The Role of Retrotransposons in Shaping Human Genome Evolution

Transposable elements (TEs) are segments of DNA within a cell or organism's genome that literally "jump" from one genomic location to another, either themselves or their duplicated sequences. Once misclassified as neutral DNA without functions, these ubiquitous components are actually known to play crucial roles in shaping evolution by either altering the regulatory landscape of genes or providing the raw material of evolution. They are found across the genomes of all higher organisms, including humans, and make up a significant portion of our genetic blueprint.

Image Credit: Motion Drama/

Image Credit: Motion Drama/

Retrotransposons are a special class of TEs that employ a unique "copy-paste" mechanism to multiply their numbers. Instead of directly jumping within the genome, they first transcribe their DNA into RNA, then use this RNA template to create complementary DNA copies that insert themselves at new locations into the genome. This "copy and paste" mechanism can rapidly amplify the number of a given TE in a genome, contributing significantly to its overall content.

Barbara McClintock's pioneering work on TEs began by observing their influence on specific phenotypic traits in maize. This led her to call them "controlling elements" due to their ability to alter gene expression and generate diverse phenotypic patterns, like kernel color variations. Through her meticulous analysis of such phenotypic patterns, McClintock identified mobile genetic elements that could "jump" around the genome, causing these changes.

However, despite the profound significance of McClintock's discovery, the functional importance of TEs remained largely unrecognized until the 1980s. This was partly due to the limitations of technology at the time. She was finally awarded the Nobel Prize in Physiology or Medicine in 1983.

Retrotransposons in Human Genome Evolution

From an evolutionary point of view, transposable elements (TEs) are not intrinsically good or bad (or even neutral); their impact depends entirely on their location within the genome and their outcomes in the particular environment where the host organism lives. For example, consider a scenario where an active human retrotransposon jumps into the exon of a gene, disrupting its coding sequence and potentially leading to the loss of a crucial protein. This would be clearly deleterious.

Conversely, the same TE might eventually insert into the promoter region of an oncogene, effectively silencing its expression. This could have a beneficial outcome by suppressing cancer-causing activity. Finally, a retrotransposon insertion into a gene that is not expressed in a given cell type will likely have no effect and, therefore, be neutral.

Adding another layer of complexity to the functional significance of TEs is the fact that TEs are often composed of repetitive sequences, making them prime targets for epigenetic mechanisms like DNA methylation. Inactivation of TEs through epigenetic mechanisms can sometimes spread beyond the element itself, silencing nearby genes or even entire linkage groups. Thus, TE-mediated epigenetic phenomena exert additional effects on the potential benefits and drawbacks of their activity.

Benefits and Detriments of Retrotransposons

Retrotransposons like LINE-1 (L1) and Alu TEs remain active in human genomes, meaning they can still replicate and jump to different regions. This ongoing activity is a major driving force behind genetic disorders and genome instability.

Thus, to date, researchers have identified over 120 LINE-1-mediated insertions linked to human genetic diseases.1 When inherited through the germinal line, these insertions result in autosomal dominant, autosomal recessive, and X-linked disorders.

For example, a LINE-1 insertion into the RPS6KA3 gene is associated with Coffin-Lowry syndrome, a rare congenital condition affecting various body parts and causing intellectual disability.2 Similarly, an Alu retrotransposon insertion into the BRCA1 gene is a major risk factor for hereditary cancer.3

However, TE-mediated sequence duplication is not always bad. Retrotransposons are one proposed evolutionary mechanism for gene duplication, which is critical for generating new genes and driving adaptive novelty.4,5 In primates, large genomic sequences exceeding 50 kilobases have been shown to be duplicated through retrotransposon-mediated mobilization. Notably, a specific group of retrotransposons has been identified as responsible for duplicating the AMAC gene three times in the human genome, predating the divergence of humans and African great apes.6

Retrotransposition events have also played a key role in the neofunctionalization of genes, where a duplicate gene takes on a new function distinct from its ancestor.4

By acquiring novel roles, duplicated genes can contribute to the evolution of new traits and species diversification. One remarkable example comes from a family of the neofunctionalized Ty3/gypsy retrotransposon genes found in mammals.7 These genes, once active "jumping" TEs, lost their ability to replicate and insert themselves independently before the evolutionary split between mice and humans. However, they didn't disappear entirely. Instead, they evolved to become expressed genes in various tissues, including the brain.7

Recent Discoveries and Research Advances

Transposable elements (TEs) are being harnessed for their inherent mobility, revolutionizing genome engineering technologies. For example, piggyBac DNA transposons are now being used as powerful tools for transgenesis and targeted mutagenesis.

These tools can efficiently insert or delete genes, holding immense potential for gene therapy and functional genomics studies. More intriguingly, certain TEs called Miniature Inverted- Transposable Elements (MITEs), which have shown to be active under stress conditions during the course of evolution, can be used for shaping evolutionary patterns and phenotypes.

Consequently, the evolutionary potential of stress-activated MITEs might be combined with the groundbreaking CRISPR-Cas genome editing system to effectively "direct" the evolution of crops.5 Regarding retrotransposons, recent discoveries highlight their regulatory potential, demonstrating their influence on noncoding RNA transcription and shaping the mammalian transcriptional and epigenomic landscapes.8 These discoveries reshape our understanding of human genetics by offering new insights into the mechanisms of disease development, suggesting potential therapeutic targets for conditions linked to dysregulated gene expression and epigenetic alterations.

Future Directions in TE and Retrotransposon Research

TEs, in general, and retrotransposons, in particular, were once considered "junk parasitic DNA," but research shows they play crucial roles in gene regulation. They can act as switches for other genes, influence chromatin structure, generate non-coding RNAs with diverse functions, and even activate under stress.4,5 This unveils a complex interplay between different genomic elements in regulating gene expression.

Retrotransposon are particularly beneficial in evolutionary terms because they carry the molecular machinery to jump, even between species (a process known as horizontal gene transfer), potentially carrying beneficial genes and accelerating evolution. Studying their dynamics will help us understand how genomes evolve at a macroevolutionary scale and adapt to changing environments, shedding light on the diversity of life.

Specific TE families jump to sequence-specific genome patterns (e.g., inverted repeats), and this process can be triggered by stress conditions or DNA damage. Harnessing this knowledge could allow us to exploit TE insertions to selectively switch genes on or off in the genome, with potential therapeutic applications.

For example, the association between telomere shortening and aging is well-established; thereby genome genome-engineered TEs could potentially be used to add telomere sequences in aged cells, potentially delaying the aging process.


TEs, in general, and retrotransposons, in particular, are not merely "junk DNA," but rather, they represent dynamic elements that shaped (and shape) our genome in profound ways. Their role in gene duplication, neofunctionalization, regulatory modulation, and evolutionary adaptation continues to be fascinating areas of research with significant implications for understanding not only evolution but also human health and disease.


  • Hancks, D. C., & Kazazian, H. H. (2016). Roles for retrotransposon insertions in human disease. Mobile DNA, 7(1), 1-28.
  • Martínez-Garay I, Ballesta MJ, Oltra S, Orellana C, Palomeque A, Moltó MD, Prieto F, Martínez F. Intronic L1 insertion and F268S, novel mutations in RPS6KA3 (RSK2) causing Coffin–Lowry syndrome. Clin Genet. 2003;64:491–6.
  • Qian Y, Mancini-DiNardo D, Judkins T, Cox HC, Daniels C, Holladay J, Ryder M, Coffee B, Bowles KR, Roa BB. Identification of retrotransposon insertion mutations in hereditary cancer. Presented at the 65th annual meeting of the American Society of Human Genetics 2015.
  • Vaschetto, L. M., & Ortiz, N. (2019). The role of sequence duplication in transcriptional regulation and genome evolution. Current Genomics, 20(6), 405-408.
  • Vaschetto, L. M. (2018). Modulating signaling networks by CRISPR/Cas9-mediated transposable element insertion. Current genetics, 64(2), 405-412.
  • Xing, J., Wang, H., Belancio, V. P., Cordaux, R., Deininger, P. L., & Batzer, M. A. (2006). Emergence of primate genes by retrotransposon-mediated sequence transduction. Proceedings of the National Academy of Sciences, 103(47), 17608-17613.
  • Brandt, J., Veith, A. M., & Volff, J. N. (2005). A family of neofunctionalized Ty3/gypsy retrotransposon genes in mammalian genomes. Cytogenetic and Genome Research, 110(1-4), 307-317.
  • Mangiavacchi, A., Liu, P., Della Valle, F., & Orlando, V. (2021). New insights into the functional role of retrotransposon dynamics in mammalian somatic cells. Cellular and Molecular Life Sciences, 78(13), 5245-5256.

Last Updated: Feb 1, 2024

Dr. Luis Vaschetto

Written by

Dr. Luis Vaschetto

After completing his Bachelor of Science in Genetics in 2011, Luis continued his studies to complete his Ph.D. in Biological Sciences in March of 2016. During his Ph.D., Luis explored how the last glaciations might have affected the population genetic structure of Geraecormobious Sylvarum (Opiliones-Arachnida), a subtropical harvestman inhabiting the Parana Forest and the Yungas Forest, two completely disjunct areas in northern Argentina.


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