life Review Cancer, Retrogenes, and Evolution Klaudia Staszak and Izabela Makałowska * Institute of Human Biology and Evolution, Faculty of Biology, Adam Mickiewicz University in Poznan, 61-614 Poznan, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-61-8295835 Abstract: This review summarizes the knowledge about retrogenes in the context of cancer and evolution. The retroposition, in which the processed mRNA from parental genes undergoes reverse transcription and the resulting cDNA is integrated back into the genome, results in additional copies of existing genes. Despite the initial misconception, retroposition-derived copies can become functional, and due to their role in the molecular evolution of genomes, they have been named the “seeds of evolution”. It is convincing that retrogenes, as important elements involved in the evolution of species, also take part in the evolution of neoplastic tumors at the cell and species levels. The occurrence of specific “resistance mechanisms” to neoplastic transformation in some species has been noted. This phenomenon has been related to additional gene copies, including retrogenes. In addition, the role of retrogenes in the evolution of tumors has been described. Retrogene expression correlates with the occurrence of specific cancer subtypes, their stages, and their response to therapy. Phylogenetic insights into retrogenes show that most cancer-related retrocopies arose in the lineage of primates, and the number of identified cancer-related retrogenes demonstrates that these duplicates are quite important players in human carcinogenesis. Keywords: retrogenes; retroposition; cancer; tumor evolution; species evolution 1. Introduction Citation: Staszak, K.; Makałowska, I. A large part of the eukaryotic genome contains sequences that result from the activity Cancer, Retrogenes, and Evolution. of transposable elements. Until recently, most of them were considered insignificant. It Life 2021, 11, 72. https://doi.org/ turned out that transposable elements importantly influenced the evolution of genomes. 10.3390/life11010072 Identifying the possible functions of “junk DNA” constitutes one of the greatest discoveries in genomic analyses [1–3]. The term “junk DNA” also refers to pseudogenes; however, an Received: 19 December 2020 increasing number of studies support the functionality of many pseudogenes and their Accepted: 15 January 2021 role in various human diseases. Findings from studies in cell culture, animal models, and Published: 19 January 2021 clinical samples confirm the role of pseudogenes in tumorigenesis [4–6]. This includes retrocopies that are usually called “processed pseudogenes” or “retropseudogenes” and Publisher’s Note: MDPI stays neutral have been classified as gene copies with no functional significance. Nevertheless, as the with regard to jurisdictional claims in published maps and institutional affil- quantity of data from high-throughput experiments increases, new functionally important iations. retrocopies are identified, including those associated with various diseases [7,8], especially with many types of cancer [9,10]. The phenomenon of neoplasm is widespread across the evolutionary tree, but its incidence varies between species. Surprisingly, the risk of cancer transformation does not seem to depend strongly on individual species’ body size or life expectancy [11]. Copyright: © 2021 by the authors. Studies on a group of elephants have shown that among them, there is a low rate of tumor Licensee MDPI, Basel, Switzerland. transformation compared to other mammals. Elephants have 20 copies of the TP53 gene, This article is an open access article distributed under the terms and a well-known oncosuppressor, 19 of which are retropseudogenes. The presence of this conditions of the Creative Commons gene’s additional copies is proposed to be related to an increased apoptotic response in the Attribution (CC BY) license (https:// elephant population [12]. The occurrence of resistance mechanisms to cancer has also been creativecommons.org/licenses/by/ described in other animal species. A good example is the unusual tolerance to hypoxia in 4.0/). naked mole-rats [13]. Life 2021, 11, 72. https://doi.org/10.3390/life11010072 https://www.mdpi.com/journal/life Life 2021, 11, x FOR PEER REVIEW 2 of 16 Life 2021, 11, 72 2 of 17 Many studies have described the relationship between the expression level of retrogenes and the incidence of specific neoplasms [14,15], and the connection between these two appears to go beyond this. Retrogenes are known as important evolutionary players that can affect Many studies have described the relationship between the expression level of retro- genomegenes diversity and the [16–20], incidence which of specific is due neoplasms to, amon [14g,15 other], and things, the connection their much between faster these evolution than intwo the appears case of to goprotein-coding beyond this. Retrogenes genes. In are cancer, known asthere important is also evolutionary a rapid accumulation players of mutationsthat canand affect the formation genome diversity of qualitatively [16–20], which differe is duent to,populations among other of things, cancer their cells. much In addition, it has beenfaster demonstrated evolution than that in the internal case of protein-codingdiversity is the genes. result In of cancer, natural there selection, is also a rapidwhich shapes accumulation of mutations and the formation of qualitatively different populations of the tumorcancer during cells. Inits addition,development it has been[11]. demonstratedNatural selection that internal evidently diversity also isdetermines the result of the fate of retrocopies.natural These selection, connections which shapes thebetween tumor duringretrogenes its development and cancer [11]. Naturalgave selectionreasons for an evolutionary-basedevidently also determinesoverview theof retrogenes fate of retrocopies. in cancerous These connections contexts (Figure between 1). retrogenes and cancer gave reasons for an evolutionary-based overview of retrogenes in cancerous contexts (Figure1). Figure 1. Schematic view of the relationship between retrogenes, cancer, and evolution. 2. Retrocopies and Their Functions New gene copies may be obtained by polyploidization, irregular crossing over, or Figure 1. SchematicDNA- view or of RNA-mediated the relationship duplication between [retrogenes,21]. Until recently, cancer, onlyand DNA-basedevolution. duplication was considered to be functionally relevant. However, later studies have revealed that 2. RetrocopiesRNA-based and duplication Their Functions provides copies that may play a vital role in the cell [3,22–24]. The formation of retrocopy begins with the transcription of a parental gene. The Newprocessed gene mRNA copies goes may to thebe cytoplasm,obtained whereby poly L1 retrotransposon-derivedploidization, irregular proteins crossing bind over, or DNA- toor itsRNA-mediated polyA tail. The processduplication takes place[21]. withUntil the recently, participation only of DNA-based reverse transcriptase, duplication was consideredendonuclease, to be functionally and chaperones. relevant. Parental Howe gene’sver, mRNA later anneals studies to the have broken revealed DNA ends, that RNA- based duplicationundergoing reverse provides transcription, copies that and may the resultingplay a vital cDNA role is in integrated the cell [3,22–24]. back into the genome in the form of a retrocopy (Figure2a). Retrocopies are devoid of introns and regu- The formation of retrocopy begins with the transcription of a parental gene. The latory elements. They are equipped with a poly-A tail along with flanking repeats. These processedcopies mRNA were long goes considered to the cytoplasm, to be “dead-on-arrival” where L1 and retrotransposon-de classified as transcriptionalrived proteins noise bind to its polyAdue to theirtail. highThe similarity process totakes the parental place genes.with the Nevertheless, participation to promote of reverse transcription, transcriptase, endonuclease,retrotransposed and chaperones. transcripts can Parental take advantage gene’s of mRNA adjacent anneals gene regulatory to the broken regions andDNA ends, undergoing reverse transcription, and the resulting cDNA is integrated back into the genome in the form of a retrocopy (Figure 2a). Retrocopies are devoid of introns and regulatory elements. They are equipped with a poly-A tail along with flanking repeats. These copies were long considered to be “dead-on-arrival” and classified as transcriptional noise due to their high similarity to the parental genes. Nevertheless, to promote transcription, retrotransposed transcripts can take advantage of adjacent gene regulatory regions and use distant CpG sequences or sometimes even parts of their own sequences. Life 2021, 11, x FOR PEER REVIEW 3 of 16 Furthermore, retrocopy insertion into the intron of another gene often leads to the acquisition of the host’s regulatory machinery [22,25]. Retrocopies that acquired transcriptional ability are called retrogenes. In the process of evolution, they may be subject to subfunctionalization and take over some of the parental genes’ functions (Figure 2b). A good example is retrogene SLC5A3 and the parental gene SLC5A1. Proteins encoded by these genes contain solute binding domains, but they differ in activity. Retrocopy-derived protein is a sodium-dependent myo-inositol transporter. In turn, parental-derived proteins participate in the transport of glucose and galactose [24]. Another functional