Collectively, the genetic variants in this population are outside the range of previously described human diversity. That’s despite the fact that the present-day southern African hunter-gatherer populations are largely derived from southern African ancestors.
What’s distinct?
Estimates of the timing of when this ancient south African population branched off from any modern-day populations place the split at over 200,000 years ago, or roughly around the origin of modern humans themselves. But this wasn’t some odd, isolated group; estimates of population size based on the frequency of genetic variation suggest it was substantial.
Instead, the researchers suggest that climate and geography kept the group separate from other African populations and that southern Africa may have served as a climate refuge, providing a safe area from which modern humans could expand out to the rest of the continent when conditions were favorable. That’s consistent with the finding that some of the ancient populations in eastern and western Africa contain some southern African variants by around 5,000 years ago.
As far as genetic traits are concerned, the population looked like pretty much everyone else present at the time: brown eyes, high skin pigmentation, and no lactose tolerance. None of the older individuals had genetic resistance to malaria or sleeping sickness that are found in modern populations. In terms of changes that affect proteins, the most common are found in genes involved in immune function, a pattern that’s seen in many other human populations. More unusually, genes that affect kidney function also show a lot of variation.
So there’s nothing especially distinctive or modern apparent in this population, especially not in comparison to any other populations we know of in Africa at the same time. But they are unusual in that they suggest there was a large, stable, and isolated group from other populations present in Africa at the time. Over time, we’ll probably get additional evidence that fits this population into a coherent picture of human evolution. But for now, its presence is a bit of an enigma, given how often other populations intermingled in our past.
Many dog breeds are noted for their personalities and behavioral traits, from the distinctive vocalizations of huskies to the herding of border collies. People have worked to identify the genes associated with many of these behaviors, taking advantage of the fact that dogs can interbreed. But that creates its own experimental challenges, as it can be difficult to separate some behaviors from physical traits distinctive to the breed—small dog breeds may seem more aggressive simply because they feel threatened more often.
To get around that, a team of researchers recently did the largest gene/behavior association study within a single dog breed. Taking advantage of a population of over 1,000 golden retrievers, they found a number of genes associated with behaviors within that breed. A high percentage of these genes turned out to correspond to regions of the human genome that have been associated with behavioral differences as well. But, in many cases, these associations have been with very different behaviors.
Gone to the dogs
The work, done by a team based largely at Cambridge University, utilized the Golden Retriever Lifetime Study, which involved over 3,000 owners of these dogs filling out annual surveys that included information on their dogs’ behavior. Over 1,000 of those owners also had blood samples obtained from their dogs and shipped in; the researchers used these samples to scan the dogs’ genomes for variants. Those were then compared to ratings of the dogs’ behavior on a range of issues, like fear or aggression directed toward strangers or other dogs.
Using the data, the researchers identified when different regions of the genome were frequently associated with specific variants. In total, 14 behavioral tendencies were examined, and 12 genomic regions were associated with specific behaviors, and another nine showed somewhat weaker associations. For many of these traits, it was difficult to find much because golden retrievers are notoriously friendly and mellow dogs, so they tended to score low on traits like aggression and fear.
That result was significant, as some of these same regions of the genome had been associated with very different behaviors in populations that were a mix of breeds. For example, two different regions associated with touch sensitivity in golden retrievers had been linked to a love of chasing and owner-directed aggression in a non-breed-specific study. That finding suggests that the studies were identifying genes that may be involved in setting the stage for behaviors, but were directed into specific outcomes by other genetic or environmental factors.
The researchers argue that this setup lets Evo “link nucleotide-level patterns to kilobase-scale genomic context.” In other words, if you prompt it with a large chunk of genomic DNA, Evo can interpret that as an LLM would interpret a query and produce an output that, in a genomic sense, is appropriate for that interpretation.
The researchers reasoned that, given the training on bacterial genomes, they could use a known gene as a prompt, and Evo should produce an output that includes regions that encode proteins with related functions. The key question is whether it would simply output the sequences for proteins we know about already, or whether it would come up with output that’s less predictable.
Novel proteins
To start testing the system, the researchers prompted it with fragments of the genes for known proteins and determined whether Evo could complete them. In one example, if given 30 percent of the sequence of a gene for a known protein, Evo was able to output 85 percent of the rest. When prompted with 80 percent of the sequence, it could return all of the missing sequence. When a single gene was deleted from a functional cluster, Evo could also correctly identify and restore the missing gene.
The large amount of training data also ensured that Evo correctly identified the most important regions of the protein. If it made changes to the sequence, they typically resided in the areas of the protein where variability is tolerated. In other words, its training had enabled the system to incorporate the rules of evolutionary limits on changes in known genes.
So, the researchers decided to test what happened when Evo was asked to output something new. To do so, they used bacterial toxins, which are typically encoded along with an anti-toxin that keeps the cell from killing itself whenever it activates the genes. There are a lot of examples of these out there, and they tend to evolve rapidly as part of an arms race between bacteria and their competitors. So, the team developed a toxin that was only mildly related to known ones, and had no known antitoxin, and fed its sequence to Evo as a prompt. And this time, they filtered out any responses that looked similar to known antitoxin genes.
A young woolly mammoth now known as Yuka was frozen in the Siberian permafrost for about 40,000 years before it was discovered by local tusk hunters in 2010. The hunters soon handed it over to scientists, who were excited to see its exquisite level of preservation, with skin, muscle tissue, and even reddish hair intact. Later research showed that, while full cloning was impossible, Yuka’s DNA was in such good condition that some cell nuclei could even begin limited activity when placed inside mouse eggs.
Now, a team has successfully sequenced Yuka’s RNA—a feat many researchers once thought impossible. Researchers at Stockholm University carefully ground up bits of muscle and other tissue from Yuka and nine other woolly mammoths, then used special chemical treatments to pull out any remaining RNA fragments, which are normally thought to be much too fragile to survive even a few hours after an organism has died. Scientists go to great lengths to extract RNA even from fresh samples, and most previous attempts with very old specimens have either failed or been contaminated.
A different view
The team used RNA-handling methods adapted for ancient, fragmented molecules. Their scientific séance allowed them to explore information that had never been accessible before, including which genes were active when Yuka died. In the creature’s final panicked moments, its muscles were tensing and its cells were signaling distress—perhaps unsurprising since Yuka is thought to have died as a result of a cave lion attack.
It’s an exquisite level of detail, and one that scientists can’t get from just analyzing DNA. “With RNA, you can access the actual biology of the cell or tissue happening in real time within the last moments of life of the organism,” said Emilio Mármol, a researcher who led the study. “In simple terms, studying DNA alone can give you lots of information about the whole evolutionary history and ancestry of the organism under study. “Obtaining this fragile and mostly forgotten layer of the cell biology in old tissues/specimens, you can get for the first time a full picture of the whole pipeline of life (from DNA to proteins, with RNA as an intermediate messenger).”
Once that was done, the researchers started looking through the genomes of species that have been identified as breaking down industrial contaminants. The breakdown of complex molecules typically involves more than one enzyme, and the genes for these enzymes tend to end up clustered together so they can be produced as a single, large RNA that encodes all the proteins needed. This simplifies regulating their production, making it easy to ensure the bacteria only make the proteins if the molecule they break down is actually present. In this case, the clusters ranged from just three genes all the way up to 11.
Once nine of these gene clusters were identified, the DNA that would encode them was ordered and assembled into a single DNA molecule in yeast. The researchers took some time while ordering this DNA to better optimize the genes to be active and produce proteins in Vibrio natriegens, as opposed to whatever species the genes were normally used by.
From yeast, each of these individual gene clusters was inserted into Vibrio natriegens, creating different strains that could digest one of the following: benzene, toluene, phenol, naphthalene, biphenyl, DBF29, and dibenzothiophene (DBT). (Some of the nine clusters target the same contaminant.) Each of these bacterial strains was then put in a solution with the chemical they were engineered to digest. Five of the nine worked, giving researchers strains that could digest biphenyl, phenol, napthalene, DBF, and toluene.
Good, but limited
From there, the researchers developed a system that would enable them to iteratively insert a new gene cluster at the tail end of a previously inserted gene cluster. This allowed them to build up a cluster of clusters, eventually including all five of the ones that had shown activity in the earlier tests. Given two days, this single strain could remove about a quarter of the phenol, a third of the biphenyl, 30 percent of the DBF, all of the naphthalene, and nearly all of the toluene.
A thousand years ago, the people living in Chaco Canyon were building massive structures of intricate masonry and trading with locations as far away as Mexico. Within a century, however, the area would be largely abandoned, with little indication that the same culture was re-established elsewhere. If the people of Chaco Canyon migrated to new homes, it’s unclear where they ended up.
Around the same time that construction expanded in Chaco Canyon, far smaller pueblos began appearing in the northern Rio Grande Valley hundreds of kilometers away. These have remained occupied to the present day in New Mexico; although their populations shrank dramatically after European contact, their relationship to the Chaco culture has remained ambiguous. Until now, that is. People from one of these communities, Picuris Pueblo, worked with ancient DNA specialists to show that they are the closest relatives of the Chaco people yet discovered, confirming aspects of the pueblo’s oral traditions.
A pueblo-driven study
The list of authors of the new paper describing this genetic connection includes members of the Pueblo government, including its present governor. That’s because the study was initiated by the members of the Pueblo, who worked with archeologists to get in contact with DNA specialists at the Center for GeoGenetics at the University of Copenhagen. In a press conference, members of the Pueblo said they’d been aware of the power of DNA studies via their use in criminal cases and ancestry services. The leaders of Picuris Pueblo felt that it could help them understand their origin and the nature of some of their oral history, which linked them to the wider Pueblo-building peoples.
After two years of discussions, the collaboration settled on a plan of research, and the ancient DNA specialists were given access to both ancient skeletons at Picuris Pueblo, as well as samples from present-day residents. These were used to generate complete genome sequences.
The first clear result is that there is a strong continuity in the population living at Picuris. The ancient skeletons range from 500 to 700 years old, and thus date back to roughly the time of European contact, with some predating it. They also share strong genetic connections to the people of Chaco Canyon, where DNA has also been obtained from remains. “No other sampled population, ancient or present-day, is more closely related to Ancestral Puebloans from Pueblo Bonito [in Chaco Canyon] than the Picuris individuals are,” the paper concludes.
Enlarge/ The African Lungfish, showing it’s thin, wispy fins.
When it was first discovered, the coelacanth caused a lot of excitement. It was a living example of a group of fish that was thought to only exist as fossils. And not just any group of fish. With their long, stalk-like fins, coelacanths and their kin are thought to include the ancestors of all vertebrates that aren’t fish—the tetrapods, or vertebrates with four limbs. Meaning, among a lot of other things, us.
Since then, however, evidence has piled up that we’re more closely related to lungfish, which live in freshwater and are found in Africa, Australia, and South America. But lungfish are a bit weird. The African and South American species have seen the limb-like fins of their ancestors reduced to thin, floppy strands. And getting some perspective on their evolutionary history has proven difficult because they have the largest genomes known in animals, with the South American lungfish genome containing over 90 billion base pairs. That’s 30 times the amount of DNA we have.
But new sequencing technology has made tackling that sort of challenge manageable, and an international collaboration has now completed the largest genome ever, one where all but one chromosome carry more DNA than is found in the human genome. The work points to a history where the South American lungfish has been adding 3 billion extra bases of DNA every 10 million years for the last 200 million years, all without adding a significant number of new genes. Instead, it seems to have lost the ability to keep junk DNA in check.
Going long
The work was enabled by a technology generically termed “long-read sequencing.” Most of the genomes that were completed were done using short reads, typically in the area of 100–200 base pairs long. The secret was to do enough sequencing that, on average, every base in the genome should be sequenced multiple times. Given that, a cleverly designed computer program could figure out where two bits of sequence overlapped and register that as a single, longer piece of sequence, repeating the process until the computer spit out long strings of contiguous bases.
The problem is that most non-microbial species have stretches of repeated sequence (think hundreds of copies of the bases G and A in a row) that were longer than a few hundred bases long—and nearly identical sequences that show up in multiple locations of the genome. These would be impossible to match to a unique location, and so the output of the genome assembly software would have lots of gaps of unknown length and sequence.
This creates extreme difficulty for genomes like that of the lungfish, which is filled with non-functional “junk” DNA, all of which is typically repetitive. The software tends to produce a genome that’s more gap than sequence.
Long-read technology gets around that by doing exactly what its name implies. Rather than being able to sequence fragments of 200 bases or so, it can generate sequences that are thousands of base pairs long, easily covering the entire repeat that would have otherwise created a gap. One early version of long-read technology involved stuffing long DNA molecules through pores and watching for different voltage changes across the pore as different bases passed through it. Another had a DNA copying enzyme make a duplicate of a long strand and watch for fluorescence changes as different bases were added. These early versions tended to be a bit error-prone but have since been improved, and several newer competing technologies are now on the market.
Back in 2021, researchers used this technology to complete the genome of the Australian lungfish—the one that maintains the limb-like fins of the ancestors that gave rise to tetrapods. Now they’re back with the genomes from African and South American species. These species seem to have gone their separate ways during the breakup of the supercontinent Gondwana, a process that started nearly 200 million years ago. And having the genomes of all three should give us some perspective on the features that are common to all lungfish species, and thus are more likely to have been shared with the distant ancestors that gave rise to tetrapods.
The basic outline of the interactions between modern humans and Neanderthals is now well established. The two came in contact as modern humans began their major expansion out of Africa, which occurred roughly 60,000 years ago. Humans picked up some Neanderthal DNA through interbreeding, while the Neanderthal population, always fairly small, was swept away by the waves of new arrivals.
But there are some aspects of this big-picture view that don’t entirely line up with the data. While it nicely explains the fact that Neanderthal sequences are far more common in non-African populations, it doesn’t account for the fact that every African population we’ve looked at has some DNA that matches up with Neanderthal DNA.
A study published on Thursday argues that much of this match came about because an early modern human population also left Africa and interbred with Neanderthals. But in this case, the result was to introduce modern human DNA to the Neanderthal population. The study shows that this DNA accounts for a lot of Neanderthals’ genetic diversity, suggesting that their population was even smaller than earlier estimates had suggested.
Out of Africa early
This study isn’t the first to suggest that modern humans and their genes met Neanderthals well in advance of our major out-of-Africa expansion. The key to understanding this is the genome of a Neanderthal from the Altai region of Siberia, which dates from roughly 120,000 years ago. That’s well before modern humans expanded out of Africa, yet its genome has some regions that have excellent matches to the human genome but are absent from the Denisovan lineage.
One explanation for this is that these are segments of Neanderthal DNA that were later picked up by the population that expanded out of Africa. The problem with that view is that most of these sequences also show up in African populations. So, researchers advanced the idea that an ancestral population of modern humans left Africa about 200,000 years ago, and some of its DNA was retained by Siberian Neanderthals. That’s consistent with some fossil finds that place anatomically modern humans in the Mideast at roughly the same time.
There is, however, an alternative explanation: Some of the population that expanded out of Africa 60,000 years ago and picked up Neanderthal DNA migrated back to Africa, taking the Neanderthal DNA with them. That has led to a small bit of the Neanderthal DNA persisting within African populations.
To sort this all out, a research team based at Princeton University focused on the Neanderthal DNA found in Africans, taking advantage of the fact that we now have a much larger array of completed human genomes (approximately 2,000 of them).
The work was based on a simple hypothesis. All of our work on Neanderthal DNA indicates that their population was relatively small, and thus had less genetic diversity than modern humans did. If that’s the case, then the addition of modern human DNA to the Neanderthal population should have boosted its genetic diversity. If so, then the stretches of “Neanderthal” DNA found in African populations should include some of the more diverse regions of the Neanderthal genome.
One of the challenges of working with ancient DNA samples is that damage accumulates over time, breaking up the structure of the double helix into ever smaller fragments. In the samples we’ve worked with, these fragments scatter and mix with contaminants, making reconstructing a genome a large technical challenge.
But a dramatic paper released on Thursday shows that this isn’t always true. Damage does create progressively smaller fragments of DNA over time. But, if they’re trapped in the right sort of material, they’ll stay right where they are, essentially preserving some key features of ancient chromosomes even as the underlying DNA decays. Researchers have now used that to detail the chromosome structure of mammoths, with some implications for how these mammals regulated some key genes.
DNA meets Hi-C
The backbone of DNA’s double helix consists of alternating sugars and phosphates, chemically linked together (the bases of DNA are chemically linked to these sugars). Damage from things like radiation can break these chemical linkages, with fragmentation increasing over time. When samples reach the age of something like a Neanderthal, very few fragments are longer than 100 base pairs. Since chromosomes are millions of base pairs long, it was thought that this would inevitably destroy their structure, as many of the fragments would simply diffuse away.
But that will only be true if the medium they’re in allows diffusion. And some scientists suspected that permafrost, which preserves the tissue of some now-extinct Arctic animals, might block that diffusion. So, they set out to test this using mammoth tissues, obtained from a sample termed YakInf that’s roughly 50,000 years old.
The challenge is that the molecular techniques we use to probe chromosomes take place in liquid solutions, where fragments would just drift away from each other in any case. So, the team focused on an approach termed Hi-C, which specifically preserves information about which bits of DNA were close to each other. It does this by exposing chromosomes to a chemical that will link any pieces of DNA that are close physical proximity. So, even if those pieces are fragments, they’ll be stuck to each other by the time they end up in a liquid solution.
A few enzymes are then used to convert these linked molecules to a single piece of DNA, which is then sequenced. This data, which will contain sequence information from two different parts of the genome, then tells us that those parts were once close to each other inside a cell.
Interpreting Hi-C
On its own, a single bit of data like this isn’t especially interesting; two bits of genome might end up next to each other at random. But when you have millions of bits of data like this, you can start to construct a map of how the genome is structured.
There are two basic rules governing the pattern of interactions we’d expect to see. The first is that interactions within a chromosome are going to be more common than interactions between two chromosomes. And, within a chromosome, parts that are physically closer to each other on the molecule are more likely to interact than those that are farther apart.
So, if you are looking at a specific segment of, say, chromosome 12, most of the locations Hi-C will find it interacting with will also be on chromosome 12. And the frequency of interactions will go up as you move to sequences that are ever closer to the one you’re interested in.
On its own, you can use Hi-C to help reconstruct a chromosome even if you start with nothing but fragments. But the exceptions to the expected pattern also tell us things about biology. For example, genes that are active tend to be on loops of DNA, with the two ends of the loop held together by proteins; the same is true for inactive genes. Interactions within these loops tend to be more frequent than interactions between them, subtly altering the frequency with which two fragments end up linked together during Hi-C.
Enlarge/ An artist’s conception of one of the last mammoths of Wrangel Island.
Beth Zaiken
A small group of woolly mammoths became trapped on Wrangel Island around 10,000 years ago when rising sea levels separated the island from mainland Siberia. Small, isolated populations of animals lead to inbreeding and genetic defects, and it has long been thought that the Wrangel Island mammoths ultimately succumbed to this problem about 4,000 years ago.
A paper in Cell on Thursday, however, compared 50,000 years of genomes from mainland and isolated Wrangel Island mammoths and found that this was not the case. What the authors of the paper discovered not only challenges our understanding of this isolated group of mammoths and the evolution of small populations, it also has important implications for conservation efforts today.
A severe bottleneck
It’s the culmination of years of genetic sequencing by members of the international team behind this new paper. They studied 21 mammoth genomes—13 of which were newly sequenced by lead author Marianne Dehasque; others had been sequenced years prior by co-authors Patrícia Pečnerová, Foteini Kanellidou, and Héloïse Muller. The genomes were obtained from Siberian woolly mammoths (Mammuthus primigenius), both from the mainland and the island before and after it became isolated. The oldest genome was from a female Siberian mammoth who died about 52,300 years ago. The youngest were from Wrangel Island male mammoths who perished right around the time the last of these mammoths died out (one of them died just 4,333 years ago).
Enlarge/ Wrangel Island, north of Siberia has an extensive tundra.
Love Dalén
It’s a remarkable and revealing time span: The sample included mammoths from a population that started out large and genetically healthy, went through isolation, and eventually went extinct.
Mammoths, the team noted in their paper, experienced a “climatically turbulent period,” particularly during an episode of rapid warming called the Bølling-Allerød interstadial (approximately 14,700 to 12,900 years ago)—a time that others have suggested might have led to local woolly mammoth extinctions. However, the genomes of mammoths studied through this time period don’t indicate that the warming had any adverse effects.
Adverse effects only appeared—and drastically so—once the population was isolated on that island.
The team’s simulations indicate that, at its smallest, the total population of Wrangel Island mammoths was fewer than 10 individuals. This represents a severe population bottleneck. This was seen genetically through increased runs of homozygosity within the genome, caused when both parents contribute nearly identical chromosomes, both derived from a recent ancestor. The runs of homozygosity within isolated Wrangel Island mammoths were four times as great as those before sea levels rose.
Despite that dangerously tiny number of mammoths, they recovered. The population size, as well as inbreeding level and genetic diversity, remained stable for the next 6,000 years until their extinction. Unlike the initial population bottleneck, genomic signatures over time seem to indicate inbreeding eventually shifted to pairings of more distant relatives, suggesting either a larger mammoth population or a change in behavior.
Within 20 generations, their simulations indicate, the population size would have increased to about 200–300 mammoths. This is consistent with the slower decrease in heterozygosity that they found in the genome.
Long-lasting negative effects
The Wrangel Island mammoths may have survived despite the odds, and harmful genetic defects may not have been the reason for their extinction, but the research suggests their story is complicated.
At about 7,608 square kilometers today, a bit larger than the island of Crete, Wrangel Island would have offered a fair amount of space and resources, although these were large animals. For 6,000 years following their isolation, for example, they suffered from inbreeding depression, which refers to increased mortality as a result of inbreeding and its resulting defects.
That inbreeding also boosted the purging of harmful mutations. That may sound like a good thing—and it can be—but it typically occurs because individuals carrying two copies of harmful mutations die or fail to reproduce. So it’s good only if the population survives it.
The team’s results show that purging genetic mutations can be a lengthy evolutionary process. Lead author Marianne Dehasque is a paleogeneticist who completed her PhD at the Centre for Palaeogenetics. She explained to Ars that, “Purging harmful mutations for over 6,000 years basically indicates long-lasting negative effects caused by these extremely harmful mutations. Since purging in the Wrangel Island population went on for such a long time, it indicates that the population was experiencing negative effects from these mutations up until its extinction.”
Human brains (and the brains of other vertebrates) are able to process information faster because of myelin, a fatty substance that forms a protective sheath over the axons of our nerve cells and speeds up their impulses. How did our neurons evolve myelin sheaths? Part of the answer—which was unknown until now—almost sounds like science fiction.
Led by scientists from Altos Labs-Cambridge Institute of Science, a team of researchers has uncovered a bit of the gnarly past of how myelin ended up covering vertebrate neurons: a molecular parasite has been messing with our genes. Sequences derived from an ancient virus help regulate a gene that encodes a component of myelin, helping explain why vertebrates have an edge when it comes to their brains.
Prehistoric infection
Myelin is a fatty material produced by oligodendrocyte cells in the central nervous system and Schwann cells in the peripheral nervous system. Its insulating properties allow neurons to zap impulses to one another at faster speeds and greater lengths. Our brains can be complex in part because myelin enables longer, narrower axons, which means more nerves can be stacked together.
The un-myelinated brain cells of many invertebrates often need to rely on wider—and therefore fewer—axons for impulse conduction. Rapid impulse conduction makes quicker reactions possible, whether that means fleeing danger or capturing prey.
So, how do we make myelin? A key player in its production appears to be a type of molecular parasite called a retrotransposon.
Like other transposons, retrotransposons can move to new locations in the genome through an RNA intermediate. However, most retrotransposons in our genome have picked up too many mutations to move about anymore.
RNLTR12-int is a retrotransposon that is thought to have originally entered our ancestors’ genome as a virus. Rat genomes now have over 100 copies of the retrotransposon.
An RNA made by RNLTR12-int helps produce myelin by binding to a transcription factor or a protein that regulates the activity of other genes. The RNA/protein combination binds to DNA near the gene for myelin basic protein, or MBP, a major component of myelin.
“MBP is essential for the membrane growth and compression of [central nervous system] myelin,” the researchers said in a study recently published in Cell.
Technical knockout
To find out whether RNLTR12-int really was behind the regulation of MBP and, therefore, myelin production, the research team had to knock its level down and see if myelination still happened. They first experimented on rat brains before moving on to zebrafish and frogs.
When they inhibited RNLTR12-int, the results were drastic. In the central nervous system, genetically edited rats produced 98 percent less MBP than those where the gene was left unedited. The absence of RNLTR12-int also caused the oligodendrocytes that produce myelin to develop much simpler structures than they would normally form. When RNLTR12-int was knocked out in the peripheral nervous system, it reduced myelin produced by Schwann cells.
The researchers used a SOX10 antibody to show that SOX10 bound to the RNLTR12-int transcript in vivo. This was an important result, since there are lots of non-coding RNAs made by cells, and it wasn’t clear whether any RNA would work or if it was specific to RNLTR12-int.
Do these results hold up in other jawed vertebrates? Using CRISPR-CAS9 to perform knockout tests with retrotransposons related to RNLTR12-int in frogs and zebrafish showed similar results.
Myelination has enriched the vertebrate brain so it can work like never before. This is why the term “brain food” is literal. Healthy fats are so important for our brains; they help form myelin since it is a fatty acid. Think about that next time you’re pulling an all-nighter while reaching for a handful of nuts.
There are many mysteries in life that we end up shrugging off. Why is urine yellow? It just is, right? Rather than flush that 125-year-old question down the toilet, scientists sought out the answer, discovering a previously unknown microbial enzyme was to blame.
The enzyme that has eluded us for so long is now known as bilirubin reductase. It was identified by researcher and assistant professor Brantley Hall of the University of Maryland, who was part of a team based at the university and the National Institutes of Health.
Bilirubin is an orange pigment released by red blood cells after they die. Gut microbes then use bilirubin reductase to break down bilirubin into colorless urobilinogen, which degrades into yellowish urobilin, giving urine that infamous hue. While urobilin previously had an association with the color of urine, the enzyme that starts the process by producing urobilinogen was unknown until now.
“Though it was previously thought that multiple enzymes were involved in the reduction of bilirubin, our results support the finding that a single enzyme performs the reduction of bilirubin to urobilinogen,” the research team said in a study recently published in Nature Microbiology.
Gut feeling
Because some gut bacteria had been known to reduce bilirubin, Hall and his team knew where to start but wanted to fill in the unknowns by finding out which particular species actually do this—and how. This meant they had to find the gene responsible for encoding bilirubin reductase.
Previous studies had found that the species Clostridiodes difficile was capable of reducing bilirubin (though the mechanism it used was unknown). Using C. difficile as a basis for comparison, the team cultured different species of gut bacteria and exposed them to bilirubin to see whether that bacteria could produce urobilinogen, detecting its presence using a fluorescence assay.
The fluorescence assay told Hall and his colleagues that there were nine strains within the tested species that they thought were capable of reducing bilirubin, although how these bacteria were breaking it down was still unclear. After the fluorescence assay, the genomes of the most closely related strains were analyzed, and several turned out to share a gene that encoded an enzyme that could reduce bilirubin—bilirubin reductase.
Bacterial strains that metabolized bilirubin using bilirubin reductase all came from species that were found to belong to a single clade (the researchers informally referred to it as the bilirubin reductase clade). Within that clade, most of these species are from the class Clostridia in the phylum Firmicutes, a phylum of bacteria important to gut health.
More than … you know
The discovery of bilirubin reductase goes beyond the origin of urine color. After identifying the enzyme, the researchers found out that, while bilirubin reductase is present in healthy adults, there is a deficit in newborns and adults with inflammatory bowel disease, which could eventually influence future treatments
By sequencing infant gut genomes, Hall and his team saw that bilirubin reductase was often missing during the first few months of life. Too much bilirubin building up in the blood turns the skin and the whites of the eyes yellow, a symptom known as jaundice. Most infants have some level of jaundice, but it usually goes away on its own.
The absence of bilirubin reductase is also associated with pigmented gallstones in adults with inflammatory bowel disease (inflammatory bowel disease or IBD is a general term that can refer to several different diagnoses). Sequencing adult gut genomes showed that there was a deficit of this enzyme in most patients with Crohn’s disease or ulcerative colitis whose gut genomes were sequenced.
“With the knowledge of the species, genes, and enzymes involved in bilirubin reduction, future research can now focus on the extent to which gut microbial bilirubin metabolism affects…the role of bilirubin reduction in health and disease,” the researchers said in the same study.
There is still more research to be done on bilirubin reductase and the health implications it could have. The team thinks there may be a link between the amount of urobilin produced in the body and insulin resistance, obesity, heart disease, and even heart failure. Next to that, we finally know why urine is yellow.
