After woolly mammoths became extinct in mainland Europe and Siberia approximately 10,500 years ago, a small population survived on remote islands north of the Arctic Circle. Isolated from human hunters and protected from climate change by their high latitude, these mammoths lived for another 6,000 years.
The cause of their eventual extinction has long been a subject of speculation, but a new study published in the journal Genome Biology and Evolution may hold the answer: inbreeding. Scientists compared Wrangel Island mammoth DNA to earlier mammoth DNA and to modern-day elephants, identifying mutations that could be harmful to survival. To validate the theory, the scientists resurrected several of the mutated genes and tested them in living animals.
As part of this work, scientists at the University of Chicago and the University at Buffalo enlisted Brian Mitchell, PhD, associate professor of Cell and Developmental Biology and co-author of the study, to test mutations in the gene HYLS in living animals.
Read more about the study and Mitchell’s experience in the Q&A below.
How did you get involved in this project?
When Vincent Lynch, the lead author of the study, was comparing genetic sequences from older mammoths to the Wrangel Island mammoths, several genes jumped out as likely important. One of these genes, HYLS, is a gene that when mutated in humans causes a horrible embryonic lethal disease called hydrolethalus syndrome.
We had previously characterized this gene HYLS and found that it caused mutations in cilia, which are known to be involved in signaling for lots of different pathways. My lab studies cilia, and work from my lab and many others has indicated that defects in primary cilia lead to a wide range of problems.
How did your collaborators identify potentially harmful mutations?
While there are many interesting variations to the study of DNA, the ability to reliably predict the transcription of DNA into RNA and, ultimately, the translation into protein sequences facilitates our ability to compare various genomes. However, if there are mutations in the DNA, then the predicted protein products may not be functional. While one can easily test this in many living lab animals, this has been a challenge for extinct animals.
Our collaborators compared the genomes of several woolly mammoths from different places and time periods as well as modern day elephants who are evolutionarily quite close. Most of the genomes lined up pretty closely but the last living population on Wrangle Island didn’t match up. Due to geographical isolation and low population numbers, it was predicted that this population accumulated a large number of deleterious mutations.
How did you test these mutations in woolly mammoth DNA in living animals?
My lab uses frog embryos as our model system. We took frogs and depleted their HYLS gene, finding they did not develop properly. Then, we inserted the human equivalent of HYLS into their genome and found that it rescued the phenotype. This established that the mammalian HYLS is close enough to act as a substitute.
Then, we inserted the mutated Wrangel Island mammoth HYLS and we found that also caused developmental problems. This allowed us to conclude that the gene we found in this extinct woolly mammoth is not a functional gene.
Do you think this could have been the cause of extinction?
I think that’s a fairly well established evolutionary principle: if you take a small population and you put it on an island, there’s going to be inbreeding and that’s going to lead to more frequent and harmful genetic mutations. However, it is hard to establish if a particular mutation is actually deleterious. Here we showed that the Wrangel Island HYLS was not functional and likely contributed to the demise of this population.
It would be nice to do this type of analysis in a much broader study. We did it with a handful of genes and really you probably want to do it with one hundred or so. But, that would be a big project, and the funding for woolly mammoth studies is a little low.
What did you think of this experience?
While this work was outside of our typical focus, my lab prides ourselves on performing curiosity driven science and I am extremely gratified that we’re still able to do that. This was a cool experience, and it adds some additional motivation for the community to find as much frozen DNA as possible so that we can learn more about every extinct animal.