Cancer-resistant blind mole rat

 

Cancer-resistant blind mole rat gets genome sequence

Cancer-resistant blind mole rat gets genome sequence

Scientists have sequenced the genome of the blind mole rat, a mammal that digs with its teeth, has skin over its eyes and lives for more than 20 years.

Its underground lifestyle means coping with no light, very little oxygen and an awful lot of dirt.

It is also resistant to cancer, like its distant cousin the naked mole rat.

The new work, published in the journal Nature Communications, will help unpick those secrets and the wider adaptation of animals to difficult environments.

Among the results were what the researchers believe are the genetic signatures of the mole rat’s complete loss of vision and its impressive tolerance of low oxygen (or “hypoxia”).

They also discovered how its special cancer-fighting mechanism might have evolved.

One of the study’s lead authors, Prof Eviatar Nevo from the University of Haifa in Israel, has studied blind mole rats for more than 50 years. In all of that time, a spontaneous tumour has never been discovered.

Even when treated with carcinogenic chemicals, these remarkable rodents were incredibly resistant to cancer.

Most animals rely on cells detecting a cancerous malfunction and shutting themselves down (programmed cell death or “apoptosis”), but the blind mole rat’s immune system attacks tumours and causes “necrosis” instead. The new study reports that genes involved in this immune defence have been favoured by evolution, and some have been expanded or duplicated.

All this may have happened because one of the key mediators of the normal cell-shutdown defence, a protein called p53, is mutated in the mole rats as part of their adaptation to low oxygen.

The mole rat spends its entire life under the ground, where oxygen is scarce. In other animals this would send p53 into overdrive.

“When there is low oxygen, in other species, [normal p53] would mean that some cells would die from apoptosis – but not in blind mole rats, because that would be a disaster,” said Dr Denis Larkin from the Royal Veterinary College in London, one of the study’s authors.

So the mole rats have evolved a unique trade-off, weakening p53 and boosting the immune system’s necrotic defence, which “the cancer doesn’t know how to deal with,” Dr Larkin told BBC News.

The genome study was carried out by a large team of researchers that also spanned China, Israel, the US and Denmark. Dr Larkin was involved in piecing together the evolution of the animal’s chromosomes, having done similar work on other genomes ranging from the pig to the yak.

He told the BBC the findings would shift the blind mole rat to “a new level” in the research community. “When you have the whole genome… you can more efficiently use the species as a model – for cancer resistance, or adaptation to hypoxia, or other medical challenges.”

The naked mole rat, also studied for its cancer resistance, is a distant relative of the blind mole rat

Dr Philippa Brice, from the genomics think-tank PHG Foundation at the University of Cambridge, told BBC News the mole rats and their “really unusual lifestyle” had already been valuable to scientists studying cancer resistance. She agreed that the genome sequence would mean more rapid progress.

“Now that their complete genome is available, it will make it much easier to probe their unique genetic features, with potential applications for human medical research,” Dr Brice said.

The blind mole rat (the newly sequenced species is Spalax galili) is only distantly related to the naked mole rat (Heterocephalus glaber), another unusual, subterranean critter with remarkable cancer resistance.

Their evolutionary histories diverged over 70 million years ago, according to calculations in the new study, and the two mole rats adapted completely separately to life underground.

In fact, the furry-but-blind Spalax is a closer cousin to the common house mouse than to the “sabre-toothed sausage” lookalike Heterocephalus.

 

Hominin DNA suggests link to mystery population

A dig at the Sima de los Huesos cave in Spain, the site of ancient hominin fossils.

Hominin DNA baffles experts  Analysis of oldest sequence from a human ancestor suggests link to mystery population.

Hominin DNA baffles experts
Analysis of oldest sequence from a human ancestor suggests link to mystery population.

 

Another ancient genome, another mystery. DNA gleaned from a 400,000-year-old femur from Spain has revealed an unexpected link between Europe’s hominin inhabitants of the time and a cryptic population, the Denisovans, who are known to have lived much more recently in southwestern Siberia.

The DNA, which represents the oldest hominin sequence yet published, has left researchers baffled because most of them believed that the bones would be more closely linked to Neanderthals than to Denisovans. “That’s not what I would have expected; that’s not what anyone would have expected,” says Chris Stringer, a palaeoanthropologist at London’s Natural History Museum who was not involved in sequencing the femur DNA.

The fossil was excavated in the 1990s from a deep cave in a well-studied site in northern Spain called Sima de los Huesos (‘pit of bones’). This femur and the remains of more than two dozen other hominins found at the site have previously been attributed either to early forms of Neanderthals, who lived in Europe until about 30,000 years ago, or to Homo heidelbergensis, a loosely defined hominin population that gave rise to Neanderthals in Europe and possibly humans in Africa.

But a closer link to Neanderthals than to Denisovans was not what was discovered by the team led by Svante Pääbo, a molecular geneticist at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany.

The team sequenced most of the femur’s mitochondrial genome, which is made up of DNA from the cell’s energy-producing structures and passed down the maternal line. The resulting phylogenetic analysis ­— which shows branches in evolutionary history — placed the DNA closer to that of Denisovans than to Neanderthals or modern humans. “This really raises more questions than it answers,” Pääbo says.

The team’s finding, published online in Nature this week, does not necessarily mean that the Sima de los Huesos hominins are more closely related to the Denisovans, a population that lived thousands of kilometres away and hundreds of thousands of years later, than to nearby Neanderthals. This is because the mitochondrial genome tells the history of just an individual’s mother, and her mother, and so on.

 

Nuclear DNA, by contrast, contains material from both parents (and all of their ancestors) and typically provides a more accurate overview of a population’s history. But this was not available from the femur.

With that caveat in mind, researchers interested in human evolution are scrambling to explain the surprising link, and everyone seems to have their own ideas.

Pääbo notes that previously published full nuclear genomes of Neanderthals and Denisovans suggest that the two had a common ancestor that lived up to 700,000 years ago. He suggests that the Sima de los Huesos hominins could represent a founder population that once lived all over Eurasia and gave rise to the two groups. Both may have then carried the mitochondrial sequence seen in the caves. But these mitochondrial lineages go extinct whenever a female does not give birth to a daughter, so the Neanderthals could have simply lost that sequence while it lived on in Denisovan women.

“I’ve got my own twist on it,” says Stringer, who has previously argued that the Sima de los Huesos hominins are indeed early Neanderthals. He thinks that the newly decoded mitochondrial genome may have come from another distinct group of hominins. Not far from the caves, researchers have discovered hominin bones from about 800,000 years ago that have been attributed to an archaic hominin called Homo antecessor, thought to be a European descendant of Homo erectus. Stringer proposes that this species interbred with a population that was ancestral to both Denisovans and Sima de los Huesos hominins, introducing the newly decoded mitochondrial lineage to both populations .

This scenario, Stringer says, explains another oddity thrown up by the sequencing of ancient hominin DNA. As part of a widely discussed and soon-to-be-released analysis of high-quality Denisovan and Neanderthal nuclear genomes, Pääbo’s team suggests that Denisovans seem to have interbred with a mysterious hominin group.

The situation will become clearer if Pääbo’s team can eke nuclear DNA out of the bones from the Sima de los Huesos hominins, which his team hopes to achieve within a year or so.

Obtaining such sequences will not be simple, because nuclear DNA is present in bone at much lower levels than mitochondrial DNA. And even obtaining the partial mitochondrial genome was not easy: the team had to grind up almost two grams of bone and relied on various technical and computational methods to sequence the contaminated and damaged DNA and to arrange it into a genome. To make sure that they had identified genuine ancient sequences, they analysed only very short DNA strands that contained chemical modifications characteristic of ancient DNA.

Clive Finlayson, an archaeologist at the Gibraltar Museum, calls the latest paper “sobering and refreshing”, and says that too many ideas about human evolution have been derived from limited samples and preconceived ideas. “The genetics, to me, don’t lie,” he adds.

Even Pääbo admits that he was befuddled by his team’s latest discovery. “My hope is, of course, eventually we will not bring turmoil but clarity to this world,” he says.