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Homoeologs: What Are They and How Do We Infer Them?

2016; Elsevier BV; Volume: 21; Issue: 7 Linguagem: Inglês

10.1016/j.tplants.2016.02.005

1878-4372

Natasha Glover, Henning Redestig, Christophe Dessimoz,

Plant Reproductive Biology

The term homoeology has been used inconsistently in historical and modern contexts. Homoeologs are pairs of genes that originated by speciation and were brought back together in the same genome by allopolyploidization. Homoeologs are not necessarily one-to-one or positionally conserved. Evolution-based computational methods have emerged to infer homoeologs from sequencing data. The evolutionary history of nearly all flowering plants includes a polyploidization event. Homologous genes resulting from allopolyploidy are commonly referred to as 'homoeologs', although this term has not always been used precisely or consistently in the literature. With several allopolyploid genome sequencing projects under way, there is a pressing need for computational methods for homoeology inference. Here we review the definition of homoeology in historical and modern contexts and propose a precise and testable definition highlighting the connection between homoeologs and orthologs. In the second part, we survey experimental and computational methods of homoeolog inference, considering the strengths and limitations of each approach. Establishing a precise and evolutionarily meaningful definition of homoeology is essential for understanding the evolutionary consequences of polyploidization. The evolutionary history of nearly all flowering plants includes a polyploidization event. Homologous genes resulting from allopolyploidy are commonly referred to as 'homoeologs', although this term has not always been used precisely or consistently in the literature. With several allopolyploid genome sequencing projects under way, there is a pressing need for computational methods for homoeology inference. Here we review the definition of homoeology in historical and modern contexts and propose a precise and testable definition highlighting the connection between homoeologs and orthologs. In the second part, we survey experimental and computational methods of homoeolog inference, considering the strengths and limitations of each approach. Establishing a precise and evolutionarily meaningful definition of homoeology is essential for understanding the evolutionary consequences of polyploidization. Many plants – and virtually all angiosperms – have undergone at least one round of polyploidization in their evolutionary history [1Soltis D.E. et al.Polyploidy and angiosperm diversification.Am. J. Bot. 2009; 96: 336-348Crossref PubMed Scopus (853) Google Scholar, 2Adams K.L. Wendel J.F. Polyploidy and genome evolution in plants.Curr. Opin. Plant Biol. 2005; 8: 135-141Crossref PubMed Scopus (945) Google Scholar, 3Jiao Y. et al.Ancestral polyploidy in seed plants and angiosperms.Nature. 2011; 473: 97-100Crossref PubMed Scopus (1410) Google Scholar]. In particular, numerous important crop species, such as Arachis hypogaea (peanut), Avena sativa (oat), Brassica juncea (mustard greens), Brassica napus (rapeseed), Coffea arabica (coffee), Gossypium hirsutum (cotton), Mangifera indica (mango), Nicotiana tabacum (tobacco), Prunus cerasus (cherry), Triticum turgidum (durum wheat), and Triticum aestivum (bread wheat), exhibit allopolyploidy (see Glossary), a type of whole-genome duplication via hybridization followed by genome doubling [4Soltis P.S. Soltis D.E. The role of hybridization in plant speciation.Annu. Rev. Plant Biol. 2009; 60: 561-588Crossref PubMed Scopus (928) Google Scholar]. This hybridization usually occurs between two related species, thus merging the genomic content from two divergent species into one (Box 1).Box 1Allo- versus AutopolyploidyWhat Are the Types of Polyploidy?The criteria for distinguishing and classifying natural polyploids has been subject to a long-standing debate [89Grant V. Plant Speciation.2nd edn. Columbia University Press, 1981: 298-306Google Scholar, 90Soltis D.E. et al.Advances in the study of polyploidy since plant speciation.New Phytol. 2004; 161: 173-191Crossref Scopus (576) Google Scholar]. In this review we adopt the most widespread definition, which is based on a taxonomic framework: allopolyploids result from genome doubling following a hybridization between two different species (interspecific), whereas autopolyploids result from genome doubling within one species (intraspecific).What Are the Biological Differences between Allo- and Autopolyploids?Historically, polyploid types were distinguished by their chromosome pairing behavior observed under the microscope during metaphase I of meiosis [91Müntzing A. The evolutionary significance of autopolyploidy.Hereditas. 1936; 21: 363-378Crossref Scopus (182) Google Scholar].Since autopolyploids are formed by genome doubling within the same species, by consequence autopolyploids originate with an identical set of chromosomes. This means there is an equal opportunity for the homologous chromosomes to pair at meiosis. Thus, autopolyploids are more likely than allopolyploids to form multivalent chromosome configurations – the association of three or more chromosomes during the first meiotic division (Figure IA ).By contrast, allopolyploids usually form bivalent chromosome associations during meiosis. Allopolyploids are derived from different species; thus, the chromosome sets have begun to diverge before the hybridization event. The chromosomes are non-identical and this is one reason why there is a tendency for homologous chromosomes to pair over homoeologous chromosomes, resulting in diploid-like pairing behavior (Figure IB).Caveats and Risks of Using Chromosome Pairing to Define Homoeologous ChromosomesDistinguishing autopolyploids from allopolyploids based on chromosome pairing has proved to be inadequate [92Gupta P.K. Cytogenetics. Rastogi, 2007Google Scholar]. It is impossible to make phylogenetic inferences or statements on homology based on chromosome pairing because pairing behavior is not exact, with many exceptions to the rule. Pairing is at least partially under genetic control, is influenced by the environment, and can be observed between homoeologous and non-homoeologous chromosomes [93Sears E.R. Genetic control of chromosome pairing in wheat.Annu. Rev. Genet. 1976; 10: 31-51Crossref PubMed Scopus (328) Google Scholar, 94de Wet J.M.J. Harlan J.R. Chromosome pairing and phylogenetic affinities.Taxon. 1972; 21: 67-70Crossref Google Scholar, 95Seberg O. Petersen G. A critical review of concepts and methods used in classical genome analysis.Bot. Rev. 1998; 64: 372-417Crossref Scopus (39) Google Scholar]. What Are the Types of Polyploidy? The criteria for distinguishing and classifying natural polyploids has been subject to a long-standing debate [89Grant V. Plant Speciation.2nd edn. Columbia University Press, 1981: 298-306Google Scholar, 90Soltis D.E. et al.Advances in the study of polyploidy since plant speciation.New Phytol. 2004; 161: 173-191Crossref Scopus (576) Google Scholar]. In this review we adopt the most widespread definition, which is based on a taxonomic framework: allopolyploids result from genome doubling following a hybridization between two different species (interspecific), whereas autopolyploids result from genome doubling within one species (intraspecific).What Are the Biological Differences between Allo- and Autopolyploids? Historically, polyploid types were distinguished by their chromosome pairing behavior observed under the microscope during metaphase I of meiosis [91Müntzing A. The evolutionary significance of autopolyploidy.Hereditas. 1936; 21: 363-378Crossref Scopus (182) Google Scholar]. Since autopolyploids are formed by genome doubling within the same species, by consequence autopolyploids originate with an identical set of chromosomes. This means there is an equal opportunity for the homologous chromosomes to pair at meiosis. Thus, autopolyploids are more likely than allopolyploids to form multivalent chromosome configurations – the association of three or more chromosomes during the first meiotic division (Figure IA ). By contrast, allopolyploids usually form bivalent chromosome associations during meiosis. Allopolyploids are derived from different species; thus, the chromosome sets have begun to diverge before the hybridization event. The chromosomes are non-identical and this is one reason why there is a tendency for homologous chromosomes to pair over homoeologous chromosomes, resulting in diploid-like pairing behavior (Figure IB).Caveats and Risks of Using Chromosome Pairing to Define Homoeologous Chromosomes Distinguishing autopolyploids from allopolyploids based on chromosome pairing has proved to be inadequate [92Gupta P.K. Cytogenetics. Rastogi, 2007Google Scholar]. It is impossible to make phylogenetic inferences or statements on homology based on chromosome pairing because pairing behavior is not exact, with many exceptions to the rule. Pairing is at least partially under genetic control, is influenced by the environment, and can be observed between homoeologous and non-homoeologous chromosomes [93Sears E.R. Genetic control of chromosome pairing in wheat.Annu. Rev. Genet. 1976; 10: 31-51Crossref PubMed Scopus (328) Google Scholar, 94de Wet J.M.J. Harlan J.R. Chromosome pairing and phylogenetic affinities.Taxon. 1972; 21: 67-70Crossref Google Scholar, 95Seberg O. Petersen G. A critical review of concepts and methods used in classical genome analysis.Bot. Rev. 1998; 64: 372-417Crossref Scopus (39) Google Scholar]. Allopolyploidization has been studied since at least the early 1900s. Some of the first investigations were about chromosome numbers and pairing patterns of hybrid species [5Aase H. Cytology of cereals.Bot. Rev. 1935; 1: 467-496Crossref Scopus (9) Google Scholar, 6Kihara H. Cytologische und genetische Studien bei wichtigen Getreidearten mit besonderer Rücksicht auf das Verhalten der Chromosomen und die Sterilität in den Bastarden. Kyoto Imperial University, 1924Google Scholar]. The term homoeologous was coined to distinguish chromosomes that pair readily during meiosis from those that pair only occasionally during meiosis [7Huskins C.L. A cytological study of Vilmorin's unfixable dwarf wheat.J. Genet. 1931; 25: 113-124Crossref Scopus (20) Google Scholar]. However, the definition of homoeology has varied and at times been used inconsistently. Homoeology has been broadly used to denote the relationship between 'corresponding' genes or chromosomes derived from different species in an allopolyploid. Accurately identifying homoeologs is key to studying the genetic consequences of polyploidization; knowing the evolutionary correspondence between genes across subgenomes allows us to more accurately estimate gene gain or loss after polyploidization (reviewed in [8Doyle J.J. et al.Evolutionary genetics of genome merger and doubling in plants.Annu. Rev. Genet. 2008; 42: 443-461Crossref PubMed Scopus (512) Google Scholar, 9Moghe G.D. Shiu S-H. The causes and molecular consequences of polyploidy in flowering plants.Ann. N. Y. Acad. Sci. 2014; 1320: 16-34Crossref PubMed Scopus (49) Google Scholar]) and to study the major structural rearrangements or conservation between homoeologous chromosomes. Additionally, we can study the functional divergence of homoeologs on polyploidization, particularly in terms of expression (reviewed in [2Adams K.L. Wendel J.F. Polyploidy and genome evolution in plants.Curr. Opin. Plant Biol. 2005; 8: 135-141Crossref PubMed Scopus (945) Google Scholar, 8Doyle J.J. et al.Evolutionary genetics of genome merger and doubling in plants.Annu. Rev. Genet. 2008; 42: 443-461Crossref PubMed Scopus (512) Google Scholar, 10Buggs R.J.A. et al.The legacy of diploid progenitors in allopolyploid gene expression patterns.Philos. Trans. R. Soc. Lond. B: Biol. Sci. 2014; 369: 20130354Crossref PubMed Scopus (72) Google Scholar, 11Jackson S. Chen Z.J. Genomic and expression plasticity of polyploidy.Curr. Opin. Plant Biol. 2010; 13: 153-159Crossref PubMed Scopus (234) Google Scholar, 12Madlung A. Wendel J.F. Genetic and epigenetic aspects of polyploid evolution in plants.Cytogenet. Genome Res. 2013; 140: 270-285Crossref PubMed Scopus (117) Google Scholar, 13Yoo M-J. et al.Nonadditive gene expression in polyploids.Annu. Rev. Genet. 2014; 48: 485-517Crossref PubMed Scopus (133) Google Scholar]), epigenetic patterns (reviewed in [8Doyle J.J. et al.Evolutionary genetics of genome merger and doubling in plants.Annu. Rev. Genet. 2008; 42: 443-461Crossref PubMed Scopus (512) Google Scholar, 12Madlung A. Wendel J.F. Genetic and epigenetic aspects of polyploid evolution in plants.Cytogenet. Genome Res. 2013; 140: 270-285Crossref PubMed Scopus (117) Google Scholar]), alternative splicing [14Zhou R. et al.Extensive changes to alternative splicing patterns following allopolyploidy in natural and resynthesized polyploids.Proc. Natl. Acad. Sci. U.S.A. 2011; 108: 16122-16127Crossref PubMed Scopus (81) Google Scholar], and diploidization (reviewed in [8Doyle J.J. et al.Evolutionary genetics of genome merger and doubling in plants.Annu. Rev. Genet. 2008; 42: 443-461Crossref PubMed Scopus (512) Google Scholar]). From a crop improvement viewpoint, identifying homoeologs that may have been functionally conserved is important for elucidating or engineering the genetic basis for traits of interest [15Chen A. Dubcovsky J. Wheat TILLING mutants show that the vernalization gene VRN1 down-regulates the flowering repressor VRN2 in leaves but is not essential for flowering.PLoS Genet. 2012; 8: e1003134Crossref PubMed Scopus (163) Google Scholar, 16Peng P.F. et al.Expression divergence of FRUITFULL homeologs enhanced pod shatter resistance in Brassica napus.Genet. Mol. Res. 2015; 14: 871-885Crossref PubMed Scopus (8) Google Scholar]. This high interest in the genetic and evolutionary consequences of polyploidization has driven the development of several methods for homoeolog inference. However, because of their highly redundant nature polyploid genomes have been notoriously challenging to sequence and assemble [17Schatz M.C. et al.Current challenges in de novo plant genome sequencing and assembly.Genome Biol. 2012; 13: 243Crossref PubMed Scopus (139) Google Scholar]. Recent breakthroughs in sequencing and assembly methods suggest that we are finally overcoming this hurdle [18Ming R. Wai C.M. Assembling allopolyploid genomes: no longer formidable.Genome Biol. 2015; 16: 27Crossref PubMed Scopus (15) Google Scholar, 19Doležel J. et al.Chromosomes in the flow to simplify genome analysis.Funct. Integr. Genomics. 2012; 12: 397-416Crossref PubMed Scopus (81) Google Scholar, 20Kellogg E.A. Genome sequencing: long reads for a short plant.Nat. Plants. 2015; 1: 15169Crossref PubMed Scopus (3) Google Scholar] and as increasing numbers of polyploid genomes are sequenced there will be a growing interest in homoeology inference. Thus, it is necessary to establish a common framework. Here we examine the current and common definitions of homoeology and point out imprecise usage in the literature, from historical definitions to modern understandings. We advocate a precise and evolutionarily meaningful definition of homoeology and connect homoeology and orthology inference. We then review homoeolog inference methods and discuss advantages and disadvantages of each approach. It is first important to make the distinction between homology and homoeology. The prefix 'homo-' comes from the Latin (and ancient Greek) word for 'same', whereas the prefix 'homoeo' means 'similar to' [21Merriam-Webster Dictionary. http://www.merriam-webster.com/dictionary/homeo-Google Scholar]. Homoeology has alternatively been spelled as 'homeology' (Box 2). Both terms have a history of varied and, at times, inconsistent usage in different fields, but in biology it is now generally accepted that homology indicates 'common ancestry'; by contrast, 'homoeology' is more ambiguous.Box 2Alternative Spellings of HomoeologyTo make homoeology even more confusing, there are alternative spellings that exist in the literature. The original spelling by Huskins [7Huskins C.L. A cytological study of Vilmorin's unfixable dwarf wheat.J. Genet. 1931; 25: 113-124Crossref Scopus (20) Google Scholar] uses an 'œ' diphthong borrowed from Latin. This 'œ' has been transliterated in modern usage to the 'oe' in 'homoeolog'. However, the alternative spelling 'homeolog' has also been used extensively.Which spelling is more popular? Based on our survey of the literature, homoeolog and its derivatives has 1779 mentions, while homeolog has just 738 mentions (Figure I).Thus, since it is the most common spelling, we recommend retention of the original homoeology spelling. Regarding pronunciation, it is more difficult to gauge usage across the community, but the Merriam-Webster medical dictionary pronounces homoeologous as 'ho-mee-o-log-ous' (http://www.merriam-webster.com/medical/homoeologous). Thus, conveniently, the two alternative spellings are pronounced in the same way. To make homoeology even more confusing, there are alternative spellings that exist in the literature. The original spelling by Huskins [7Huskins C.L. A cytological study of Vilmorin's unfixable dwarf wheat.J. Genet. 1931; 25: 113-124Crossref Scopus (20) Google Scholar] uses an 'œ' diphthong borrowed from Latin. This 'œ' has been transliterated in modern usage to the 'oe' in 'homoeolog'. However, the alternative spelling 'homeolog' has also been used extensively. Which spelling is more popular? Based on our survey of the literature, homoeolog and its derivatives has 1779 mentions, while homeolog has just 738 mentions (Figure I). Thus, since it is the most common spelling, we recommend retention of the original homoeology spelling. Regarding pronunciation, it is more difficult to gauge usage across the community, but the Merriam-Webster medical dictionary pronounces homoeologous as 'ho-mee-o-log-ous' (http://www.merriam-webster.com/medical/homoeologous). Thus, conveniently, the two alternative spellings are pronounced in the same way. The term homoeologous was first used in a cytogenetics study of allopolyploid wheat, where Huskins (1931) defined it as 'phylogenetically similar but not strictly homologous chromosomes' in a hybrid. Huskins goes on to explain further:To distinguish between chromosomes which come within the commonly accepted meaning of the term homologous and those which are, as evidenced by their pairing behavior, similar only in part, the latter might be referred to as homœologous chromosomes, signifying similarity but not identity…This term would include chromosomes of different 'genomes' which pair occasionally in allopolyploids, often causing the appearance of mutant or aberrant forms, and also, as a corollary, chromosomes which pair irregularly in many interspecific hybrids. [7Huskins C.L. A cytological study of Vilmorin's unfixable dwarf wheat.J. Genet. 1931; 25: 113-124Crossref Scopus (20) Google Scholar] Two decades later, in the 1949 Dictionary of Genetics, R.L. Knight defines homoeologous chromosomes as 'chromosomes that are homologous in parts of their length' [22Knight R.L. Dictionary of Genetics. Chronica Botanica, 1949Google Scholar]. Thus, in its historical context, a pair of homoeologous chromosomes is thought of as being similar but exhibiting only infrequent pairing during meiosis. In a survey of 93 studies of autopolyploids and 78 studies of allopolyploids, multivalent pairing (pairing between more than two chromosomes) on average occurred more in autopolyploids than in allopolyploids (∼29% vs 8%) [23Ramsey J. Schemske D.W. Neopolyploidy in flowering plants.Annu. Rev. Ecol. Syst. 2002; 33: 589-639Crossref Scopus (765) Google Scholar]. Although chromosome pairing patterns give a good indication of homology type, this should not be used as a criterion (Box 1). Over the years, the definition of homoeology has evolved and diverged to have different usages depending on the scientific field of study or topic. The term homoeologous can mean different things and may not be as simple as 'genes duplicated by polyploidy' [24Adams K.L. Evolution of duplicate gene expression in polyploid and hybrid plants.J. Hered. 2007; 98: 136-141Crossref PubMed Scopus (194) Google Scholar]. Table 1 highlights the differences between the different definitions of homoeology depending on the context in which it is used. The variation among definitions depends on the level of biological analysis: at the chromosome, gene, or sequence level.Table 1Varied Usages of the Term 'Homoeology' in Different Areas of ResearchContextDefinitionRefsRecombinationHomoeologous: 'sequences that are similar but imperfectly matched'96Waldman A.S. Ensuring the fidelity of recombination in mammalian chromosomes.Bioessays. 2008; 30: 1163-1171Crossref PubMed Scopus (33) Google ScholarCytogeneticsHomoeologous chromosomes: 'those which once were homologous, i.e. essentially identical, but have become so different that they rarely pair [during meiosis]'97O'mara J.G. The cytogenetics of Triticale.Bot. Rev. 1953; 19: 587-605Crossref Scopus (15) Google ScholarEvolutionary biologyHomoeologous: 'duplicated genes or chromosomes that are derived from different parental species and are related by ancestry'98Comai L. The advantages and disadvantages of being polyploid.Nat. Rev. Genet. 2005; 6: 836-846Crossref PubMed Scopus (1534) Google ScholarComputational biologyHomoeologs: 'orthologs between subgenomes'35Altenhoff A.M. et al.The OMA orthology database in 2015: function predictions, better plant support, synteny view and other improvements.Nucleic Acids Res. 2015; 43: D240-D249Crossref PubMed Scopus (145) Google ScholarThis reviewHomoeologs: pairs of genes or chromosomes in the same species that originated by speciation and were brought back together in the same genome by allopolyploidization Open table in a new tab Even in modern evolutionary biology contexts, the term homoeolog has been used inconsistently. For instance, some have used it not just in the context of allopolyploids but to relate duplicates created by autopolyploidy as well (for example, [25Freeling M. Bias in plant gene content following different sorts of duplication: tandem, whole-genome, segmental, or by transposition.Annu. Rev. Plant Biol. 2009; 60: 433-453Crossref PubMed Scopus (588) Google Scholar, 26Schnable J.C. et al.Genome-wide analysis of syntenic gene deletion in the grasses.Genome Biol. Evol. 2012; 4: 265-277Crossref PubMed Scopus (106) Google Scholar]). This is, however, at odds with the original description of homoeologs as belonging to an allopolyploid genome [7Huskins C.L. A cytological study of Vilmorin's unfixable dwarf wheat.J. Genet. 1931; 25: 113-124Crossref Scopus (20) Google Scholar]. There are biological differences between genes that arise due to speciation versus duplication [27Tatusov R.L. et al.A genomic perspective on protein families.Science. 1997; 278: 631-637Crossref PubMed Scopus (2750) Google Scholar] and thus also, conceivably, between allo- versus autopolyploids. Autopolyploids by definition are created by genome doubling, with an exact copy of the genome formed. By contrast, allopolyploids are formed by the merger of closely related species that have already started to diverge. Although still poorly understood, these fundamental differences could have significant effects on the genome of the polyploid. Hybridization can induce a 'genome shock' prompting epigenetic or expression changes that might not be present with strictly genome doubling per se [8Doyle J.J. et al.Evolutionary genetics of genome merger and doubling in plants.Annu. Rev. Genet. 2008; 42: 443-461Crossref PubMed Scopus (512) Google Scholar, 28Ng D.W-K. et al.Proteomic divergence in Arabidopsis autopolyploids and allopolyploids and their progenitors.Heredity. 2012; 108: 419-430Crossref PubMed Scopus (61) Google Scholar, 29Parisod C. et al.Evolutionary consequences of autopolyploidy.New Phytol. 2010; 186: 5-17Crossref PubMed Scopus (472) Google Scholar, 30Wang J. et al.Genomewide nonadditive gene regulation in Arabidopsis allotetraploids.Genetics. 2006; 172: 507-517Crossref PubMed Scopus (477) Google Scholar]. The functional consequences of genes duplicated by allo- vs autopolyploidy still needs to be investigated, which is why a clear distinction of terminology between the two is important. Furthermore, this usage of homoeolog overlaps with another term – ohnologs – used to denote genes resulting from whole-genome duplication [31Wolfe K. Robustness – it's not where you think it is.Nat. Genet. 2000; 25: 3-4Crossref PubMed Scopus (110) Google Scholar]. The term homoeolog has even been used to refer to similar chromosomal regions in different species [32Conner J.A. et al.Comparative mapping of the Brassica S locus region and its homeolog in Arabidopsis: implications for the evolution of mating systems in the Brassicaceae.Plant Cell Online. 1998; 10: 801-812Crossref PubMed Scopus (82) Google Scholar, 33Peng J.H. et al.Chromosome bin map of expressed sequence tags in homoeologous group 1 of hexaploid wheat and homoeology with rice and Arabidopsis.Genetics. 2004; 168: 609-623Crossref PubMed Scopus (71) Google Scholar, 34Ware D. et al.Gramene: a resource for comparative grass genomics.Nucleic Acids Res. 2002; 30: 103-105Crossref PubMed Scopus (162) Google Scholar]. Although closely related species do have similar chromosomes and gene content, this latter usage is unorthodox: the term homoeolog has been overwhelmingly used to denote relationships within polyploids, and therefore within a single species rather than between closely related species. A cross-species definition of homoeology is also redundant with that of orthology. Consequently, there is a need for a unifying, evolutionarily precise definition of homoeology, formulated in terms of the key events that gave rise to the genes in question. The ideal definition should be as consistent as possible with the widespread usage of the term and should complement the other '-log' terms, which have served the community well. We define homoeologs as pairs of genes or chromosomes in the same species that originated by speciation and were brought back together in the same genome by allopolyploidization. Figure 1 depicts how this definition complements the other 'log' terms. In particular, the analogy between homoeologs and orthologs implies that homoeologs can be thought of as orthologs between subgenomes of an allopolyploid [35Altenhoff A.M. et al.The OMA orthology database in 2015: function predictions, better plant support, synteny view and other improvements.Nucleic Acids Res. 2015; 43: D240-D249Crossref PubMed Scopus (145) Google Scholar]. Note that the term 'paleolog' is sometimes used to denote ancient polyploidization events. The term is convenient for plants such as soybean where the polyploidization event occurred more than a few million years ago and where it is unknown whether these were auto- or allopolyploidization events [36Pfeil B.E. et al.Placing paleopolyploidy in relation to taxon divergence: a phylogenetic analysis in legumes using 39 gene families.Syst. Biol. 2005; 54: 441-454Crossref PubMed Scopus (138) Google Scholar]. Because of the analogy between homoeology and orthology, homoeologs are under the same common misconceptions that afflict orthologs: the notion that homoeologs necessarily in a one-to-one relationship or that they have remained strictly in their ancestral positions since speciation. Since homoeology is characterized by an initial speciation event, once the progenitor species of the future allopolyploid begin to diverge, the corresponding genes in each new species that descended from a common ancestral gene start diverging in sequence (Figure 2). The sequence divergence will depend on the time since the progenitor divergence and other factors (the same factors that contribute to ortholog divergence such as selection pressure, duplication events, and others). In addition to genic sequence divergence, other scale evolutionary events may occur, including single-gene duplications, deletions, and rearrangements. As a consequence, orthologous relationships are not necessarily one-to-one between species and may exist in one-to-many or many-to-many relationships, especially among highly duplicated plant genomes [37Gabaldón T. Koonin E.V. Functional and evolutionary implications of gene orthology.Nat. Rev. Genet. 2013; 14: 360-366Crossref PubMed Scopus (337) Google Scholar]. The same is true for homoeologous relationships. Depending on the duplication (and loss) rate since the divergence of the progenitor species, there may be more than one homoeologous copy of a given gene per subgenome (Figure 2). In many plant species, a high degree of collinearity, or conservation of gene order [38Tang H. et al.Synteny and collinearity in plant genomes.Science. 2008; 320: 486-488Crossref PubMed Scopus (752) Google Scholar], has been observed between homoeologous chromosomes in polyploids. Genes tend to stay in their ancestral position since divergence, leading to the concept of positional orthology [39Dewey C.N. Positional orthology: putting genomic evolutionary relationships into context.Brief. Bioinform. 2011; 12: 401-412Crossref PubMed Scopus (55) Google Scholar] and, analogously in allopolyploids, of positional homoeology. However, there may be rearrangement of homoeologs via single-gene duplication/translocation either before or after polyploidization, going against the widespread notion that homoeologous genes are always positional (i.e., have remained in their ancestral location), as stated for example in [25Freeling M. Bias in plant gene content following different sorts of duplication: tandem, whole-genome, segmental, or by transposition.Annu. Rev. Plant Biol. 2009; 60: 433-453Crossref PubMed Scopus (588) Google Scholar]. Although we can expect that most homoeologs remain positionally conserved and in a one-to-one relationship after polyploidization, these are only