The Mystery Behind Transposons, Nature's Jumping Genes: Part 1

2022/07/06

Did you know that while the human genome contains all genetic information, only about 2% of it is what we usually call "genes"? The remaining 98% consists of transposable elements (TEs), also known as "jumping genes," and their remnants, as well as other unidentified sequences. We are beginning to realize that these jumping genes, which until recently were called "junk" and thought to have no function, are, in fact, the key differentiator between species.

Professor Haruhiko Siomi and his colleagues in the Department of Molecular Biology at the Keio University School of Medicine have been studying transposons in golden hamsters, having mapped the golden hamster genome. He has discovered that golden hamsters are more closely related to humans in some genes than mice, despite the conventional popularity of mice in gene research. By applying genetic modification technology, he has succeeded in creating a golden hamster that lacks PIWI genes, which are thought to regulate the transposons that move along chromosomes, damaging genes and causing cancer. Results showed that golden hamsters lacking PIWIL1 or PIWIL3 in the developmental stages were unable to develop embryos after fertilization (Nature Cell Biology).

The study would not have been possible with mice due to genetic differences, and there are high hopes for the utility of golden hamsters in future genetic research.

As mammals closely related to humans, mice have been used extensively to study genes and life phenomena. However, Prof. Siomi says that as research has progressed, it has become clear that mice are different from humans in unexpected ways.

“For example, mice cannot catch COVID-19 (SARS-CoV-2). Hamsters, however, can be infected and have symptoms just like humans. Even the smallest hamster can have a bad fit of coughing.”

For this reason, Prof. Siomi says, many hamsters are currently being used in SARS-CoV-2 research. It has also become clear that the type and status of PIWI genes expressed during sperm and oocyte formation are similar in golden hamsters and humans, while it is known that mice, which resemble golden hamsters, are quite different from humans in this respect.

So, where do the differences between species come from?

“If we look at just the proteins in the amino acid sequences of human and chimpanzee genes, they are nearly identical. In fact, we humans, chimpanzees, and other mammals such as mice share sets of proteins with pretty much the same amino acid sequences. Despite these similarities, humans and chimpanzees—and humans and mice— differ in when, where, and to what extent these proteins are expressed. ”

We are just beginning to understand how transposons and their remnants contribute to when, where, and to what extent a protein is expressed. It’s also thought that they could also potentially play a significant role in species differentiation.

Transposons, also known as “jumping genes” in English, are DNA sequences that move from one location on the genome to another, leaving an old copy behind and allowing a new copy to enter somewhere else in the genome. A simple interpretation of this is that each time a transposon jumps, or “transposes,” it duplicates, creating a copy of itself in the process. Thus, transposons, which occupy as much as 50% of the human genome, have been shown to be a factor in determining the size and bulk of the genome.

"This is why, for example, there are so many copies of transposons in the human genome—anywhere between 800,000 and 1.5 million. In other words, what was originally a single element has moved around the genome between 800,000 and 1.5 million times over the course of our evolution, resulting in the ever-growing size of the human genome. Not only has our genome grown larger, but its sequence has also changed as a result of evolution. Recent research has interpreted transposons as "control sequences" used to determine when, where, and how much of a particular protein is expressed.”

Until recently, transposon research focused exclusively on diseases caused by transposition. However, attention is now turning to the role of transposons in speciation, the evolutionary process by which one lineage splits into two reproductively isolated groups of organisms.

Transposons can jump in many different places. “In cancer cells, for example, transposons can move quite violently,” explains Prof. Siomi. These transpositions can also be transmitted to the next generation when transposons are newly inserted in germ cells such as sperm and eggs. Therefore, in order to prevent extra transpositions from occurring during germ cell formation, organisms have a mechanism to suppress transposon expression using small RNAs called PIWI-interacting RNAs (piRNAs), which specifically bind to transposons. piRNAs are also loaded onto PIWI proteins, which in turn silence transposons.

The PIWI-piRNA pathway is present in almost all animals in both male and female germ cells. But, for some reason, despite being one of the most widely used experimental animals, the mouse has little ovarian PIWI protein expression, and the piRNA pathway in the female germline is still not well understood. ”

That is why Siomi and his colleagues focused on the golden hamster, which has a PIWI protein called the PIWIL3, a protein absent in mice but expressed in other animal species, including humans.

“Unlike mice, which have long been used extensively in research, the golden hamster’s genome database was still incomplete. We began our research by analyzing their genome to build a new database and then studied what happens when we genetically modify hamsters that express PIWI and piRNA in both testes and ovaries so that they no longer express the PIWI gene. This process causes spermatogenesis to stop midway in the testes, just as in mice, and sperm is not formed, resulting in male infertility. We found that this was also the case in females, where seemingly normal eggs are formed but do not develop when fertilized by normal sperm.”

In functional egg formation, transposons are expressed to some extent during egg maturation. However, by eliminating the PIWI gene, which suppresses transposon expression, we can allow for their proliferation, leading to the failure of normal egg formation and female infertility, demonstrated for the first time in this study.

“I believe that this could be an important finding for humans in the future. Many couples want children but cannot have them due to infertility of unknown causes. In cases such as these, even though the father's sperm production and the mother's eggs appear normal, a mutation of the PIWI gene may be one cause of their inexplicable infertility. ”

In Part 2, Prof. Siomi explores new topics on how transposons are a key player in the diversity of species survival, despite their bad reputation. He also shares a message with aspiring researchers in the field.

Continued in Part 2