Gene duplications: evolutionary role Ariadna Pedraza Mensa Genomics, 2017 Master’s Degree in Advanced Genetics - UAB

DNA-based gene duplication (segmental duplications) Origin of new genes DNA-based gene duplication (segmental duplications) Ohno’s model for duplications fate RNA-based gene duplication (retroposition) Evolutionary role of duplications: DNA vs. RNA-based gene duplications Evolution of new gene functions More copies are always an advantage? Out-of-the-X chromosome movements The origin of mammalian sex chromosomes EVO-DEVO: only structural genes? Conclusions

Often by combining mechanisms Origin of new genes Often by combining mechanisms (Long et al. 2003)

Errors during recombination DNA-based gene duplication (segmental duplications) Errors during recombination (Hurles, 2004)

Ohno’s model for duplications fate (1973) On an evolutionary scale, gene duplication may result in new functions via different scenarios: Nonfunctionalization: The most likely outcome is loss of function in one of the two gene copies (→ pseudogene). In some cases: Neofunctionalization: One gene copy may retain the original function while the other acquires a novel, evolutionarily advantageous (adaptive) function. Subfunctionalization: Both genes can specialize to perform complementary functions. (Conrad et al. 2007)

RNA-based gene duplication (retroposition) Based on the reverse transcription of mRNA intermediates. → Intronless retroposed gene copies, with a poly(A) tail. → LINEs provide the enzymes necessary for retroposition. → To be functional, need to obtain a core promoter and probably other elements, such as enhancers, that regulate their expression. * Only genes which are expressed in the germ line can be duplicated via this mechanism (presence of mRNA is needed during this stage). (Kaessmann et al. 2009)

Evolutionary role

DNA vs. RNA-based gene duplications The fundamental differences between these two major duplication mechanisms have significant consequences for the evolutionary fates of resulting gene copies and their analysis: DNA duplications (segmental duplications): Daughter copies inherit the genetic features (exons, introns and regulatory elements) of the ancestral gene. → Likely to exhibit similar expression patterns in their early evolution: one copy is initially functionally redundant.

Evolution of new gene functions CNVs provide with new genetic material that can act as a substrate for mutations This changes can be selected by positive Darwinian selection New gene functions arise in the gene copies → Accelerated evolution of new genes: rapid changes in their sequence, structure and expression. * In the last instance, all these changes in new genes can lead to species divergence.

More copies are always an advantage? (Conrad et al. 2007)

DNA vs. RNA-based gene duplications The fundamental differences between these two major duplication mechanisms have significant consequences for the evolutionary fates of resulting gene copies and their analysis: DNA duplications (segmental duplications): Daughter copies inherit the genetic features (exons, introns and regulatory elements) of the ancestral gene. → Likely to exhibit similar expression patterns in their early evolution: one copy is initially functionally redundant. RNA-based duplications: Lack introns and less likely to have strong regulatory elements following their emergence. → Retrocopies that do become transcribed are probably more prone to evolve new expression patterns: novel functional roles from the beginning. → Copies most of the times are located on chromosomes different from that of the parental gene copy (“vehicle” for interchromosomal gene movements).

Out-of-the-X chromosome movements Retrogenes might easily evolve into functional autosomal substitutes of their X-linked parental genes during the late stages of spermatogenesis. Their X-linked parents (usually broadly expressed housekeeping genes) are transcriptionally silenced during these stages due to the male meiotic sex chromosome inactivation (MSCI). Autosomal retrogenes are specifically expressed in the testis during the meiotic stages of spermatogenesis. (Kaessmann et al. 2009)

The origin of mammalian sex chromosomes Selectively driven out-of-the-X gene transfer started in the eutherian and marsupial lineages. Given that meiotic sex chromosome inactivation is the selective force that is driving genes off the X chromosome, MSCI had to emerge in the common ancestor of eutherians and marsupials, after their separation from the monotreme lineage. Mammalian sex chromosomes were originated in the common ancestor of eutherians and marsupials (evolving from an ancestral pair of autosomes), and not in the common ancestor of all mammals, and are therefore much younger than previously thought1 (Kaessmann et al. 2009)

EVO-DEVO: only structural genes? Evolutionary developmental biology (”evo devo”) claims that adaptive mutations affecting morphology are more likely to occur in the cis-regulatory regions than in the protein-coding regions of genes. A change in a cis-regulatory element may affect only the specific temporal or spatial expression of its single attendant gene → could produce the differences in timing or tissue expression said to be involved in most evolutionary innovations. A change in a cis-regulatory region is supposed to have a higher probability of being adaptive than is a random change in a structural gene or transcription factor → Changes in cis-regulatory elements are more likely to be fixed in evolution.

Conclusions The classical model of new gene origination by duplication and retroposition have been found to shape the structures of protein-coding genes and the evolution of new functional proteins. Genes rapidly diverge after duplication, due to the accumulation of new mutations in the duplicated gene. This is can be positively selected and give rise to functionally new genes. Gene duplication plays an important role in genome evolution and phenotypic variability, but can also cause disease phenotypes. RNA-based duplications are an important mechanism to the sex chromosomes origin in mammals. The protein-coding sequence and cis-regulatory regions of duplicated genes evolve independently, and both are important to explain divergence.

References Conrad and Antonarakis. 2007. Gene duplication: a drive for phenotypic diversity and cause of human disease. Annu Rev Genomics Hum Genet. 8:17-35. Review. Hoekstra HE, Coyne JA. 2007. The locus of evolution: evo-devo and the genetics of adaptation. Evolution. 61(5):995-1016. Review. Hurles M. 2004. Gene Duplication: The Genomic Trade in Spare Parts. PLoS Biol2(7): e206. https://doi.org/10.1371/journal.pbio.0020206. Katju V, Lynch M. 2006. On the formation of novel genes by duplication in the Caenorhabditis elegans genome. Mol Biol Evol. 23(5):1056-67. Kaessmann H, Vinckenbosch N, Long M. 2009. RNA-based gene duplication: mechanistic and evolutionary insights. Nat Rev Genet 10(1):19-31. Review. Long M, Betrán E, Thornton K, Wang W. 2003. The origin of new genes: glimpses from the young and the old. Nat Rev Genet. 4(11):865-75. Review.

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