Weddell Seals have the impressive ability to dive to depths approaching one kilometre for up to an hour at a time. Now, insights from a genomics study led by scientists at the Earlham Institute have highlighted the role that microRNAs can play in driving this adaptive evolution.
Weddell Seals have the impressive ability to dive to depths approaching one kilometre for up to an hour at a time. Many physiological adaptations, from extreme cardiovascular control to precise lipid metabolism, have been identified which allow this elite diving capability. Now, insights from a genomics study led by scientists at the Earlham Institute have highlighted the role that microRNAs can play in driving this adaptive evolution.
How long can you hold your breath?
Now imagine plunging into a frosted mass of water, scouting the profound murk for Antarctic cod, diving all the way down to the deep seabed to scavenge for shrimp, squid and crustaceans. Your body has shut off most of its functions outside of the core, yet your brain - despite the near zero degree temperatures - is switched on to tactile sensations thanks to the whiskers abundant in nerve endings which help you navigate this extreme hunting ground, even in the pitch darkness of winter.
Each foray into the icy depths is a masterclass in fine control and tuning. The blood and muscles, well equipped to deal with periods of anoxia, are rich in haemoglobin and myoglobin which store abundant oxygen. That precious life resource is then economised through judicious lipid metabolism. The alveoli of the lungs, under the intense pressures of the deep, collapse entirely - helping to avoid the bends.
We’re talking about the Weddell Seal, an Antarctic-dwelling mammal that can dive to depths approaching 1km in freezing cold waters while chasing prey for up to sixty minutes. This impressive feat is enabled through a number of adaptations, including extreme cardiovascular control while submerged and a finely tuned metabolism able to cope with hypoxia.
A better understanding of how Weddell Seals have developed such adaptations has relevance for a number of human conditions, including hypoxia and hyperlipidaemia (high cholesterol, for example), yet until now there has been a relative lack of understanding of these adaptations at the genetic level.
An Earlham Institute-led team has, therefore, probed the adaptive evolution of deep diving in Weddell Seals through investigating a potent regulator of genes in mammals - microRNA (miRNA). The findings, work of first author Dr Luca Penso-Dolfin (now a scientist at the German Cancer Research Centre) along with collaborator Dr Allyson Hindle at the University of Nevada, were recently published in BMC Genomics - representing the first ever miRNA annotation of the Weddell Seal genome.
This impressive feat is enabled through a number of adaptations, including enhanced oxygen storage capacity in the blood and muscles, extreme cardiovascular control while submerged, and lipid-based metabolism under hypoxia.
A genetic dimmer switch (which you can read about in more detail here), miRNA acts after genes have been activated - intervening before genes can then go on to make proteins. This is possible due to the nature of miRNAs, which are small pieces of RNA that bind to the messenger RNA (mRNA) copy of DNA that relays the information from gene to protein.
Once the miRNA has targeted the mRNA, that mRNA is destroyed. In this way, miRNA is a way for cells to make more or less of a certain gene product, which is why - from the same DNA sequence - we get different cells and tissues which perform different functions. From the same set of genes, we get eyes that can see, blood that can transport oxygen, and hands that can feel. Much of this is down to the fine-tuning performed by miRNAs.
An interesting feature of seals is that because pups are born on the ice, the young must go through a development phase before they leave their safe platform for the open sea, which includes a period of fasting. This differs in an important way compared to, say, cetaceans - which give birth to young in the open water.
The difference provides researchers with a perfect opportunity to study some of the changes that manifest in growing seals that then allow them to dive as adults, a very strong candidate behind these changes being the post-transcriptional regulation by miRNAs.
By comparing miRNA throughout different tissues (heart, brain, plasma and muscle) relevant to the Seals’ special physiology at different life stages, the team was able to note some interesting differences in how genes are regulated between adults and pups, and between different tissue types, and therefore shed some light on the specific miRNAs that might lead to particular adaptations, and even genetic pathways linked to disease in humans.
As an example; several of the most differentially expressed miRNAs (miRNAs in much greater amounts in one tissue compared to all of the others), in the hearts of Weddell Seals were found, through computational analysis, to target genes linked to known cardiac diseases such as cardiomyopathy - a disease of heart muscle that makes it more difficult to pump blood around the body and can lead to heart attack.
Overall, the team identified hundreds of miRNAs that were more abundant in different tissues, including 80 that were expressed differently across all tissues between adults and pups, and another 188 that showed age-related changes in specific tissues. Among these were miRNAs completely unique to the Weddell Seal.
By comparing miRNA throughout different tissues (heart, brain, plasma and muscle) relevant to the Seals’ special physiology at different life stages, the team was able to note some interesting differences in how genes are regulated between adults and pups.
To explore the development of the elite diving ability of seals specifically, the team looked at miRNAs which differed in expression level between adults and pups. In total there were 220 tissue specific differences noted in the brain, heart and muscles (no differences were noted in the blood plasma miRNAs).
Among these, and of great relevance to elite diving, were several miRNAs that targeted genes involved in the hypoxia response - which of course comes strongly into play during respiration while holding your breath. One miRNA, which showed a reduced expression in the heart in adult seals compared to pups (and a strongly reduced expression overall), was predicted to target a gene, Egln3, which itself regulates the hypoxia response as well as the glycolysis pathway during respiration.
Another interesting target identified was the nitric oxide (NO) signalling pathway. NO is an incredibly potent vasodilator in mammals, and therefore of great potential interest when understanding how animals can regulate their blood flow while diving in icy seas. A related finding was that, of the miRNAs completely unique to the Weddell Seal, three showed an increase in both the heart and skeletal muscles of adults and targeted an important gene involved in vasoconstriction, as well as several lipid transporters.
Among these were several miRNAs that targeted genes involved in the hypoxia response - which of course comes strongly into play during respiration while holding your breath.
The examples above are predictions developed using powerful computational algorithms. To confirm their importance relevant to elite diving would require functional validation of their biology in seals.
There are also always considerations when it comes to the samples used. For example, the team noticed very few differences in miRNA expression in blood plasma between pups and adults. However, while muscle, heart and brain tissue was collected from dead seals (pups dying of natural causes in their first week of life), blood was collected from live animals - and so as not to disrupt the relationship between mother and pup, this was performed on young seals after weaning. In this way, it’s possible that differences in miRNA in the blood between adults and pups were underrepresented.
All this considered, the study - which provides the first ever, and thorough, miRNA annotation of the Weddell Seal genome - identified a number of miRNAs that link very well with the physiological adaptations of Weddell Seals which enable their elite diving ability.
The study of non-human genomes has the potential to unlock previously inaccessible therapeutic angles. Understanding the genes and their modifications that allow other organisms to live in extreme environments, from blazing hot deserts to icy tundra, has strongly relevant consequences for identifying targets in human disease.
Professor Federica Di Palma said, “this study provides a fantastic platform for future studies from both an evolutionary and a biomedical perspective. The results point towards useful hypotheses to follow up on, providing an avenue to probe how the extreme adaptations of the Weddell Seal can inform research into therapies for conditions ranging from hypoxia through to high cholesterol and cardiovascular disease.”
“The next stage”, according to co-author Dr Wilfried Haerty, “is to focus on secondary comparative genomics studies to isolate genomic regions specific to the Weddell Seal and other deep diving animals relative to other mammals including humans, enabling the identification of targets to further explore.”
The study - which provides the first ever, and thorough, miRNA annotation of the Weddell Seal genome - identified a number of miRNAs that link very well with the physiological adaptations of Weddell Seals which enable their elite diving ability.
