糖心视频

When people think of DNA, they usually think of genes, the parts that code for proteins and drive inherited traits. But there's a whole lot of DNA beyond genes that we are just starting to understand. One such mysterious region is the centromere, the area where chromosomes narrow, which helps them divide properly.

This region is what my lab has been studying since our founding in 2021 at the University of Rome Sapienza, in Italy鈥攁lthough my fascination with centromeres began much earlier, when I was a student in Cambridge nearly two decades ago, studying how mitotic cells respond to DNA damage.

My interest in human centromeres deepened during my 10 years as a research scientist at Rockefeller University, where I began uncovering an interesting feature of centromeric DNA that had been largely overlooked: its inherent instability. This was just one of the many paradoxes centromeres embody: How can such a fast-evolving, unstable DNA sequence maintain the conserved and essential function in chromosome segregation?

To make matters more complicated, centromeres were considered for decades to be the "black boxes" of the genome: repetitive, hard to sequence, nearly impossible to assemble. To this day, it's still challenging to tell whether you've assembled them correctly, something my lab and others are actively working on.

So the long stretches of repetitive centromeric DNA remained mostly ignored. And that's precisely what drew me to them. I've always been drawn to the unknown, especially things deemed experimentally impossible. During my Ph.D., many labs were studying DNA repair, but what happened in mitosis was not widely explored because the mitotic phase was too short, tricky to catch and difficult to work with experimentally. With my passion for discovery fueled by challenge, centromeres are arguably the ultimate challenge in the study of our genome.

What follows is a personal recount of the journey behind our study, recently in Science, where we describe how we were able to numerically and visually represent centromere DNA for the first time, essentially cracking a hidden layer of genome architecture. It opens a new way of reading DNA, beyond the linear string of A's, T's, G's, and C's.

I often explain it like this: DNA is like an instruction manual inside the cell. Imagine that manual divided into chapters, with each chapter being copied as the cell divides. These chapters, known as chromosomes, need to remain linked until the cell is ready to split. The centromere serves as the anchor point in the center where the cell's control system grips and manages duplication. We discovered that the centromere actually has its own unique barcode鈥攍ike a serial number stamped onto each chapter's binding. Until recently, no one had been able to read these barcodes. Now we can.

Even more strikingly, each chromosome has its own specific barcode and that barcode remains consistent across individuals. This suggests an evolutionarily conserved architecture, something ancient and fundamental about how our genome is organized. Indeed, we found similar patterns in primates.

That kind of conservation gives us a powerful new way to compare the "bindings" of DNA between individuals, species, and even in disease. Just like scanning a barcode reveals key information about a product, we can now imagine "scanning" centromeres to learn about genome evolution, disease risk, and chromosomal behavior in cancer and other disorders.

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This journey began in 2020, at the height of the pandemic. I had just returned to Italy from New York and was pregnant with my third child. Starting a lab under those conditions wasn't easy, many said it was the worst possible time, but I was determined to build an international team focused on centromeres, the long-overlooked frontier of the human genome.

That's when Luca Corda, first author on the paper, reached out asking to join the lab. He was my very first student. I proposed a project titled The Missing Genome, referring to the unresolved gaps left in our official human genome reference, especially around centromeres, at the time

In the lab, we were just obtaining long reads of centromeric DNA for the first time, and with the team we started to "walk" along these sequences with the same curiosity and awe I imagine an astronaut might feel on a new planet. But, exploring the long stretches of repetitive letters, I quickly realized that鈥攋ust like must have been on the lunar surface鈥攚ithout landmarks, it was almost impossible to find a way to orient yourself.

Having lived in New York for a decade, I likened it to walking the streets of the city鈥攜ou need street numbers to know where you are going. We realized we could use short, repeating motifs as markers and measure the distances between them. Just like restriction digestion enzymes cut DNA into fragments of different sizes, measuring distances between the repeating markers gave us a kind of internal coordinate system, a way to navigate the centromere and create a numerical representation of each chromosome.

That insight led to our first "eureka moment": the discovery of a barcode system embedded within centromeres, unique to each chromosome. The second breakthrough came when we realized that the barcodes weren't changing, but they showed up consistently in different people. At the time, there were only a handful of human genomes assembled and released, yet we found the same barcodes in them. To convince ourselves further, we embarked on another major challenge for the lab: assemble a human diploid genome at chromosome-level entirely in a single lab鈥攎y lab in Italy!

Low and behold, even in , there was the same centromeric barcode for each chromosome present in both haplotypes! This was unexpected. We knew that centromeric DNA is highly variable, not just across people, but even between the maternal and paternal haplotypes of the same chromosome.

I like to describe centromeres as our genetic "last names" or "family names," inherited distinctly from each parent, while the rest of the genome mixes and reshuffles to make us, a new unique individual. These "signatures" reflect our ancestral origins. Yet, despite the variability in sequence, the underlying barcode structure was preserved.

To analyze these patterns systematically, Luca built what we now call the GCP. At first it was a joking acronym from our initials, but it's now formally known as the Genomic Centromere Profiling pipeline鈥攑ublicly available on our Giunta lab GitHub.

The GCP is a way to make our discovery useful for the wider scientific community to study centromere and human DNA using a different approach than looking at sequences. GCP lets us annotate the DNA, decode it into barcodes, color profile it and compare the distance values across individuals.

Suddenly, we weren't just looking at repetitive DNA, we were seeing the hidden structure inside it. And that opened the door to yet another surprising finding, something else that extended beyond centromeres.

We found that the centromeric motif we used to generate these barcodes wasn't limited to the centromere as previously thought. It appeared along the arms of chromosomes too, in an organized position and orientation. This pattern gave rise to a new concept: the Human Centeny Map.

"Centeny" is a word we coined to describe this motif-based positional organization across the genome. It's inspired by "synteny," which refers to the conservation of gene order between species. But instead of genes, centeny uses a single centromeric motif, its orientation and spacing, to perform comparative genomics. The Human Centeny Map is a kind of in silico cytogenetic map. It's like chromosome banding, but done computationally and at a different level of resolution.

Our findings offer a way of looking at human DNA through a new lens鈥攂eyond just sequences and genes, with insights into genome structure, organization, and evolution鈥攁nd finally bringing centromeres out of the darkness and into focus鈥攗nder a new light.

The work is part of a broader effort within the Giunta Lab, supported by the Italian Cancer Research Foundation (AIRC) and more recently by the European Research Council (ERC), to investigate the role of centromeres in cancer and other genetic diseases. For more than 50 years, the field has focused on genes, and rightly so. But now, we're entering a new phase.

With today's sequencing and computational technologies, we can finally explore all parts of the genome, including the repetitive, the unstable, the "unreadable." Over the next decade, I envision the shift from genetics to genomics to continue. That's where many important questions鈥攁nd answers鈥攎ay lie.

Our work on centromere barcodes and centeny is just one part of that shift. There's still so much we don't know about how centromeres are shaped and how chromosomes are organized, how they evolve, how they go awry in disease. But we now have a language (including those at our fingertips with exciting new AI-driven tools like Alpha-genome!)鈥攁nd roadmaps like centeny and our barcodes, to start asking new questions.

This story is part of , where researchers can report findings from their published research articles. for information about Science X Dialog and how to participate.

Simona Giunta is Associate Professor of Human Genomics & Head of the Laboratory of Genome Evolution at the University of Rome Sapienza. With research experience spanning three continents, she has established a niche in human centromere mutagenesis, building on her expertise in genome stability and chromosome dynamics. The Giunta Lab employs innovative multidisciplinary approaches from long-read sequencing to super-resolution imaging to investigate centromere instability in human diseases. Simona earned her Ph.D. at the University of Cambridge, followed by a UICC Fellowship at CSIRO (Australia). After a decade as Research Scientist at the Rockefeller University (USA), she received the Rita Levi-Montalcini, Marie Curie Fellowship, and AIRC Start-Up Grant to establish her lab in back in Italy. Among her many accolades and awards stands out the prestigious ERC grant to study human centromere variation. Simona is a passionate advocate for science communication and gender equality in STEM.