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Complete X and Y chromosome sequences of living great ape species determined

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Complete X and Y chromosome sequences of living great ape species determined


Newly generated, complete “end-to-end” reference genomes for the sex chromosomes of five great ape species and one lesser ape species — produced by an international collaborative team led by researchers at Penn State, the National Human Genome Research Institute and the University of Washington — highlight extremely rapid changes on the male-specific Y chromosome among ape species. These findings shed light on the evolution of sex chromosomes and inform understanding of diseases related to genes on these chromosomes in both apes and humans.

“The Y chromosome is important for human fertility, and the X chromosome harbors genes critical for reproduction, cognition and immunity,” said Kateryna Makova, Verne M. Willaman Chair of Life Sciences, professor of biology at Penn State and leader of the research team. “Our study opens doors for many future investigations of sex chromosomes, how they evolved, and diseases associated with them. The living non-human great ape species we studied are all endangered. The availability of their complete sex chromosome sequences will facilitate studies of their sex-specific dispersal in the wild and of their genes important for reproduction and fertility.”

Such reference genomes act as a representative example that are useful for future studies of these species. The team found that, compared to the X chromosome, the Y chromosome varies greatly across ape species and harbors many species-specific sequences. However, it is still subject to purifying natural selection — an evolutionary force that protects its genetic information by removing harmful mutations.

The new study appears May 29 in the journal Nature.

“Researchers sequenced the human genome in 2001, but it wasn’t actually complete,” Makova said. “The technology available at the time meant that certain gaps weren’t filled in until a renewed effort led by the Telomere-to-Telomere, or T2T, Consortium in 2022-23. We leveraged the experimental and computational methods developed by the Human T2T Consortium to determine the complete sequences for the sex chromosomes of our closest living relatives — great apes.”

The team produced complete sex chromosome sequences for five species of great apes — chimpanzee, bonobo, gorilla, Bornean orangutan and Sumatran orangutan, which comprise most great ape species living today — as well as a lesser ape, siamang. They generated sequences for one individual of each species. The resulting reference genomes act as a map of genes and other chromosomal regions, which can help researchers sequence and assemble the genomes of other individuals of that species. Previous sex chromosome sequences for these species were incomplete or — for the Bornean orangutan and siamang — did not exist.

“The Y chromosome has been challenging to sequence because it contains many repetitive regions, and, because traditional short-read sequencing technology decodes sequences in short bursts, it is difficult to put the resulting segments in the correct order,” said Karol Pál, postdoctoral researcher at Penn State and a co-first author of the study. “T2T methods use long-read sequencing technologies that overcome this challenge. Combined with advances in computational analysis, on which we collaborated with Adam Phillippy’s group at the NHGRI, this allowed us to completely resolve repetitive regions that were previously difficult to sequence and assemble. By comparing the X and Y chromosomes to each other and among species, including to the previously generated human T2T sequences of the X and the Y, we learned many new things about their evolution.”

High variability on the Y chromosome

“Sex chromosomes started like any other chromosome pair, but the Y has been unique in accumulating many deletions, other mutations and repetitive elements because it does not exchange genetic information with other chromosomes over most of its length,” said Makova, who is also the director of the Center for Medical Genomics at Penn State.

As a result, across the six ape species, the research team found that the Y chromosome was much more variable than the X over a variety of characteristics, including size. Among the studied apes, the X chromosome ranges in size from 154 million letters of the ACTG alphabet — representing the nucleotides that make up DNA — in chimpanzee and human to 178 million letters in gorilla. In contrast, the Y chromosome ranges from 30 million DNA letters in siamang to 68 million letters in Sumatran orangutan.

The amount of DNA sequence shared between species was also more variable on the Y. For example, about 98% of the X chromosome aligns between human and chimpanzee, but only about a third of the Y aligns between them. The researchers found that this is in part because the Y chromosome is more likely to be rearranged or have portions of its genetic material duplicated.

Additionally, the percentage of the chromosome occupied by sequences that are repeated is highly variable on the Y. Whereas, depending on the species, 62% to 66% of the X chromosomes are occupied by repetitive elements, 71% to 85% of the Y chromosomes are occupied by them. These percentages are higher on both the X and the Y than in other chromosomes in the human genome.

How the Y has survived

“We found the ape Y to be shrinking, accumulating many mutations and repeats, and losing genes,” Makova said. “So why hasn’t the Y chromosome disappeared, as some previous hypotheses suggested? In collaboration with Sergei Kosakovsky Pond from Temple University and others, we found that the Y chromosome still has a number of genes evolving under purifying selection — a type of natural selection that keeps gene sequences intact. Many of these genes are important for spermatogenesis. This means that the Y chromosome is unlikely to disappear any time soon.”

The researchers found that many genes on the Y chromosome seem to use two strategies to survive. The first takes advantage of genetic redundancy — the presence of multiple copies of the same gene on a chromosome — so that intact copies of the gene can compensate for copies that might acquire mutations. The team quantified this genetic redundancy by completing the landscape of multi-copy gene families on ape sex chromosomes for the first time.

The second survival strategy takes advantage of palindromes, where the sequence of letters in the DNA alphabet is followed by the same, but inverted sequence, for example, ACTG-GTCA. When located within a palindrome, genes benefit from the palindrome’s ability to correct mutations.

“We found that the Y chromosome can exchange genetic information with itself between the repeated sequences of the two palindrome arms, which fold so that the inverted sequences align,” Pál said. “When two copies of the same gene are located within palindromes, and one copy is hit by a mutation, the mutation can be rescued by the genetic exchange with another copy. This can compensate for the Y’s lack of genetic information exchange with the other chromosomes.”

The research team obtained the complete sequences of palindromes on ape sex chromosomes also for the first time, as they were previously difficult to sequence and study. They found that palindromes are particularly abundant and long on the ape Y chromosome, yet they are usually only shared among closely related species.

In collaboration with Michael Schatz and his team at Johns Hopkins University, the researchers also studied the sex chromosomes of 129 individual gorillas and chimpanzees to better understand the genetic variation within each species and search for evidence of natural selection and other evolutionary forces acting on them.

“We obtained substantial new information from previously studied gorilla and chimpanzee individuals by aligning their sex chromosome sequencing reads to our new reference sequences,” said Zachary Szpiech, assistant professor of biology at Penn State and an author of the paper. “While increasing the sample size in the future will be very helpful to improve our ability to detect signatures of different evolutionary forces, this can be ethically and logistically challenging when working with endangered species, so it is critical that we can get the most out of the data we do have.”

The researchers explored a variety of factors that could explain variation on the Y chromosome within gorillas and within chimpanzees, and this analysis revealed additional signatures of purifying selection on the Y. This confirms the role of this type of natural selection on the Y, as was discovered in their previous analyses of genes.

“The powerful combination of bioinformatic techniques and evolutionary analyses that we used allows us to better explain the evolutionary processes acting on sex chromosomes in our closest living relatives, great apes,” said Christian Huber, assistant professor of biology at Penn State and an author of the paper. “Additionally, the reference genomes we produced will be instrumental for future studies of primate evolution and human diseases.”

In addition to Makova, Pál, Szpiech and Huber, the research team at Penn State includes Kaivan Kamali, computational scientist in the departments of biology and of biochemistry and molecular biology; Troy LaPolice, graduate student in bioinformatics and genomics; Paul Medvedev, professor of computer science and engineering and of biochemistry and molecular biology; Sweetalana, research assistant in the department of biology; Huiqing Zeng, research technologist in biology; Xinru Zhang, graduate student in bioinformatics and genomics; Robert Harris, assistant research professor of biology, now retired; Barbara McGrath, associate research professor of biology, now retired; and Sarah Craig, associate research professor of biology, currently a program officer at the National Institutes of Health. The co-authors also included Penn State alumni Monika Cechova, currently a postdoctoral fellow at the University of California Santa Cruz, and Melissa Wilson, currently an associate professor at Arizona State University.

In addition to Makova, the team was co-led by co-corresponding study authors Adam Phillippy, senior investigator at NHGRI, and Evan Eichler, professor of Genome Sciences at the University of Washington. A full list of authors for this paper is available here.

Funding from the National Institutes of Health supported this research.



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Prying open the AI black box

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Prying open the AI black box


Artificial intelligence continues to squirm its way into many aspects of our lives. But what about biology, the study of life itself? AI can sift through hundreds of thousands of genome data points to identify potential new therapeutic targets. While these genomic insights may appear helpful, scientists aren’t sure how today’s AI models come to their conclusions in the first place. Now, a new system named SQUID arrives on the scene armed to pry open AI’s black box of murky internal logic.

SQUID, short for Surrogate Quantitative Interpretability for Deepnets, is a computational tool created by Cold Spring Harbor Laboratory (CSHL) scientists. It’s designed to help interpret how AI models analyze the genome. Compared with other analysis tools, SQUID is more consistent, reduces background noise, and can lead to more accurate predictions about the effects of genetic mutations.

How does it work so much better? The key, CSHL Assistant Professor Peter Koo says, lies in SQUID’s specialized training.

“The tools that people use to try to understand these models have been largely coming from other fields like computer vision or natural language processing. While they can be useful, they’re not optimal for genomics. What we did with SQUID was leverage decades of quantitative genetics knowledge to help us understand what these deep neural networks are learning,” explains Koo.

SQUID works by first generating a library of over 100,000 variant DNA sequences. It then analyzes the library of mutations and their effects using a program called MAVE-NN (Multiplex Assays of Variant Effects Neural Network). This tool allows scientists to perform thousands of virtual experiments simultaneously. In effect, they can “fish out” the algorithms behind a given AI’s most accurate predictions. Their computational “catch” could set the stage for experiments that are more grounded in reality.

“In silico [virtual] experiments are no replacement for actual laboratory experiments. Nevertheless, they can be very informative. They can help scientists form hypotheses for how a particular region of the genome works or how a mutation might have a clinically relevant effect,” explains CSHL Associate Professor Justin Kinney, a co-author of the study.

There are tons of AI models in the sea. More enter the waters each day. Koo, Kinney, and colleagues hope that SQUID will help scientists grab hold of those that best meet their specialized needs.

Though mapped, the human genome remains an incredibly challenging terrain. SQUID could help biologists navigate the field more effectively, bringing them closer to their findings’ true medical implications.



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Iron meteorites hint that our infant solar system was more doughnut than dartboard

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Iron meteorites hint that our infant solar system was more doughnut than dartboard


Four and a half billion years ago, our solar system was a cloud of gas and dust swirling around the sun, until gas began to condense and accrete along with dust to form asteroids and planets. What did this cosmic nursery, known as a protoplanetary disk, look like, and how was it structured? Astronomers can use telescopes to “see” protoplanetary disks far away from our much more mature solar system, but it is impossible to observe what ours might have looked like in its infancy — only an alien billions of light years away would be able to see it as it once was.

Fortunately, space has dropped a few clues — fragments of objects that formed early in solar system history and plunged through Earth’s atmosphere, called meteorites. The composition of meteorites tells stories of the solar system’s birth, but these stories often raise more questions than answers.

In a paper published in Proceedings of the National Academy of Sciences, a team of planetary scientists from UCLA and Johns Hopkins University Applied Physics Laboratory reports that refractory metals, which condense at high temperatures, such as iridium and platinum, were more abundant in meteorites formed in the outer disk, which was cold and far away from the sun. These metals should have formed close to the sun, where the temperature was much higher. Was there a pathway that moved these metals from the inner disk to the outer?

Most meteorites formed within the first few million years of solar system history. Some meteorites, called chondrites, are unmelted conglomerations of grains and dust left over from planet formation. Other meteorites experienced enough heat to melt while their parent asteroids were forming. When these asteroids melted, the silicate part and the metallic part separated due to their difference in density, similar to how water and oil don’t mix.

Today, most asteroids are located in a thick belt between Mars and Jupiter. Scientists think that Jupiter’s gravity disrupted the course of these asteroids, causing many of them to smash into each other and break apart. When pieces of these asteroids fall to Earth and are recovered, they are called meteorites.

Iron meteorites are from the metallic cores of the earliest asteroids, older than any other rocks or celestial objects in our solar system. The irons contain molybdenum isotopes that point toward many different locations across the protoplanetary disk in which these meteorites formed. That allows scientists to learn what the chemical composition of the disk was like in its infancy.

Previous research using the Atacama Large Millimeter/submillimeter Array in Chile has found many disks around other stars that resemble concentric rings, like a dartboard. The rings of these planetary disks, such as HL Tau, are separated by physical gaps, so this kind of disk could not provide a route to transport these refractory metals from the inner disk to the outer.

The new paper holds that our solar disk likely didn’t have a ring structure at the very beginning. Instead, our planetary disk looked more like a doughnut, and asteroids with metal grains rich in iridium and platinum metals migrated to the outer disk as it rapidly expanded.

But that confronted the researchers with another puzzle. After the disk expansion, gravity should have pulled these metals back into the sun. But that did not happen.

“Once Jupiter formed, it very likely opened a physical gap that trapped the iridium and platinum metals in the outer disk and prevented them from falling into the sun,” said first author Bidong Zhang, a UCLA planetary scientist. “These metals were later incorporated into asteroids that formed in the outer disk. This explains why meteorites formed in the outer disk — carbonaceous chondrites and carbonaceous-type iron meteorites — have much higher iridium and platinum contents than their inner-disk peers.”

Zhang and his collaborators previously used iron meteorites to reconstruct how water was distributed in the protoplanetary disk.

“Iron meteorites are hidden gems. The more we learn about iron meteorites, the more they unravel the mystery of our solar system’s birth,” Zhang said.



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Supermassive black hole appears to grow like a baby star

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Supermassive black hole appears to grow like a baby star


Supermassive black holes pose unanswered questions for astronomers around the world, not least “How do they grow so big?” Now, an international team of astronomers, including researchers from Chalmers University of Technology in Sweden, has discovered a powerful rotating, magnetic wind that they believe is helping a galaxy’s central supermassive black hole to grow. The swirling wind, revealed with the help of the ALMA telescope in nearby galaxy ESO320-G030, suggests that similar processes are involved both in black hole growth and the birth of stars.

Most galaxies, including our own Milky Way have a supermassive black hole at their centre. How these mind-bogglingly massive objects grow to weigh as much as millions or billions of stars is a long-standing question for astronomers.

In search of clues to this mystery, a team of scientists led by Mark Gorski (Northwestern University and Chalmers) and Susanne Aalto (Chalmers) chose to study the relatively nearby galaxy ESO320-G030, only 120 million light years distant. It’s a very active galaxy, forming stars ten times as fast as in our own galaxy.

“Since this galaxy is very luminous in the infrared, telescopes can resolve striking details in its centre. We wanted to measure light from molecules carried by winds from the galaxy’s core, hoping to trace how the winds are launched by a growing, or soon to be growing, supermassive black hole. By using ALMA, we were able to study light from behind thick layers of dust and gas,” says Susanne Aalto, Professor of Radio Astronomy at Chalmers University of Technology.

To zero in on dense gas from as close as possible to the central black hole, the scientists studied light from molecules of hydrogen cyanide (HCN). Thanks to ALMA’s ability to image fine details and trace movements in the gas — using the Doppler effect — they discovered patterns that suggest the presence of a magnetised, rotating wind.

While other winds and jets in the centre of galaxies push material away from the supermassive black hole, the newly discovered wind adds another process, that can instead feed the black hole and help it grow.

“We can see how the winds form a spiralling structure, billowing out from the galaxy’s centre. When we measured the rotation, mass, and velocity of the material flowing outwards, we were surprised to find that we could rule out many explanations for the power of the wind, star formation for example. Instead, the flow outwards may be powered by the inflow of gas and seems to be held together by magnetic fields,” says Susanne Aalto.

The scientists think that the rotating magnetic wind helps the black hole to grow.

Material travels around the black hole before it can fall in — like water around a drain. Matter that approaches the black hole collects in a chaotic, spinning disk. There, magnetic fields develop and get stronger. The magnetic fields help lift matter away from the galaxy, creating the spiralling wind. Losing matter to this wind also slows the spinning disk — that means that matter can flow more easily into the black hole, turning a trickle into a stream.

For Mark Gorski, the way this happens is strikingly reminiscent of a much smaller-scale environment in space: the swirls of gas and dust that lead up to the birth of new stars and planets.

“It is well-established that stars in the first stages of their evolution grow with the help of rotating winds — accelerated by magnetic fields, just like the wind in this galaxy. Our observations show that supermassive black holes and tiny stars can grow by similar processes, but on very different scales,” says Mark Gorski.

Could this discovery be a clue to solving the mystery of how supermassive black holes grow? In the future, Mark Gorski, Susanne Aalto and their colleagues want to study other galaxies which may harbour hidden spiralling outflows in their centres.

“Far from all questions about this process are answered. In our observations we see clear evidence of a rotating wind that helps regulate the growth of the galaxy’s central black hole. Now that we know what to look for, the next step is to find out how common a phenomenon this is. And if this is a stage which all galaxies with supermassive black holes go through, what happens to them next?,” asks Mark Gorski.



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