of a redundant gamma-globin gene in the atelid clade of New World monkeys: implications concerning fetal globin gene expression Proc Natl Acad Sci USA 92 2607–2611 Occurrence Handle1:CAS:528:DyaK2MXksl2rsrg%3D Occurrence Handle7535927

    CAS  PubMed  Google Scholar 

  • CM Meireles J Czelusniak MP Schneider JA Muniz MC Brigido HS Ferreira M Goodman (1999) ArticleTitleMolecular phytogeny of ateline new world monkeys (Platyrrhini, atelinae) based on gamma-globin gene sequences: evidence that brachyteles is the sister group of lagothrix Mol Phylogenet Evol 12 10–30 Occurrence Handle10.1006/mpev.1998.0574 Occurrence Handle1:CAS:528:DyaK1MXis1KksLs%3D Occurrence Handle10222158

    Article  CAS  PubMed  Google Scholar 

  • SV Muse BS Gaut (1994) ArticleTitleA likelihood approach for comparing synonymous and nonsynonymous nucleotide substitution rates, with applications to the chloroplast genome Mol Biol Evol 11 715–725 Occurrence Handle1:CAS:528:DyaK2cXlvFOjsL8%3D Occurrence Handle7968485

    CAS  PubMed  Google Scholar 

  • R Nielsen Z Yang (1998) ArticleTitleLikelihood models for detecting positively selected amino acid sites and applications to the HIV-1 envelope gene Genetics 148 929–936 Occurrence Handle1:CAS:528:DyaK1cXks1eitr8%3D Occurrence Handle9539414

    CAS  PubMed  Google Scholar 

  • T Ohta (1993) ArticleTitlePattern of nucleotide substitution in growth hormone-prolactin gene family: a paradigm for evolution by gene duplication Genetics 134 1271–1276 Occurrence Handle1:CAS:528:DyaK2cXht1KltLs%3D Occurrence Handle8375661

    CAS  PubMed  Google Scholar 

  • SL Page Ch Chiu M Goodman (1999) ArticleTitleMolecular phytogeny of Old World monkeys (Cercopithecidae) as inferred from gamma-globin DNA sequences Mol Phylogenet Evol 13 348–359 Occurrence Handle10.1006/mpev.1999.0653 Occurrence Handle1:CAS:528:DyaK1MXotFOhu7s%3D Occurrence Handle10603263

    Article  CAS  PubMed  Google Scholar 

  • MF Perutz K Imai (1980) ArticleTitleRegulation of oxygen affinity of mammalian haemoglobins J Mol Biol 136 183–191 Occurrence Handle1:CAS:528:DyaL3cXht1elurk%3D Occurrence Handle7373649

    CAS  PubMed  Google Scholar 

  • J Piatigorsky G Wistow (1991) ArticleTitleThe recruitment of crystallins: new functions precede gene duplication Science 252 1078–1079 Occurrence Handle1:CAS:528:DyaK3MXkt1ehtr0%3D Occurrence Handle2031181

    CAS  PubMed  Google Scholar 

  • C Poyart H Wajcman J Kister (1992) ArticleTitleMolecular adaptation of hemoglobin function in mammals Respir Physiol 90 3–17 Occurrence Handle10.1016/0034-5687(92)90130-O Occurrence Handle1:CAS:528:DyaK3sXls1Ontg%3D%3D Occurrence Handle1455096

    Article  CAS  PubMed  Google Scholar 

  • HF Rosenberg JB Domachowske (1999) ArticleTitleEosinophils, riobnucleases and host defence: solving the puzzle Immunol Res 20 261–274 Occurrence Handle1:CAS:528:DC%2BD3cXhsF2ktrs%3D Occurrence Handle10741866

    CAS  PubMed  Google Scholar 

  • E Susko Y Inagaki C Field ME Holder AJ Roger (2002) ArticleTitleTesting for differences in rates-across-sites distributions in phylogenetic subtrees Mol Biol Evol 19 1514–1523 Occurrence Handle1:CAS:528:DC%2BD38XntVyhtL8%3D Occurrence Handle12200479

    CAS  PubMed  Google Scholar 

  • DL Swofford (2000) PAUP* Phylogenetic analysis using parsimony (*and other methods) Version 4 Sinauer Sunderland, MA

    Google Scholar 

  • J Taylor Y Peer ParticleVan de A Meyer (2001) ArticleTitleGenome duplication, divergent resolution and speciation Trends Genet 17 299–301 Occurrence Handle10.1016/S0168-9525(01)02318-6 Occurrence Handle1:CAS:528:DC%2BD3MXjslSitLk%3D Occurrence Handle11377777

    Article  CAS  PubMed  Google Scholar 

  • DA Tagle BF Koop M Goodman JL Slightom DL Hess RT Jones (1988) ArticleTitleEmbryonic ε and γ globin genes of a prosimian primate (Galago crassicaudatus) J Mol Biol 203 439–455 Occurrence Handle1:CAS:528:DyaL1MXktlCnsrs%3D Occurrence Handle3199442

    CAS  PubMed  Google Scholar 

  • JR True SB Carrol (2002) ArticleTitleGene co-option in physiological and morphological evolution Annu Rev Cell Dev Biol 18 53–80 Occurrence Handle10.1146/annurev.cellbio.18.020402.140619 Occurrence Handle1:CAS:528:DC%2BD38XptVOru7g%3D Occurrence Handle12142278

    Article  CAS  PubMed  Google Scholar 

  • Z Yang (1994) ArticleTitleMaximum likelihood phylogenetic estimation from DNA sequences with variable rates over sites: approximate methods J Mol Evol 39 306–314 Occurrence Handle1:CAS:528:DyaK2cXmt1eit7c%3D Occurrence Handle7932792

    CAS  PubMed  Google Scholar 

  • Z Yang (1997) ArticleTitlePAML: A program package for phylogenetic analysis by maximum likelihood Appl Biosci 13 555–556 Occurrence Handle1:CAS:528:DyaK2sXntlGnu7s%3D

    CAS  Google Scholar 

  • Z Yang (1998) ArticleTitleLikelihood ratio tests for detecting positive selection and application to primate lysozyme evolution Mol Biol Evol 15 568–573 Occurrence Handle1:CAS:528:DyaK1cXislensL4%3D Occurrence Handle9580986

    CAS  PubMed  Google Scholar 

  • Z Yang JP Bielawski (2000) ArticleTitleStatistical methods for detecting molecular adaptation Trends Ecol Evolut 15 496–503 Occurrence Handle10.1016/S0169-5347(00)01994-7

    Article  Google Scholar 

  • Z Yang R Nielsen (2002) ArticleTitleCodon-substitution models for detecting molecular adaptation at individual sites along specific lineages Mol Biol Evol 19 908–917 Occurrence Handle1:CAS:528:DC%2BD38Xks1Ojtbk%3D Occurrence Handle12032247

    CAS  PubMed  Google Scholar 

  • Z Yang R Nielsen N Goldman A-MK Pedersen (2000) ArticleTitleCodon-substitution models for heterogeneous selection pressure at amino acid sites Genetics 155 431–449 Occurrence Handle1:CAS:528:DC%2BD3cXjslKhtb4%3D Occurrence Handle10790415

    CAS  PubMed  Google Scholar 

  • J Zhang HF Rosenberg (2002) ArticleTitleComplementary advantageous substitutions in the evolution of an antiviral RNase of higher primates Proc Natl Acad Sci USA 99 5486–5491 Occurrence Handle10.1073/pnas.072626199 Occurrence Handle1:CAS:528:DC%2BD38XjtFKltr8%3D Occurrence Handle11917138

    Article  CAS  PubMed  Google Scholar 

  • J Zhang HF Rosenberg M Nei (1998) ArticleTitlePositive Darwinian selection after gene duplication in primate ribonuclease genes Proc Natl Acad Sci USA 95 3708–3713 Occurrence Handle10.1073/pnas.95.7.3708 Occurrence Handle1:CAS:528:DyaK1cXitlKjtrc%3D Occurrence Handle9520431

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Valuable discussions were contributed by Gabriela Aguileta. We thank Katherine A. Dunn and Gabriela Aguileta for constructive comments on the manuscript. This research was supported by a UK Biotechnology and Biological Sciences Research Council Grant.

Author information

Authors and Affiliations

  1. Department of Biology, University College London, London, WC1E 6BT, UK

    Joseph P. Bielawski & Ziheng Yang

  2. Department of Biology, Dalhousie University, Halifax, Nova Scotia, B3H 4JI, Canada

    Joseph P. Bielawski

Authors
  1. Joseph P. Bielawski
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ziheng Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joseph P. Bielawski.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bielawski, J.P., Yang, Z. A Maximum Likelihood Method for Detecting Functional Divergence at Individual Codon Sites, with Application to Gene Family Evolution. J Mol Evol 59, 121–132 (2004). https://doi.org/10.1007/s00239-004-2597-8

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00239-004-2597-8

Keywords

Search

Navigation