Tag Archives: #multicellular

How Does Unicellular Life Transition To Multicellular Life? (Biology)

Biologist Professor Lutz Becks and his team observe the genetic imprint of the surprisingly rapid transition from unicellular to multicellular life

How does unicellular life transition to multicellular life? The research team of Professor Lutz Becks at the Limnological Institute of the University of Konstanz has taken a major step forward in explaining this very complex process. They were able to demonstrate – in collaboration with a colleague from the Alfred Wegner Institute (AWI) – that the unicellular green algae Chlamydomonas reinhardtii, over only 500 generations, develops mutations that provide the first step towards multicellular life. This experimentally confirmed a theory on the origin of multicellular life, which says that the evolution of cell groups and the subsequent steps towards multicellularity can only take place when cell groups are both better at reproduction and more likely to survive than single cells. These findings have been published in the current edition of Nature Communications from 9 July 2021.

The experiment is based on the theory that multicellular organisms originally evolved from single cells and, in a first step, colonies of identical daughter cells form that do not separate after division. An important but so far experimentally untested condition of this general theory is that, at first, colonies with a higher probability of survival emerge. In a second step, these colonies then develop further to increased reproduction. Only then can the next steps towards specialization in somatic and germ cells follow. Lutz Becks, professor of aquatic ecology and evolution, and his team have experimentally tested the conditions that cause the transition from unicellularity to colony formation.

Colonies with identical daughter cells that do not separate after division. In the experiment, the colony was observed over 500 generations in the presence of a predator (rotifer Brachinous calyciflorus). The image shows the same colony after 0, 6, 12 and 18 hours. The cell marked by the arrow divides into eight daughter cells in the first 6 hours, which stick together after cell division instead of separating and swimming away as their ancestor in the experiment. © University of Konstanz

Too large for predators

As a condition for the development of colonies with a high probability of survival and simultaneously a high reproduction rate, the team created selection pressure by adding a predator to the sample with the algal cells, in this case a multicellular rotifer. Initially, an individual algal cell is unprotected against the predator. Mutations causing the cells to grow in colonies that stick together after cell division increase the probability of survival because predators can no longer, or at least not as easily, eat the colonies.

Video: The rotifer Brachinous calyciflorus eats single cells of the green alga Chlamydomonas reinhardtii. © University of Konstanz

Video: The rotifer Brachinous calyciflorus tries to eat a colony of the green alga Chlamydomonas reinhardtii, which, however, is too big for its mouth © University of Konstanz

The alga Chlamydomonas reinhardtii belongs to a group of algae in which different stages of evolutionary multicellularity can be found and which all descend from a unicellular ancestor. Consequently, the pre-requisites were met for observing the evolution of colonies in the experiment in real time. Ten different cell lines of the alga were isolated and grown in cultures. A predator was added to some, not to others, with all other experimental conditions being the same.

Cell specialization visible on the genome level
A closer look at the evolved cell properties after 500 generations revealed that colonies grew significantly more often in the media with predators and had a significantly higher reproductive rate than colonies growing without predators. Lutz Becks: “The distribution of colony types that survive and those that reproduce quickly fits exactly with the theory we tested. Not only have we shown that they exist, but also that they evolve repeatedly under certain conditions.”

This not only confirmed the underlying theory, but also proved that the evolutionary step happened very quickly. It takes about half a year for the required 500 generations to develop. What was surprising for the scientists was that the evolved adaptations of the cells were also reproducible at the genome level. “We had actually expected that the formation of colonies can be achieved by different mechanisms in the algal cells and we would therefore find different mutations. In fact, we have seen a very high level of repeatability. This suggests that the selection pressure has had a very targeted effect,” says Lutz Becks. 

Main image caption: Green alga Chlamydomonas reinhardtii growing on solid medium. For the experimental evolution study, we used 10 different strains of Chlamydomonas reinhardtii and grew them in liquid cultures with and without a predator for 6 months before we tested for evolutionary changes. © AG Becks

Reference: Bernardes, J.P., John, U., Woltermann, N. et al. The evolution of convex trade-offs enables the transition towards multicellularity. Nat Commun 12, 4222 (2021). https://doi.org/10.1038/s41467-021-24503-z

Provided by University of Konstanz

Oxygen And Multicellularity, A Complicated Relationship (Astronomy)

A study published in Nature Communications challenges the prevailing theory on the development of multicellular life forms on Earth, according to which the concentration of gas in the atmosphere played a crucial role in the evolution of large and complex organisms. The new findings instead highlight that oxygen would have behaved like a double-edged sword: providing significant metabolic benefits when abundant, but suppressing the evolution of large multicellular organisms in conditions of scarcity.

Scientists have long thought that at the basis of the transition from single-celled organisms to the first multicellular life forms was the increase in oxygen in the Earth’s atmosphere, which began 2.5 billion years ago with the so-called Great Oxygenation Event . This theory, called by the experts “ hypothesis of oxygen control”, Suggests that the transition from unicellular to multicellular life, in which single cells are able to cooperate with the typical mechanisms of more complex life forms, has strictly depended on the amount of oxygen available. Furthermore, the hypothesis predicts that with the increase in the concentration of oxygen in the atmosphere, the size of the multicellular organisms that populated the Earth also increased. According to a new study published this month in Nature Communications,  conducted by a team of researchers from the Georgia Institute of Technology in Atlanta (USA), this is not exactly the case.

Through laboratory experiments that used the unicellular yeast Saccharomyces cerevisiae as an animal model , and thanks to sophisticated evolutionary models, the researchers obtained important new information about the relationship between oxygenation of the early Earth and the emergence of large multicellular organisms. The results of the study suggest that the effect of oxygen on the evolution of multicellularity would not always have been positive, on the contrary: the initial oxygenation of the Earth’s atmosphere would have even severely limited the development of multicellular individuals, rather than selecting larger organisms and complex.

“The positive effect of oxygen on the evolution of multicellularity is dose-dependent: the first oxygenation of our planet would have strongly limited, and not promoted, the development of multicellular life forms”, says Ozan Gonensin Bozdag , researcher at the Georgia Institute of Technology and lead author of the study. “The positive effect of oxygen on the size of multicellular organisms was realized only when it reached high levels.”

Left, photograph obtained by confocal microscopy showing several multicellular clusters of yeast. On the right, the enlargement of a single cluster with the typical shape of a snowflake. Credits: Shane Jacobeen, Will Ratcliff, and Peter Yunker, Georgia Institute of Technology

As anticipated, the researchers used as a model the single-celled yeast Saccharomyces cerevisiae , a eukaryotic microorganism capable of obtaining energy both in the presence of oxygen through respiration and in its absence through fermentation – the chemical process that we have been using for centuries to produce bread. wine and beer. But the one used in the study is not the wild strain – or wild type , as they say in the jargon – but a mutant in the ability to divide and reproduce, and for this reason able to form a multicellular “individual” whose shape resembles the flakes of snow, hence the name snowflake yeastby which these cell clusters are called. After selecting around 800 generations of multicellular forms of this microorganism, the researchers examined their ability to evolve into larger multicellular aggregates by subjecting them to different concentrations of oxygen.

“Large sizes evolved easily when our yeasts lacked or had abundant oxygen, but not when oxygen was present at low levels,” explains Will Ratcliff , also a researcher at the Georgia Institute of Technology and co-founder. author of the study.

These results can be explained by a divergent oxygen-mediated selection mechanism that acts on the size of the organism. An outcome, also confirmed by mathematical models, of almost universal evolutionary and biophysical compromises.

“We have worked hard to show that this is actually a fairly predictable and understandable consequence of the fact that oxygen, when limited, acts as a resource if the cells that can use it get a huge metabolic benefit from it,” he adds. Ratcliff. “When oxygen is in short supply, it can’t spread much, so there’s an evolutionary incentive that leads multicellular organisms to be small in size, which allows most of their constituent cells to access oxygen. This limitation does not exist when oxygen is simply not present, or when there is enough to diffuse much deeper into the tissues [ in the internal cells of large multicellular clusters, ed. ] ».

This study, the researchers continue, not only challenges the oxygen control hypothesis, but helps us understand why the world of multicellular organisms evolved so little in the billion years after the Great Oxygenation Event. In this period – which geologists call the ” Boring Billion ” ( Boring Billion , in English), or the Middle Ages of the Earth – oxygen in the atmosphere was present, but its low levels, rather than selecting larger and more complex organisms , have exerted evolutionary pressure that has pushed multicellular organisms to remain relatively small and simple.

“In previous works, the relationship between oxygen and size of multicellular organisms has been studied mainly through the physical principles of gas diffusion,” emphasizes Bozdag. “This reasoning is fundamental, but when we study the origin of the complex multicellular life forms on our planet it is necessary to include the principles of Darwinian evolution as well,” concludes the researcher. Being able to grow microorganisms through numerous generations has made it possible to achieve this goal.

Featured image: Artistic illustration of the primeval Earth. Credits: Nasa

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Provided by INAF

Did Earth’s Early Rise in Oxygen Help Multicellular Life Evolve? (Earth Science)

A new study is taking the air out of a hypothesis linking early Earth’s oxygenation to larger, more complex organisms. Georgia Tech researchers report a more complex effect

Scientists have long thought that there was a direct connection between the rise in atmospheric oxygen, which started with the Great Oxygenation Event 2.5 billion years ago, and the rise of large, complex multicellular organisms.

That theory, the “Oxygen Control Hypothesis,” suggests that the size of these early multicellular organisms was limited by the depth to which oxygen could diffuse into their bodies. The hypothesis makes a simple prediction that has been highly influential within both evolutionary biology and geosciences: Greater atmospheric oxygen should always increase the size to which multicellular organisms can grow.

It’s a hypothesis that’s proven difficult to test in a lab. Yet a team of Georgia Tech researchers found a way — using directed evolution, synthetic biology, and mathematical modeling — all brought to bear on a simple multicellular lifeform called a ‘snowflake yeast’. The results? Significant new information on the correlations between oxygenation of the early Earth and the rise of large multicellular organisms — and it’s all about exactly how much O2 was available to some of our earliest multicellular ancestors.

“The positive effect of oxygen on the evolution of multicellularity is entirely dose-dependent — our planet’s first oxygenation would have strongly constrained, not promoted, the evolution of multicellular life,” explains G. Ozan Bozdag, research scientist in the School of Biological Sciences and the study’s lead author. “The positive effect of oxygen on multicellular size may only be realized when it reaches high levels.”

“Oxygen suppression of macroscopic multicellularity” is published in the May 14, 2021 edition of the journal Nature Communications. Bozdag’s co-authors on the paper include Georgia Tech researchers Will Ratcliff, associate professor in the School of Biological Sciences; Chris Reinhard, associate professor in the School of Earth and Atmospheric Sciences; Rozenn Pineau, Ph.D. student in the School of Biological Sciences and the Interdisciplinary Graduate Program in Quantitative Biosciences (QBioS); along with Eric Libby, assistant professor at Umea University in Sweden and the Santa Fe Institute in New Mexico.

Directing yeast to evolve in record time

“We show that the effect of oxygen is more complex than previously imagined. The early rise in global oxygen should in fact strongly constrain the evolution of macroscopic multicellularity, rather than selecting for larger and more complex organisms,” notes Ratcliff.

“People have long believed that the oxygenation of Earth’s surface was helpful — some going so far as to say it is a precondition — for the evolution of large, complex multicellular organisms,” he adds. “But nobody has ever tested this directly, because we haven’t had a model system that is both able to undergo lots of generations of evolution quickly, and able to grow over the full range of oxygen conditions,” from anaerobic conditions up to modern levels.

The researchers were able to do that, however, with snowflake yeast, simple multicellular organisms capable of rapid evolutionary change. By varying their growth environment, they evolved snowflake yeast for over 800 generations in the lab with selection for larger size.

The results surprised Bozdag. “I was astonished to see that multicellular yeast doubled their size very rapidly when they could not use oxygen, while populations that evolved in the moderately oxygenated environment showed no size increase at all,” he says. “This effect is robust — even over much longer timescales.”

Size — and oxygen levels — matter for multicellular growth

In the team’s research, “large size easily evolved either when our yeast had no oxygen or plenty of it, but not when oxygen was present at low levels,” Ratcliff says. “We did a lot more work to show that this is actually a totally predictable and understandable outcome of the fact that oxygen, when limiting, acts as a resource — if cells can access it, they get a big metabolic benefit. When oxygen is scarce, it can’t diffuse very far into organisms, so there is an evolutionary incentive for multicellular organisms to be small — allowing most of their cells access to oxygen — a constraint that is not there when oxygen simply isn’t present, or when there’s enough of it around to diffuse more deeply into tissues.”

Ratcliff says not only does his group’s work challenge the Oxygen Control Hypothesis, it also helps science understand why so little apparent evolutionary innovation was happening in the world of multicellular organisms in the billion years after the Great Oxygenation Event. Ratcliff explains that geologists call this period the “Boring Billion” in Earth’s history — also known as the Dullest Time in Earth’s History, and Earth’s Middle Ages — a period when oxygen was present in the atmosphere, but at low levels, and multicellular organisms stayed relatively small and simple.

Bozdag adds another insight into the unique nature of the study. “Previous work examined the interplay between oxygen and multicellular size mainly through the physical principles of gas diffusion,” he says. “While that reasoning is essential, we also need an inclusive consideration of principles of Darwinian evolution when studying the origin of complex multicellular life on our planet.” Finally being able to advance organisms through many generations of evolution helped the researchers accomplish just that, Bozdag adds.

This work was supported by National Science Foundation grant no. DEB-1845363 to W.C.R, NSF grant no. IOS-1656549 to W.C.R., NSF grant no. IOS-1656849 to E.L., and a Packard Foundation Fellowship for Science and Engineering to W.C.R. C.T.R. and W.C.R. acknowledge funding from the NASA Astrobiology Institute.

Featured image: Artist rendering of early Earth © NASA

Reference: Bozdag, G.O., Libby, E., Pineau, R. et al., “Oxygen suppression of macroscopic multicellularity.” (Nat Commun 12, 2838 2021). https://doi.org/10.1038/s41467-021-23104-0

Provided by Georgia Institute of technology

Research Shows We’re Surprisingly Similar To Earth’s First Animals (Earth Science)

Today’s humans share genes with oceanic creatures missing heads 

The earliest multicellular organisms may have lacked heads, legs, or arms, but pieces of them remain inside of us today, new research shows.

According to a UC Riverside study, 555-million-year-old oceanic creatures from the Ediacaran period share genes with today’s animals, including humans. 

“None of them had heads or skeletons. Many of them probably looked like three-dimensional bathmats on the sea floor, round discs that stuck up,” said Mary Droser, a geology professor at UCR. “These animals are so weird and so different, it’s difficult to assign them to modern categories of living organisms just by looking at them, and it’s not like we can extract their DNA — we can’t.”

Fossil of Dickinsonia, an Ediacaran-era animal. (Mary Droser/UCR)

However, well-preserved fossil records have allowed Droser and the study’s first author, recent UCR doctoral graduate Scott Evans, to link the animals’ appearance and likely behaviors to genetic analysis of currently living things. Their research on these links has been recently published in the journal Proceedings of the Royal Society B.

For their analysis, the researchers considered four animals representative of the more than 40 recognized species that have been identified from the Ediacaran era. These creatures ranged in size from a few millimeters to nearly a meter in length.

Kimberella were teardrop-shaped creatures with one broad, rounded end and one narrow end that likely scraped the sea floor for food with a proboscis. Further, they could move around using a “muscular foot” like snails today. The study included flat, oval-shaped Dickinsonia with a series of raised bands on their surface, and Tribrachidium, who spent their lives immobilized at the bottom of the sea.

Also analyzed were Ikaria, animals recently discovered by a team including Evans and Droser. They were about the size and shape of a grain of rice, and represent the first bilaterians — organisms with a front, back, and openings at either end connected by a gut. Evans said it’s likely Ikaria had mouths, though those weren’t preserved in the fossil records, and they crawled through organic matter “eating as they went.”

Paleontologist Scott Evans studying fossils in the Australian outback. © Droser Lab/UCR

All four of the animals were multicellular, with cells of different types. Most had symmetry on their left and right sides, as well as noncentralized nervous systems and musculature. 

Additionally, they seem to have been able to repair damaged body parts through a process known as apoptosis. The same genes involved are key elements of human immune systems, which helps to eliminate virus-infected and pre-cancerous cells. 

These animals likely had the genetic parts responsible for heads and the sensory organs usually found there. However, the complexity of interaction between these genes that would give rise to such features hadn’t yet been achieved. 

“The fact that we can say these genes were operating in something that’s been extinct for half a billion years is fascinating to me,” Evans said. 

The work was supported by a NASA Exobiology grant, and a Peter Buck postdoctoral fellowship.      
Going forward, the team is planning to investigate muscle development and functional studies to further understand early animal evolution.

“Our work is a way to put these animals on the tree of life, in some respects,” Droser said. “And show they’re genetically linked to modern animals, and to us.”

Featured image: Recreation of Ediacaran sealife displayed at the Smithsonian Institution. © Ryan Somma

Reference: Scott D. Evans, Mary L. Droser and Douglas H. Erwin, “Developmental processes in Ediacara macrofossils”, Proceedings of the Royal Society B,
Published: 24 February 2021. https://doi.org/10.1098/rspb.2020.3055

Provided by University of California Riverside

Model Of Multicellular Evolution Overturns Classic Theory (Biology)

Physicists and biologists challenge a prevailing evolutionary theory that single-celled organisms can only evolve to become multicellular life forms if doing so increases their overall productivity.

Cells can evolve specialised functions under a much broader range of conditions than previously thought, according to a study published today in eLife.

The findings, originally posted on bioRxiv*, provide new insight about natural selection, and help us understand how and why common multicellular life has evolved so many times on Earth.

Life on Earth has been transformed by the evolution of multicellular life forms. Multicellularity allowed organisms to develop specialised cells to carry out certain functions, such as being nerve cells, skin cells or muscle cells. It has long been assumed that this specialisation of cells will only occur when there are benefits. For example, if by specialising, cells can invest in two products A and B, then evolution will only favour specialisation if the total output of both A and B is greater than that produced by a generalist cell. However, to date, there is little evidence to support this concept.

“Rather than each cell producing what it needs, specialised cells need to be able to trade with each other. Previous work suggests that this only happens as long as the overall group’s productivity keeps increasing,” explains lead author David Yanni, PhD student at Georgia Institute of Technology, Atlanta, US. “Understanding the evolution of cell-to-cell trade requires us to know the extent of social interactions between cells, and this is dictated by the structure of the networks between them.”

To study this further, the team used network theory to develop a mathematical model that allowed them to explore how different cell network characteristics affect the evolution of specialisation. They separated out two key measurements of cell group fitness – viability (the cells’ ability to survive) and fecundity (the cells’ ability to reproduce). This is similar to how multicellular organisms divide labour in real life – germ cells carry out reproduction and somatic cells work to ensure the organism survives.

In the model, cells can share some of the outputs of their investment in viability with other cells, but they cannot share outputs of efforts in reproduction. So, within a multicellular group, each cell’s viability is the return on its own investment and that of others in the group, and gives an indication of the group’s fitness.

By studying how the different network structures affected the group fitness, the team came to a surprising conclusion: they found that cell specialisation can be favoured even if this reduces the group’s total productivity. In order to specialise, cells in the network must be sparsely connected, and they cannot share all the products of their labour equally. These match the conditions that are common in the early evolution of multicellular organisms – where cells naturally share viability and reproduction tasks differently, often to the detriment of other cells in the group.

“Our results suggest that the evolution of complex multicellularity, indicated by the evolution of specialised cells, is simpler than previously thought, but only if a few certain criteria are met,” concludes senior author Peter Yunker, Assistant Professor at Georgia Institute of Technology, Atlanta, US. “This contrasts directly to the prevailing view that increasing returns are required for natural selection to favour increased specialisation.”

References: David Yanni, Shane Jacobeen, Pedro Márquez-Zacarías, Joshua S Weitz, William C. Ratcliff, Peter J. Yunker, “Topological constraints in early multicellularity favor reproductive division of labor”, bioRxiv 842849; doi: https://doi.org/10.1101/842849 link: https://www.biorxiv.org/content/10.1101/842849v1

Provided by ELIFE

Researchers Turn To Trees To Determine If Multicellular Life On Exoplanets Exist (Biology)

Is there life outside our planet?

The age-old question has long been asked by scientists and researchers without much progress in finding the answer.

There have been more than 4,200 exoplanets discovered outside our solar system, and while past techniques were developed to test for life on exoplanets, none of which tested for complex, non-technological life like vegetation. Now, space telescopes may soon be able to directly view these planets—including one within the habitable zone of the Earth’s nearest star neighbor. With the help of these telescopes and a team of researchers in informatics and astronomy at Northern Arizona University, an answer to this question might not be so out of this world.

Funded by a NASA Habitable Worlds grant, a team of researchers, which includes Chris Doughty, David Trilling and Ph.D. student Andrew Abraham, published a study in the International Journal of Astrobiology that develops and tests a technique to determine whether specifically multicellular or complex-but-not-technological life can be uniquely detected outside the solar system.

In an attempt to find some answers, the team turned to one of Earth’s most common multicellular life forms—trees. More specifically, their shadows.

Graphic of conceptual design of the team’s shadow theory. Credit: Northern Arizona University

“Earth has more than three trillion trees, and each casts shadows differently than inanimate objects,” said Doughty, lead author on the paper and assistant professor in the School of Informatics, Computing, and Cyber Systems. “If you go outside at noon, almost all shadows will be from human objects or plants and there would be very few shadows at this time of day if there wasn’t multicellular life.”

The team hypothesizes that abundant upright photosynthetic multicellular life (trees) will cast shadows at high sun angles, distinguishing them from single cellular life. Therefore, using future space telescopes to observe the types of shadows cast should, in theory, determine if there are similar life forms on exoplanets.

“The difficult part is that any future space telescope will likely only have a single pixel to determine if life exists on that exoplanet,” said Abraham, who worked closely with Doughty on the study. “So, the question becomes: Can we detect these shadows indicating multicellular life with a single pixel?”

With just one pixel to work with, the team had to make sure that the shadows detected in these telescopes were conclusively multicellular life, not other exoplanet features like craters.

Drones were used to capture crater shadows at the replica moon landing site north of Flagstaff.

“It was suggested that craters might cast shadows similar to trees, and our idea would not work,” said Trilling, associate professor of astronomy. “So, we decided to look at the replica moon landing site in northern Arizona where the Apollo astronauts trained for their mission to the moon.”

Drones were used at different times of the day to determine that craters did in fact cast shadows differently than trees.

The researchers then turned to imaging to determine if their theory would work on a large scale. By using the POLDER (Polarization and Directionality of Earth’s Reflectance) satellite, the team was able to observe the shadows on Earth at different sun angles and times of day. The resolution was reduced to mimic what Earth would look like as a single pixel to a distant observer as it rotates around the sun. Then, the team compared this to similar data from Mars, the moon, Venus and Uranus to see if Earth’s multicellular life was unique.

The team found that on parts of the planet where trees were in abundance, like the Amazon basin, multicellular life could be distinguished, but when it came to observing the planet as a whole as a single pixel, distinguishing multicellular life was difficult.

However, the potential that observing shadows brings to the conversation of life on exoplanets could be closer than scientists and researchers have ever been before. Doughty believes the technique remains valid in theory—a future space telescope could rely on the shadows found in a single pixel.

“If each exoplanet was only a single pixel, we might be able to use this technique to detect multicellular life in the next few decades,” he said. “If more pixels are required, we may have to wait longer for technological improvements to answer whether multicellular life on exoplanets exists.”

References: Doughty, C., Abraham, A., Windsor, J., Mommert, M., Gowanlock, M., Robinson, T., & Trilling, D. (2020). Distinguishing multicellular life on exoplanets by testing Earth as an exoplanet. International Journal of Astrobiology, 1-8. doi:10.1017/S1473550420000270

Provided by Northern Arizona University

How To Make A Replication Origin In Multicellular Eukaryotes? (Biology)

Loading of replicative helicases onto DNA is a key event during the initiation of chromosomal DNA replication. It takes place at specific chromosomal regions termed origins and is facilitated by the ORC protein complex. By resolving the cryo-EM structures of DNA-bound ORC, researchers from the Bleichert group (now at Yale) broaden our understanding of how DNA replication is initiated in animals.

Accurate replication of chromosomal DNA is essential for the survival and propagation of living organisms. Prior to cell division, many different proteins work together and duplicate genomes by semi-conservative replication so that copied chromosomes can be segregated into daughter cells. Genome integrity is sustained by highly efficient and accurate DNA replication exactly once per cell cycle. Failure to replicate DNA precisely can alter gene copy number and chromosome ploidy, which can give rise to genomic instability and a variety of human diseases.

Eukaryotic DNA replication initiation relies on the origin recognition complex (ORC), a DNA-binding ATPase that loads the Mcm2–7 replicative helicase onto replication origins. In yeast, origins are defined by a conserved consensus sequence that is recognized by ORC. By contrast, how replication origins are defined in animals (or metazoans) has remained unclear, but chromatin cues and local DNA structure are thought to help mediate the recognition of the origins. In a new paper, researchers reported cryo-electron microscopy (cryo-EM) structures of DNA-bound Drosophila ORC with and without the co-loader Cdc6.

These structures reveal that Orc1 and Orc4 constitute the primary DNA binding site in the ORC ring and cooperate with the winged-helix domains to stabilize DNA bending. A loop region near the catalytic Walker B motif of Orc1 directly contacts DNA, allosterically coupling DNA binding to ORC’s ATPase site.

Correlating structural and biochemical data showed that DNA sequence modulates DNA binding and remodeling by ORC, and that DNA bending promotes Mcm2–7 loading in vitro. Together, these findings explain the distinct DNA sequence-dependencies of metazoan and S. cerevisiae initiators in origin recognition and support a model in which DNA geometry and bendability contribute to Mcm2–7 loading site selection in metazoans.

References: Schmidt, J.M., Bleichert, F. Structural mechanism for replication origin binding and remodeling by a metazoan origin recognition complex and its co-loader Cdc6. Nat Commun 11, 4263 (2020). https://doi.org/10.1038/s41467-020-18067-7 link: https://www.nature.com/articles/s41467-020-18067-7