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Researchers have finally deciphered a complete human genetic instruction book from cover to cover.

The completion of the human genome has been announced a couple of times in the past, but those were actually incomplete drafts. “We really mean it this time,” says Evan Eichler, a human geneticist and Howard Hughes Medical Institute investigator at the University of Washington in Seattle.

The completed genome is presented in a series of papers published online March 31 in Science and Nature Methods.

An international team of researchers, including Eichler, used new DNA sequencing technology to untangle repetitive stretches of DNA that were redacted from an earlier version of the genome, widely used as a reference for guiding biomedical research.

Deciphering those tricky stretches adds about 200 million DNA bases, about 8 percent of the genome, to the instruction book, researchers report in Science. That’s essentially an entire chapter. And it’s a juicy one, containing the first-ever looks at the short arms of some chromosomes, long-lost genes and important parts of chromosomes called centromeres — where machinery responsible for divvying up DNA grips the chromosome.

“Some of the regions that were missing actually turn out to be the most interesting,” says Rajiv McCoy, a human geneticist at Johns Hopkins University, who was part of the team known as the Telomere-to-Telomere (T2T) Consortium assembling the complete genome. “It’s exciting because we get to take the first look inside these regions and see what we can find.” Telomeres are repetitive stretches of DNA found at the ends of chromosomes. Like aglets on shoelaces, they may help keep chromosomes from unraveling.

Data from the effort are already available for other researchers to explore. And some, like geneticist Ting Wang of Washington University School of Medicine in St. Louis, have already delved in. “Having a complete genome reference definitely improves biomedical studies.… It’s an extremely useful resource,” he says. “There’s no question that this is an important achievement.”

But, Wang says, “the human genome isn’t quite complete yet.”

To understand why and what this new volume of the human genetic encyclopedia tells us, here’s a closer look at the milestone.
What did the researchers do?
Eichler is careful to point out that “this is the completion of a human genome. There is no such thing as the human genome.” Any two people will have large portions of their genomes that range from very similar to virtually identical and “smaller portions that are wildly different.” A reference genome can help researchers see where people differ, which can point to genes that may be involved in diseases. Having a view of the entire genome, with no gaps or hidden DNA, may give scientists a better understanding of human health, disease and evolution.

The newly complete genome doesn’t have gaps like the previous human reference genome. But it still has limitations, Wang says. The old reference genome is a conglomerate of more than 60 people’s DNA (SN: 3/4/21). “Not a single individual, or single cell on this planet, has that genome.” That goes for the new, complete genome, too. “It’s a quote-unquote fake genome,” says Wang, who was not involved with the project.

The new genome doesn’t come from a person either. It’s the genome of a complete hydatidiform mole, a sort of tumor that arises when a sperm fertilizes an empty egg and the father’s chromosomes are duplicated. The researchers chose to decipher the complete genome from a cell line called CHM13 made from one of these unusual tumors.

That decision was made for a technical reason, says geneticist Karen Miga of the University of California, Santa Cruz. Usually, people get one set of chromosomes from their mother and another set from their father. So “we all have two genomes in every cell.”

If putting together a genome is like assembling a puzzle, “you essentially have two puzzles in the same box that look very similar to each other,” says Miga, borrowing an analogy from a colleague. Researchers would have to sort the two puzzles before piecing them together. “Genomes from hydatidiform moles don’t present that same challenge. It’s just one puzzle in the box.”

The researchers did have to add the Y chromosome from another person, because the sperm that created the hydatidiform mole carried an X chromosome.

Even putting one puzzle together is a Herculean task. But new technologies that allow researchers to put DNA bases — represented by the letters A, T, C and G — in order, can spit out stretches up to more than 100,000 bases long. Just as children’s puzzles are easier to solve because of larger and fewer pieces, these “long reads” made assembling the bits of the genome easier, especially in repetitive parts where just a few bases might distinguish one copy from another. The bigger pieces also allowed researchers to correct some mistakes in the old reference genome.

What did they find?
For starters, the newly deciphered DNA contains the short arms of chromosomes 13, 14, 15, 21 and 22. These “acrocentric chromosomes” don’t resemble nice, neat X’s the way the rest of the chromosomes do. Instead, they have a set of long arms and one of nubby short arms.

The length of the short arms belies their importance. These arms are home to rDNA genes, which encode rRNAs, which are key components of complex molecular machines called ribosomes. Ribosomes read genetic instructions and build all the proteins needed to make cells and bodies work. There are hundreds of copies of these rDNA regions in every person’s genome, an average of 315, but some people have more and some fewer. They’re important for making sure cells have protein-building factories at the ready.

“We didn’t know what to expect in these regions,” Miga says. “We found that every acrocentric chromosome, and every rDNA on that acrocentric chromosome, had variants, changes to the repeat unit that was private to that particular chromosome.”

By using fluorescent tags, Eichler and colleagues discovered that repetitive DNA next to the rDNA regions — and perhaps the rDNA too — sometimes switches places to land on another chromosome, the team reports in Science. “It’s like musical chairs,” he says. Why and how that happens is still a mystery.

The complete genome also contains 3,604 genes, including 140 that encode proteins, that weren’t present in the old, incomplete genome. Many of those genes are slightly different copies of previously known genes, including some that have been implicated in brain evolution and development, autism, immune responses, cancer and cardiovascular disease. Having a map of where all these genes lie may lead to a better understanding of what they do, and perhaps even of what makes humans human.

One of the biggest finds may be the structure of all of the human centromeres. Centromeres, the pinched portions which give most chromosomes their characteristic X shape, are the assembly points for kinetochores, the cellular machinery that divvies up DNA during cell division. That’s one of the most important jobs in a cell. When it goes wrong, birth defects, cancer or death can result. Researchers had already deciphered the centromeres of fruit flies and the human 8, X and Y chromosomes (SN: 5/17/19), but this is the first time that researchers got a glimpse of the rest of the human centromeres.

The structures are mostly head-to-tail repeats of about 171 base pairs of DNA known as alpha satellites. But those repeats are nestled within other repeats, creating complex patterns that distinguish each chromosome’s individual centromere, Miga and colleagues describe in Science. Knowing the structures will help researchers learn more about how chromosomes are divvied up and what sometimes throws off the process.
Researchers also now have a more complete map of epigenetic marks — chemical tags on DNA or associated proteins that may change how genes are regulated. One type of epigenetic mark, known as DNA methylation, is fairly abundant across the centromeres, except for one spot in each chromosome called the centromeric dip region, Winston Timp, a biomedical engineer at Johns Hopkins University and colleagues report in Science.

Those dips are where kinetochores grab the DNA, the researchers discovered. But it’s not yet clear whether the dip in methylation causes the cellular machinery to assemble in that spot or if assembly of the machinery leads to lower levels of methylation.

Examining DNA methylation patterns in multiple people’s DNA and comparing them with the new reference revealed that the dips occur at different spots in each person’s centromeres, though the consequences of that aren’t known.

About half of genes implicated in the evolution of humans’ large, wrinkly brains are found in multiple copies in the newly uncovered repetitive parts of the genome (SN: 2/26/15). Overlaying the epigenetic maps on the reference allowed researchers to figure out which of many copies of those genes were turned on and off, says Ariel Gershman, a geneticist at Johns Hopkins University School of Medicine.

“That gives us a little bit more insight into which of them are actually important and playing a functional role in the development of the human brain,” Gershman says. “That was exciting for us, because there’s never been a reference that was accurate enough in these [repetitive] regions to tell which gene was which, and which ones are turned on or off.”

What is next?
One criticism of genetics research is that it has relied too heavily on DNA from people of European descent. CHM13 also has European heritage. But researchers have used the new reference to discover new patterns of genetic diversity. Using DNA data collected from thousands of people of diverse backgrounds who participated in earlier research projects compared with the T2T reference, researchers more easily and accurately found places where people differ, McCoy and colleagues report in Science.

The Telomere-to-Telomere Consortium has now teamed up with Wang and his colleagues to make complete genomes of 350 people from diverse backgrounds (SN: 2/22/21). That effort, known as the pangenome project, is poised to reveal some of its first findings later this year, Wang says.

McCoy and Timp say that it may take some time, but eventually, researchers may switch from using the old reference genome to the more complete and accurate T2T reference. “It’s like upgrading to a new version of software,” Timp says. “Not everyone is going to want to do it right away.”

The completed human genome will also be useful for researchers studying other organisms, says Amanda Larracuente, an evolutionary geneticist at the University of Rochester in New York who was not involved in the project. “What I’m excited about is the techniques and tools this team has developed, and being able to apply those to study other species.”

Eichler and others already have plans to make complete genomes of chimpanzees, bonobos and other great apes to learn more about how humans evolved differently than apes did. “No one should see this as the end,” Eichler says, “but a transformation, not only for genomic research but for clinical medicine, though that will take years to achieve.”

The nucleus of a comet discovered in 2014 is the largest ever spotted.

The “dirty snowball” at the center of comet C/2014 UN271 is about 120 kilometers across, researchers report in the April 10 Astrophysical Journal Letters. That makes this comet — also known as Bernardinelli-Bernstein, after its discoverers — about twice as wide as Rhode Island, says David Jewitt, an astronomer at UCLA.

Though the comet is big — and vastly larger than Halley’s comet, which measures a little more than 11 kilometers across — it will never be visible to the naked eye from Earth because it’s too far away, Jewitt says (SN: 12/14/15). The object is now about 3 billion kilometers from Earth. At its closest approach in 2031, the comet will come no closer to the sun than 1.6 billion kilometers, about the same distance as Saturn.
Jewitt and colleagues sized up the comet with the help of new images from the Hubble Space Telescope, combined with images taken by another team at far-infrared wavelengths. The analysis also revealed that the comet’s nucleus reflects only about 3 percent of the light that strikes it. That makes the object “blacker than coal,” Jewitt says.

Comet Bernardinelli-Bernstein takes about 3 million years to circle the sun in a highly elliptical orbit. At its farthest, the comet may reach about half a light-year from the sun — about one-eighth of the distance to the next nearest star.

The comet is likely “just the tip of the iceberg” as far as undiscovered comets of this size go, Jewitt says. And for every comet this size, he suggests, there could be tens of thousands of smaller objects circling the sun undetected.

A massive urban landscape that contained interconnected campsites, villages, towns and monumental centers thrived in the Amazon rainforest more than 600 years ago.

In what is now Bolivia, members of the Casarabe culture built an urban system that included straight, raised causeways running for several kilometers, canals and reservoirs, researchers report May 25 in Nature.

Such low-density urban sprawl from pre-Columbian times was previously unknown in the Amazon or anywhere else in South America, say archaeologist Heiko Prümers of the German Archaeological Institute in Bonn and colleagues. Rather than constructing huge cities densely packed with people, a substantial Casarabe population spread out in a network of small to medium-sized settlements that incorporated plenty of open space for farming, the scientists conclude.
Airborne lasers peered through dense trees and ground cover to identify structures from that low-density urban network that have long eluded land-based archaeologists.

Earlier excavations indicated that Casarabe maize farmers, fishers and hunters inhabited an area of 4,500 square kilometers. For about a century, researchers have known that Casarabe people fashioned elaborate pottery and constructed large earthen mounds, causeways and ponds. But these finds were located at isolated forest sites that are difficult to excavate, leaving the reasons for mound building and the nature of Casarabe society, which existed from about the year 500 to 1400, a mystery.

Prümers’ team opted to look through the Amazon’s lush cover from above, aiming to find relics of human activity that typically remain hidden even after careful ground surveys. The scientists used a helicopter carrying special equipment to fire laser pulses at the Amazon forest as well as stretches of grassland. Those laser pulses reflect data from the Earth’s surface. This technique, called light detection and ranging, or lidar for short, enables researchers to map the contours of now-obscured structures.

Looking at the new lidar images, “it is obvious that the mounds are platforms and pyramids standing on artificial terraces at the center of well-planned settlements,” Prümers says.

Prümers’ team conducted lidar surveys over six parts of ancient Casarabe territory. The lidar data revealed 26 sites, 11 of them previously unknown.

Two sites, Cotoca and Landívar, are much larger than the rest. Both settlements feature rectangular and U-shaped platform mounds and cone-shaped earthen pyramids atop artificial terraces. Curved moats and defensive walls border each site. Causeways radiate out from Cotoca and Landívar in all directions, connecting those primary sites to smaller sites with fewer platform mounds that then link up to what were probably small campsites or areas for specialized activities, such as butchering prey.

The Casarabe society’s network of settlements joins other ancient and present-day examples of low-density urban sprawl around the world, says archaeologist Roland Fletcher of the University of Sydney. These sites raise questions about whether only places with centralized governments that ruled over people who were packed into neighborhoods on narrow streets, such as 6,000-year-old Mesopotamian metropolises, can be defined as cities.

Some past urban settlements organized around crop growing spanned up to 1,000 square kilometers or more in tropical regions. These include locales such as Southeast Asia’s Greater Angkor roughly 700 to 800 years ago and interconnected Maya sites in Central America dating to at least 2,300 years ago (SN: 4/29/16; SN: 9/27/18). Today, extended areas outside large cities, especially in Southeast Asia, mix industrial and agricultural activities over tens of thousands of kilometers.

Clusters of interconnected Casarabe settlements ranged in area from 100 square kilometers to more than 500 square kilometers. Spread-out settlements of comparable area include 6,000-year-old sites from Eastern Europe’s Trypillia culture (SN: 2/19/20).

Tropical forests that have gone largely unexplored, such as Central Africa’s Congo Basin, probably hosted other early forms of low-density urban development, Fletcher predicts.

Only further excavations guided by lidar evidence can begin to untangle the size of the Casarabe population, Prümers says. Whether primary Casarabe sites represented seats of power in states with upper and lower classes also remains unknown, he adds.

Casarabe culture’s urban sprawl must have encompassed a considerable number of people in the centuries before the Spanish arrived and Indigenous population numbers plummeted, largely due to diseases, forced labor and slavery, says archaeologist John Walker of the University of Central Florida in Orlando.

Whatever Casarabe honchos had in mind as their tropical settlement network spread, he says, “we may have to set aside some of our strongly held ideas about what the Amazon is, and what a city is, to better understand what happened.”

Six years ago, tour guide Brenden Miles was traveling down the Kinabatangan River in the Malaysian part of Borneo, when he spotted an odd-looking primate he had never seen before. He snapped a few pictures of the strange monkey and, on reaching home, checked his images.

“At first, I thought it could be a morph of the silvered leaf monkey,” meaning a member of the species with rare color variation, Miles says. But then he noticed other little details. “Its nose was long like that of a proboscis monkey, and its tail was thicker than that of a silvered leaf [monkey],” he says. He posted a picture of the animal on Facebook and forgot all about it.

Now, an analysis of that photo and others suggests that the “mystery monkey” is a hybrid of two distantly related primate species that share the same fragmented habitat.
The putative offspring was produced when a male proboscis monkey (Nasalis larvatus) mated with a female silvered leaf monkey (Trachypithecus cristatus), researchers suggest April 26 in the International Journal of Primatology. And that conclusion has the scientists worried about the creature’s parent species.

Hybridization between closely related organisms has been observed in captivity and occasionally in the wild (SN: 7/23/21). “But hybridization across genera, that’s very rare,” says conservation practitioner Ramesh Boonratana, the regional vice-chair for Southeast Asia for the International Union for Conservation of Nature’s primate specialist group.

Severe habitat loss, fragmentation and degradation caused by expanding palm oil plantations along the Kinabatangan River could explain how the possible hybrid came to be, says primatologist Nadine Ruppert.

“Different species — even from the same genus — when they share a habitat, they may interact with each other, but they may usually not mate. This kind of cross-genera hybridization happens only when there is some ecological pressure,” says Ruppert, of the Universiti Sains Malaysia in Penang Island.

The state of Sabah, where Kinabatangan River is located, lost about 40 percent of its forest cover from 1973 to 2010, with logging and palm oil plantations being the main drivers of deforestation, a study in 2014 found.
“In certain areas, both [monkey] species are confined to small forest fragments along the river,” Ruppert says. This leads to competition for food, mates and other resources. “The animals cannot disperse and, in this case, the male of the larger species — the proboscis monkey — can easily displace the male silvered leaf monkey.”

Since 2016, there have been some more documented sightings of the mystery monkey, though these have been sporadic. The infrequent sightings and the COVID-19 pandemic has, for now, prevented researchers from gathering fecal samples for genetic analysis to reveal the monkey’s identity. Instead, Ruppert and colleagues compared images of the possible hybrid with those of the parent species, both visually as well as by using limb ratios. “If the individual was from one of the two parent species, all its measurements would be similar to that of one species,” Ruppert says. “But that is not the case with this animal.”

A photograph of a male proboscis monkey mating with a female silvered leaf monkey, along with anecdotes from boat operators and tour guides about a single male proboscis monkey hanging around a troop of female silvered leaf monkeys, has added further weight to the researchers’ conclusion.

The mystery monkey is generating a lot of excitement in the area, but Ruppert is concerned for the welfare of both proposed parent species. The International Union for Conservation of Nature classifies proboscis monkeys as endangered and silvered leaf monkeys as vulnerable. “The hybrid is gorgeous, but we don’t want to see more of them,” Ruppert says. “Both species should have a large enough habitat, dispersal opportunities and enough food to conduct their natural behaviors in the long term.”

Increasing habitat loss or fragmentation in Borneo and elsewhere as a result of changing land uses or climate change could lead to more instances of mating — or at least, attempts at mating — between species or even genera, Boonratana says.

The mystery monkey was last photographed in September of 2020 with swollen breasts and holding a baby, suggesting that the animal is a fertile female. That’s another surprising development, the researchers say, because most hybrids tend to be sterile.

Two mysterious galaxies, devoid of dark matter, could have a smashing origin story.

About 8 billion years ago, researchers propose, two dwarf galaxies slammed into one another. That cosmic crash caused the gas within those two galaxies to split up and form multiple new dwarf galaxies, including the two dark matter–free ones.

A newfound row of dwarf galaxies, more than 6 million light-years long, could have formed in the aftermath of the hypothesized crash, researchers report in the May 19 Nature. If correct, the finding could help solve the mystery of how such unusual dark matter–free galaxies form, and reveal new details about the nature of dark matter.

But other scientists are skeptical that there’s enough evidence to support this backstory. “If this is true, I think it would be really exciting. I just don’t think the bar has been met,” says astronomer Michelle Collins of the University of Surrey in Guildford, England.

In 2018, Yale University astronomer Pieter van Dokkum and colleagues reported a dwarf galaxy with no dark matter (SN: 3/28/18). The invisible, mysterious substance is typically detectable in galaxies via its gravitational effects on stars. When a second dark matter–free dwarf galaxy was found in the vicinity in 2019, it raised an obvious question: How did the two oddball galaxies form? Dark matter is generally thought to form the foundation of all galaxies, gravitationally attracting the gas that eventually forms stars. So some process must have separated the dark matter from the galaxies’ gas.

Scientists have previously seen dark matter and normal matter separate on a very large scale in the Bullet Cluster, which formed when two clusters of galaxies rammed into one another (SN: 8/23/06). Other researchers had proposed that something similar might happen with colliding dwarf galaxies, what van Dokkum and colleagues call “bullet dwarfs.”

In such a collision, the dwarf galaxies’ ethereal dark matter would continue on unperturbed, because the dark matter doesn’t interact with other matter. But the gas from the two galaxies would slam together, eventually forming multiple clumps that would each become its own galaxy, free of dark matter.

Now, van Dokkum and colleagues say that the bullet dwarf idea explains the two previously reported dark matter–free galaxies — and several other galaxies nearby. The two galaxies are moving away from each other as if they had come from the same spot, the researchers say. What’s more, the two galaxies are part of a chain of 11 galaxies aligned in a row, a structure that could have formed in the aftermath of a bullet dwarf collision.
“It’s super satisfying to finally have an explanation for these weird objects,” van Dokkum says.

But, Collins says, “there could be much more done to make it convincing.” For example, she says, the scientists didn’t measure the distances of all the galaxies from Earth. That means some of the galaxies could be much farther away than others, and it could be a coincidence that the galaxies appear to be lined up from our viewpoint.

And the researchers haven’t yet measured the velocities of all the galaxies in the trail or determined whether those galaxies are also missing their dark matter, which would help confirm whether the scenario is correct.

Other scientists are more optimistic. “The origin story is very plausible in my opinion,” says astrophysicist Eun-jin Shin of Seoul National University in South Korea. Shin cowrote a perspective article on the discovery with astrophysicist Ji-hoon Kim, also of Seoul National University, that was also published in Nature.

Computer simulations performed by Shin, Kim and others have shown that bullet dwarfs can produce such dark matter–free galaxies. If confirmed, the bullet dwarf idea could help pin down dark matter’s properties, in particular whether dark matter interacts with itself (SN: 4/5/18).

Van Dokkum and colleagues are planning additional measurements that could confirm or refute the case. But so far, he says, “It has, to me, the ring of truth.”

A speck of gold dancing to a pipe organ’s tune has helped solve a long-standing mystery: why certain wind instruments violate a mathematical formula that should describe their sound.

In 1860, physicist Hermann von Helmholtz — famous for his law of the conservation of energy — devised an equation relating the wavelength of a pipe’s fundamental tone (the lowest frequency at which it resonates) to pipe length (SN: 3/31/28). Generally, the longer a pipe is, the lower its fundamental tone will be.

But the equation doesn’t work in practice. A pipe’s fundamental tone always sounds lower than the pipe’s length suggests it should according to Helmholtz’s formula. Fixing this problem requires adding an “end correction” to the equation. In the case of open-ended pipes such as flutes and those of organs, the end correction is 0.6 times the radius of the pipe. Why this was, nobody could figure out.

A break in the case came in 2010. Instrument builder and restorer Bernhardt Edskes of Wohlen, Switzerland was tuning an organ when he spotted a piece of gold that had come loose from a pipe’s gilded lip. Air pumping through the pipe should have carried away the gold. Instead, it seemed to be trapped in a vortex just above the pipe’s upper rim.

Edskes told his friend, physicist Leo van Hemmen of the Technical University of Munich, about the observation. Together with colleagues from Munich and Wageningen University in the Netherlands, they studied how air moves through playing organ pipes using cigarette smoke.

When an organ pipe sounds, a vortex indeed forms over the pipe’s rim, the team reported March 14 in Chicago at a meeting of the American Physical Society. What’s more, this vortex is capped by a hemisphere of resonating air.
This vibrating air cap, van Hemmen says, is the long-sought explanation for the “end correction.” The cap effectively lengthens the organ pipe by the exact amount that must be tacked on to Helmholtz’s formula to explain the pipe’s fundamental tone.