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Mammoth genes that differed from their counterparts in elephants played roles in skin and hair development, fat metabolism, insulin signaling and numerous other traits. Genes linked to physical traits such as skull shape, small ears and short tails were also identified. As a test of function, a mammoth gene involved in temperature sensation was resurrected in the laboratory and its protein product characterized.
The study, published in Cell Reports on July 2, sheds light on the evolutionary biology of these extinct giants.
“This is by far the most comprehensive study to look at the genetic changes that make a woolly mammoth a woolly mammoth,” said study author Vincent Lynch, PhD, assistant professor of human genetics at the University of Chicago. “They are an excellent model to understand how morphological evolution works, because mammoths are so closely related to living elephants, which have none of the traits they had.”
Woolly mammoths last roamed the frigid tundra steppes of northern Asia, Europe and North America roughly 10,000 years ago. Well-studied due to the abundance of skeletons, frozen carcasses and depictions in prehistoric art, woolly mammoths possessed long, coarse fur, a thick layer of subcutaneous fat, small ears and tails and a brown-fat deposit behind the neck which may have functioned similar to a camel hump.
Previous efforts to sequence preserved mammoth DNA were error-prone or yielded insights into only a limited number of genes.
To thoroughly characterize mammoth-specific genes and their functions, Lynch and his colleagues deep sequenced the genomes of two woolly mammoths and three Asian elephants – the closest living relative of the mammoth. They then compared these genomes against each other and against the genome of African elephants, a slightly more distant evolutionary cousin to both mammoths and Asian elephants.
The team identified roughly 1.4 million genetic variants unique to woolly mammoths. These caused changes to the proteins produced by around 1,600 genes, including 26 that lost function and one that was duplicated. To infer the functional effects of these differences, they ran multiple computational analyses, including comparisons to massive databases of known gene functions and of mice in which genes are artificially deactivated.
Genes with mammoth-specific changes were most strongly linked to fat metabolism (including brown fat regulation), insulin signaling, skin and hair development (including genes associated with lighter hair color), temperature sensation and circadian clock biology – all of which would have been important for adapting to the extreme cold and dramatic seasonal variations in day length in the Arctic. The team also identified genes associated with the mammoth body plan, such as skull shape, small ears and short tails.
Of particular interest was the group of genes responsible for temperature sensation, which also play roles in hair growth and fat storage. The team used ancestral sequence reconstruction techniques to “resurrect” the mammoth version of one of these genes, TRPV3. When transplanted into human cells in the laboratory, the mammoth TRPV3 gene produced a protein that is less responsive to heat than an ancestral elephant version of the gene. This result is supported by observations in mice that have TRPV3 artificially silenced. These mice prefer colder environments than normal mice and have wavier hair.
Although the functions of these genes match well with the environment in which woolly mammoths were known to live, Lynch warns that it is not direct proof of their effects in live mammoths. The regulation of gene expression, for example, is extremely difficult to study through the genome alone.
“We can’t know with absolute certainty the effects of these genes unless someone resurrects a complete woolly mammoth, but we can try to infer by doing experiments in the laboratory,” he said. Lynch and his colleagues are now identifying candidates for other mammoth genes to functionally test as well as planning experiments to express mammoth proteins in elephant cells.
While his efforts are targeted toward understanding the molecular basis of evolution, Lynch acknowledges that the high-quality sequencing and analysis of woolly mammoth genomes can serve as a functional blueprint for efforts to “de-extinct” the mammoth.
“Eventually we’ll be technically able to do it. But the question is: if you’re technically able to do something, should you do it?” he said. “I personally think no. Mammoths are extinct and the environment in which they lived has changed. There are many animals on the edge of extinction that we should be helping instead.”
The sense of smell plays a decisive role in human societies, as it is linked to our taste for food, as well as our identification of pleasant and unpleasant substances.
We have about 4 million smell cells in our noses, divided into about 400 different types. There is tremendous genetic variability within and between populations for our ability to detect odours. Each smell cell carries just one type of receptor or ‘lock’ on it – the smell floats through the air, fits into the ‘lock’ and then activates the cell.
Most receptors can detect more than one smell, but one, called OR7D4, enables us to detect a very specific smell called androstenone, which is produced by pigs and is found in boar meat. People with different DNA sequences in the gene producing the OR7D4 receptor respond differently to this smell – some people find it foul, some sweet, and others cannot smell it at all. People’s responses to androstenone can be predicted by their OR7D4 DNA sequence, and vice versa.
Professor Cobb from The University of Manchester’s Faculty of Life Sciences and the other researchers studied the DNA that codes for OR7D4 from over 2,200 people from 43 populations around the world, many of them from indigenous groups. They found that different populations tend to have different gene sequences and therefore differ in their ability to smell this compound.
For example, they found that populations from Africa – where humans come from – tend to be able to smell it, while those from the northern hemisphere tend not to. This shows that when humans first evolved in Africa, they would have been able to detect this odour.
Statistical analysis of the frequencies of the different forms of the OR7D4 gene from around the world suggested that the different forms of this gene might have been subject to natural selection.
One possible explanation of this selection is that the inability to smell androstenone was involved in the domestication of pigs by our ancestors – andostroneone makes pork from uncastrated boars taste unpleasant to people who can smell it. Pigs were initially domesticated in Asia, where genes leading to a reduced sensitivity to androstenone have a high frequency.
The group also studied the OR7D4 gene in the ancient DNA from two extinct human populations, Neanderthals and the Denisovans, whose remains were found at the same site in Siberia, but who lived tens of thousands of years apart.
The group found that Neanderthal OR7D4 DNA was like our own – they would have been able to smell androstenone. The Denisovans are a mysterious group of our extinct relatives – we do not know what they looked like, and they are known from only one tooth and a finger bone, from different individuals.
Their DNA showed a unique mutation, not seen in humans or Neanderthals, that changed the structure of the OR7D4 receptor.
Team-member Hiroaki Matsunami at Duke University in the USA reconstructed the Denisovan OR7D4 and studied how this tiny part of a long-extinct nose responded to androstenone. It turned out that despite the mutation, the Denisovan nose functioned like our own. Both of our close relatives, like our early human ancestors, would have been able to detect this strange smell.
This research shows how global studies of our genes can give insight into how our taste for different foods may have been influenced by variation in our ability to smell, and, excitingly, show that it is possible to see back into deep evolutionary time and reconstruct the sensory world of our distant ancestors.
The research was carried out by scientists from the University of Alaska Fairbanks, State University of New York, Duke University and The University of Manchester, and is published in the journal Chemical Senses.
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