Nicola Silva has long focused his research on the inheritance of chromosomes from one generation to the next, with an emphasis on the meiotic phase during which sex cells are formed. At the Department of Biology at the Faculty of Medicine of Masaryk University, he discovered a protein that regulates the formation of the so-called synaptonemal complex—a protein “zipper” that plays a key role in stabilizing chromosome pairing. BRA-2 ensures that synapsis only ensues after chromosomes have correctly found their homologous partner, making this factor the first being described with this function. Its discovery, published in the journal Nature Communications, provides a remarkable lead for scientists studying infertility.
Meiosis and mitosis are terms many people recall from high school biology—can you explain them a bit more?
They are both ways cells divide. Mitosis occurs in normal body, or somatic, cells—skin, muscle, and so on. Meiosis, on the other hand, forms sex cells, meaning eggs and sperm. Both processes work with DNA—that is, with genetic information—but they proceed differently. In mitosis, the cell copies its DNA before dividing, and the two new cells end up with exactly the same genetic material. Meiosis is more complex. DNA is also copied at the start, but then two rounds of division occur. So instead of two, we get four new cells, each containing only half the original genetic information. For example, humans have 46 chromosomes, or 23 pairs—half from the mother’s egg, half from the father’s sperm. When fertilization occurs, the egg and sperm fuse, and the DNA is restored to a complete set. For this to happen correctly, the DNA must be divided evenly; the resulting cells must not contain the wrong number of chromosomes. A series of mechanisms ensures this even distribution— one of our focuses is how chromosome synapsis is accomplished.
Why is that pairing is so important?
Each of your cells contains one chromosome from your father and one from your mother—so-called parental chromosomes. These are very similar, but not identical. The two must find each other within the fairly vast environment of the cell nucleus in order to pair up. How this happens is still one of the major unanswered questions in our field. We now have tools that let us observe chromosome movement inside the nucleus. When the chromosomes do find each other, they pair and their association is stabilized by the synaptonemal complex, a protein structure that appears only in meiosis. Well, it can appear in mitotic cells too, but only in tumors—many types of cancer express meiotic proteins. But that’s another story...
How should we picture the synaptonemal complex?
Like a zipper—it literally looks like one under the microscope. By “zipping” the chromosomes together, it allows them to exchange information, which is crucial in meiosis because it generates genetic variation. This exchange happens through what’s called homologous recombination—essentially, a physical swap of DNA segments between two chromosomes. It’s how new combinations and variations arise, which is why we humans are so similar, yet each entirely unique. This information exchange is made possible by the synaptonemal complex.
“As a species, humans are not the best at doing meiosis. Sometimes I don’t understand how we evolved to this level – our method of producing sex cells is remarkably error-prone.”
Nicola Silva
What is your main research interest?
I’ve long been interested in genome stability and repair of DNA damage. When DNA structure is disrupted, the cell activates a series of emergency responses. Sometimes only one DNA strand is damaged, in worse cases both. In mitosis, damage can occur as a mistake caused by normal cell metabolism, or it can be due to genotoxic substances, poisons, alcohol, radiation, or chemotherapy—chemotherapy aims at inducing genetic instability in cancer cells, which lack some repair systems and thus die. Healthy cells are also damaged by such treatment, but they can repair themselves—or “commit suicide.”
How is that related to meiosis?
In meiosis, DNA breaks occur on purpose, so that chromosomes can exchange information. The breaks are then repaired. That’s the essence of homologous recombination. In meiotic cells, these junctions are called crossovers, and the physical points where chromosomes cross are called chiasmata—from the Latin for “crosses,” because the chromosomes literally cross over at these points. Without chiasmata, the chromosomes wouldn’t separate properly. Such uneven division can result in sex cells that are nonviable or may cause birth defects.
Your recent study focused mainly on the synaptonemal complex?
Yes, but more or less by accident. I’ve always been more interested in homologous recombination and how DNA breaks are formed and repaired during meiosis—there are many pathways involved. Similarly, there are many reasons why chromosomes fail to form proper crossovers. The environment of the nucleus is rather messy, and during meiosis it gets reorganized—chromosomes move closer until two of them face each other, and the synaptonemal complex forms between them. At that point, the zipper essentially starts closing from one end to the other.
And you’ve now discovered how this zipping happens, and the roles of BRA-2 and HIM-17—one of which you newly identified, correct?
Yes. HIM-17 has been known to be important for generating double-strand DNA breaks but was never found to be involved in promoting pairing and synapsis. BRA-2 however, was discovered by us. When I started my research group, we used CRISPR – genetic scissors – to create functional lines of model organisms with various versions of factors needed for DNA breaks. We used them to identify new proteins that might influence these breaks.
How do you identify such proteins?
These lines we made, contain small pieces of proteins (tags) fused to proteins of interest, that can be bound by commercially available antibodies. We enrich for a selected protein by using “traps” that bind these tags, so that we can ideally separate our selected player and at the same time identify the proteins that are bound to it. Then we try to identify them using mass spectrometry. That’s how we enriched HIM-17 and pulled down BRA-2 along with it. The two interact, though the mechanism is still unknown.
What makes your approach so advanced that you were the first to do this?
For the pull-downs to work efficiently, pure meiotic extracts are key. If the quality is poor, you won’t find anything. We work with the model system Caenorhabditis elegans, a small worm, very cute, and great for studying meiosis. What would take us years with mouse models we can do in weeks with C. elegans. It’s a simple model, but it includes all the key signaling and regulatory pathways that also function in humans. Several scientists have won Nobel Prizes thanks to work on these worms. We’ve mastered working with them, and colleagues from many countries keep reaching out for collaboration.
Are HIM-17 and BRA-2 found in humans too?
HIM-17 isn’t—it doesn’t have a human ortholog. Orthologs are genes that come from a common evolutionary ancestor and often serve a similar function in different species – like in worms and humans – even if the sequences differ. But BRA-2 does have a human ortholog, called ZMYND11, although it hasn’t been studied much yet. There are slight differences, but the core protein domain responsible for function is the same in humans and C. elegans. I expect researchers working on meiosis in mammals will now start looking more closely at BRA-2.
And you’ve already described how HIM-17 and BRA-2 complement each other?
Yes. HIM-17 was known to be important for breaks, but no one had shown its role in chromosome pairing and synapsis. Our study is the first to describe that. Most researchers studying the synaptonemal complex focus on its structure – we instead looked at how it’s regulated and how it forms. How its parts, already described by others, come together. BRA-2 is not a structural part of the complex, but it regulates its elongation. The synaptonemal complex is like a kind of glue that, if unregulated, could stick together non-homologous chromosomes – and that would be a disaster. Chromosomes must find their exact homologs – one from the mother, one from the father. There has to be a mechanism ensuring the complex only polymerizes between true homologs. BRA-2 is the first protein we’ve shown to be essential as a factor that stimulates this polymerization. In a way, it gives chromosomes “permission” to form the complex – verifying that they’re truly homologous.
What happens if these two proteins don’t function properly – and what causes that?
If BRA-2 is missing, only a very short section of the complex forms – often none. We also found that HIM-17 isn’t strictly necessary for the complex to form – if it’s absent, BRA-2 can partially take over its role. They function rather in parallel. But if both are missing, the complex doesn’t form at all, and the chromosomes can’t pair.
If such errors occur, it leads to infertility…
Yes, because sex cells either don’t form at all or form incorrectly – they have the wrong number of chromosomes. In worms, the mother may lay eggs, but they aren’t viable.
What could be the effects in humans?
Scientists keep discovering new mutations that negatively impact fertility – many of them linked to the synaptonemal complex. As someone who studies meiosis, I can say: as a species, humans are not the best at doing meiosis. Sometimes I don’t understand how we evolved to this level – our method of producing sex cells is remarkably error-prone. And that’s not even accounting for how long we can keep producing them. Men produce sex cells throughout life, but in women, this period is limited. As women age, chromosome stability declines, which leads to miscarriages or trisomies. In recent years, age has been shown to affect men’s fertility too.
How does meiosis differ between men and women?
It’s incredibly complex in women – it starts during embryonic development with the first meiotic division, and then the cells “sleep” for years until puberty. That’s why age matters so much for female fertility – the egg still forms, but its quality declines over time. In men, meiosis happens continuously throughout life. If there’s a defect in the synaptonemal complex, sperm still form, but they’re not viable.
How can other researchers build on your findings and move them closer to mammals?
In humans, the BRA-2 ortholog ZMYND11 has been linked to autism, mental retardation, and learning disorders. In mice, it's been associated with reduced fertility. We’ve now added another piece to the puzzle. Of course, BRA-2 needs to be verified in other models – some organisms may tolerate the mutation and live, albeit sterile; others may die in the womb. Using CRISPR, we can create targeted gene mutations and observe whether they have similar effects on sex cell development. Though with mice, that will take much longer and cost much more than with worms.
Is there already a potential practical application of your discovery?
Today, it’s estimated that about one in five couples has trouble conceiving. At fertility clinics, they do whole-genome sequencing and analyze the DNA – but they only look for known mutations. In over half of these cases, the genome seems perfectly normal. That’s called idiopathic infertility – when the cause is unknown. If we can find a new protein that might be the cause, it becomes a target in diagnostic tests. In cases like ours, we can focus on a specific mechanism. In worms, it’s influenced by BRA-2; in humans, it could be ZMYND11 or a related protein.
Which will take many more years to verify…
Science is about following clues – one after the other, building on them. But it’s also about enormous amounts of data that make no sense at all. You can spend ages trying to understand them, and only later realize what they mean – when someone comes along with a new study. Maybe like ours.
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