TRANSPOSABLE ELEMENTS AND GENOME STABILITY IN HUMAN OOGENESIS

 

When we think of evolution and genetic diversity, crossing over during meiosis often comes to mind, the process of exchanging DNA between homologous chromosomes, which creates new combinations of alleles contributing variation in offspring. However, recent research has proven that jumping genes also play a major role in the evolution of a species. 

Transposable elements (TEs) are not just jumping genes or “selfish” DNA that insert themselves into genes and cause alterations or mutations, or even become part of the genome; in some lineages, they are the major driving force for speciation and evolution, like the loss of tail in Homo sapiens (if you want to know more: How Tail Got Lost In Humans: Transposable Element In The Aid For Evolution Before 25 Million Years). 

TEs are classified into two major classes based on their mobilization mechanism: Class I elements or retrotransposons (mobilize through RNA intermediate or copy-paste mechanism) and Class II elements or DNA transposons (mobilize via DNA intermediate or cut and paste mechanism). Retrotransposons include both long terminal repeat (LTR) and non-LTR retrotransposons. LTR transposons include endogenous retroviruses (ERVs) and ERV-derived solo LTR elements; whereas, Non-LTR retrotransposons consist of long interspersed nuclear elements (LINEs) and short interspersed nuclear elements (SINEs). Even though TEs' activity plays a significant role in the genomic evolution, their movement also poses a threat to the integrity of the genome, including creating double-strand breaks and nonhomologous recombination.

Classification of Transposable Elements

Most of the TEs are extinct, but numerous retrotransposon families are still active in the human population. The active ones are autonomous (can replicate on their own) or rely on trans-acting factors expressed by other autonomous elements, i.e., non-autonomous retrotransposons use the mobilization machinery from autonomous TEs to replicate. Subfamilies like L1PA1, SVA, AluY, and HERV-K are the only lineage which causes insertional polymorphism in human individuals. These activities have been highly observed in somatic cells, such as neuronal and cancer cells, indicating their capability to mobilize post-zygotically and promote somatic mosaicism. 

In somatic cells, TE expression is prevented through epigenetic repression and DNA methylation. If TEs are expressed, it triggers innate immune pathways such as cGAS-STRING. However, in primordial germ cell formation, genome-wide epigenetic reprogramming leads to erasing the DNA methylation marks, making the window for vulnerability in cells due to TE activation. In females, this window of TE activation is open till the initiation of follicle growth, and if unchecked, can lead to meiotic arrest, genomic instability, and infertility. 

Expression profile of piRNA and PIWI protein in different stages of spermatogenesis

The piRNA pathway plays a major role in regulating the expression of TEs in this narrow window of epigenetic reprogramming by acting as a defence mechanism against TE activity in the germline. The piRNA pathway consists of a protein subfamily of ARGONAUTE known as PIWI proteins, and is associated with the piRNAs to suppress TEs via post-transcriptional cleavage and epigenetic silencing.

 Biogenesis and function of PIWI-interacting RNAs (piRNAs) in the mouse testis

Even though we know much about the piRNA pathways in models like golden hamsters, Drosophila, and zebrafish, the human piRNA pathway is less well classified, as piRNAs are diverse in each species and each has its own mechanism of repressing TEs in the germline. So we still have a poor understanding of the temporal dynamics of piRNAs during human oogenesis. To shed light on this gap, a paper titled “Integrated small and long RNA sequencing reveals piRNA mediated transposon repression during human oogenesis”, published in Nature Communications, addressed this issue by profiling small (~19 to 22 nt long) and long (~24 to 31 nt long) RNA transcriptomes in human oocytes over four developmental stages. 

Through utilizing the matched sequencing from the same individual oocytes, they found that there was a 60% of downregulation of TEs associated with an increase in the short or long piRNA. Moreover, they also found that long interspersed nuclear element-1 (L1), particularly the active L1PA subfamilies, are the primary targets of the piRNA pathway. In contrast, non-autonomous elements like Alu and SVA showed limited repression. The researchers suggested that the limited repression might be due to heavy regulation of L1, as it indirectly stops the expression of non-autonomous TEs.  

Moreover, they also found species-specific differences in TE dominance. When ERVs were most active, autonomous TEs in rodents like golden hamsters, L1 elements are dominant in humans. This explained the evolutionary shift of short-piRNAs being predominant in human oogenesis, as they primarily suppress L1. So, the expression of the particular piRNA, long or short, is regulated based on the predominantly expressed TE in the particular species.

Interestingly, TEs expression actually increased during oocyte development, which might be due to the evolutionary "adaptation lag”, where piRNAs haven't evolved enough to silence these young or new TE elements. This upregulation is considered to have functional relevance as these TE transcripts might be necessary for proper early embryonic development and chromatin organization. 

The study explained the role of piRNA in TE silencing; however, it couldn't acknowledge regarding the non-canonical roles and functional validation of the piRNAs in the suppression. This paper gave baseline information on the association of piRNA and TE silencing in oocytes, and also gave insights into the window of evolution in the oocytes due to adaptation lag. Even though these are hypotheses that have yet to be proved, they give a broader perspective on the understanding and importance of TEs towards the evolutionary drift. 

REFERENCE

Zhang, F., Zhang, H., xiao, Y. et al. Integrated small and long RNA sequencing reveals piRNA mediated transposon repression during human oogenesis. Nat Commun 17, 3804 (2026). https://doi.org/10.1038/s41467-026-70296-4

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• Springer Nature, https://share.google/JpDCy3arQ1kc49AQJ