#14 Mutation Hotspots in Cancer, Sea Cows Linked To Humans and Hidden Plastics Found...
How mapping mutation hotspots reveals new biomarkers, the extinct sea cow is linked to a human skin disease and plastics discovered at deep deaths.
🧬Mutation “Hotspots” in Cancer…
Mapping Mutation Hotspots Reveals New Biomarkers and Drivers
A research team at the University of California San Diego has identified and characterised a new key player in cancer evolution. A cluster of mutations occurring at certain regions of the genome have been shown to contribute towards the progression of roughly 10% of human cancers and could have applications in predicting patient survival rates.
The findings reported in a Nature paper on February 9th shed light on a class of mutations called clustered somatic mutations. This means that they group together at specific areas in a cells genome with somatic indicating they are not inherited mutations rather caused by internal and external factors such as aging or exposure to UV radiation, for example.
The team saw something highly irregular about these mutations and their resultant cancer development. Ludmil Alexandrov, author of the study stated that “We typically see somatic mutations occurring randomly across the genome. But when we looked closer at some of these mutations, we saw that they were occurring in these hotspots. It's like throwing balls on the floor and then suddenly seeing them cluster in a single space,". This led to multiple questions from the team as to why they cluster in this way and whether they could be indicative of cancer likelihood and type.
Clustered mutations were found to play an important role in the etiology of human cancer. They have been largely ignored in the past due to their deemed insignificance and the fact that they only make up a small percentage of all mutations seen.
The discoveries made by the team were enabled through the creation of the most comprehensive and detailed map of known clustered somatic mutations. By mapping all the mutations - both clustered and non-clustered, across 2,500 cancer patient genomes, they were able to create a map that encompassed 30 different types of cancer. The team used artificial intelligence to develop the map and went on to use these AI algorithms to detect clustered mutations within individual patients and locate the underlying mutational processes that give rise to cancer. This led them to the conclusion that roughly 10% of human cancers are contributed to, by clustered somatic mutations.
Furthermore, researchers also found clusters that can be used to predict the overall survival of the patient. The presence of clustered mutations in the BRAF gene, linked to melanoma, results in better overall patient survival compared to individuals with non-clustered mutations. On the contrary, clustered mutations in the EGFR gene results in decreased lung cancer patient survival. This work emphasizes the importance of developing AI approaches to elucidate tumour biology.
The study also shed light on the various internal and environmental factors that cause clustered somatic mutations. These were UV radiation, alcohol consumption, tobacco smoking as well as antiviral enzymes called APOBEC3. These enzymes are typically located intracellularly with the function of breaking down viruses, however, in cancer cells they are believed to be doing more harm than good.
Researchers found that cancer cells, which typically have plenty of circular rings of extrachromosomal DNA (ecDNA) and often hold known cancer driver genes, have mutation clusters occurring across individual ecDNA molecules. The team attribute these mutations to the activity of APOBEC3 enzymes. They hypothesize that APOBEC3 enzymes are mistaking ecDNA rings as foreign viruses and attempting to restrict them and “chop them up”. In doing so they cause clusters of mutations to form within individual ecDNA molecules.
🐄Sea Cow Genome Shows Links To Humans?
The Extinct Steller’s Sea Cow Genome Reveals Link To Human Skin Condition…
Steller’s sea cow was an enormous creature and a close relative of both the dugong and manatees. They were a kelp eating species that inhabited cold water locations and hunted to extinction within just three decades of discovery. An international team of scientists have analysed the genome of the species underpinning some of the unusual features of Steller’s sea cows such as their thick, bark like skin. These findings published in Science Advances on February 4th, are based on ancient DNA that is extracted from the bones of 12 sea cows. The genomic analysis was compared with that of similar species and living relative such as the dugong, manatees and cetaceans.
Through analysing the genomes, past population sizes were gathered indicating that the Steller’s sea cow population had been in decline for a long time before their extinction. Whilst Beth Shapiro, professor of ecology and evolutionary biology at UC Santa Cruz admitted that the record is not very good, the demographic analyses still shows that the population was in decline for a least half a million years prior to their human induced extinction.
Through their genomic analyses, two genes were found that were associated with skin development and were shown to be inactivated in Steller’s sea cows. These genes code for lipoxygenase enzymes. Remarkably, these are the same genes that are inactivated by mutations in humans who are affected by skin disease. This disease is called ichthyosis and characterised by thick and rough skin. Whilst co-first author Molly Cassatt-Johnstone said that “We can only speculate about what drove this adaptation in Steller’s sea cows,” “The thick skin could very well have helped them maintain their core temperature in cold water, and it could also have been defensive or protective.”
Analysis of the genomic make up of the previously mentioned marine mammals shows that the lipoxygenase genes inactivated in Steller’s sea cows are also inactivated in whales and other cetaceans. They are however active in seals, sea lions, sea otters, dugongs and manatees. Cetaceans have shown to shed their outer layer of skin rapidly which prevents the build up of thick skin that would otherwise occur in the absence of the lipoxygenase enzymes.
The researchers of the study also found similarities between Steller’s sea cows and cetaceans in certain genes involved in energy metabolism suggesting that both lineages evolved similar adaptations to cold-water habitats. This is known as convergent evolution, the process by which distantly related organisms independently evolve similar adaptations and traits. “In this case, Steller’s sea cows and whales have independently evolved mutations in the same genes, multiple times in different lineages,” Cassatt-Johnstone said.
Genomes from the past are key in helping us understand the animals of today. Understanding both human influence and environmentally triggered adaptations allows the team to better help endangered animals such as the dugong and manatees which were the initial motivation for the study.
🪥Missing Plastics Uncovered…
Scientists have uncovered plastics from deep in the ocean
Microplastics are defined as extremely small pieces of plastic debris in the environment, they originate in consumer products and industrial waste. Roughly 51 trillion pieces of microplastic are floating the surface of the ocean around the world. Hundreds of academic studies have surveyed the plastic debris on the surface or the top few meters of the ocean.
Florida Atlantic University led a study, being the first to unveil the prevalence of plastic throughout the water column. The study took place in the Southern Atlantic Ocean and describes the ocean interior as “a crucial pool of missing plastic”. The results published in the Global Change Biology journal, demonstrate the critical importance of microplastics and their integral role in the oceanic plastic inventory. Furthermore, the study shows how hotspots form of small microplastics at greater depths as a result of weak oceanic currents, resultantly leading to contact with subsurface feeder organisms such as zooplankton.
"Our study highlights the urgency for more quantification of the deep-ocean microplastics, especially the smaller size fraction, to better understand ecosystem exposure and to predict the fate and impacts of these microplastics," said Tracy Mincer a Ph.D. and senior author of the study. To help in gaining a better mechanistic understanding of how plastics sink from the ocean surface beyond the mixed layer, the research team sampled plastic particles in the South Atlantic Subtropical Gyre through in-situ high-volume filtration sampling and infrared imaging.
They found that the distribution and abundance of microplastics varied both geographically and vertically due to the complex and intertwined interactions taking place on the plastic. High density polymers were found to be highly concentrated in comparison to other microplastics, making up over 65% of total pump sample count in the study. "As plastic particles disintegrate into smaller size fractions, they can become harmful in different and unpredictable ways that are only now beginning to be understood," said Mincer. "These micron-size microplastics can move across the gut epithelium, become trapped in biomass, and have the potential to transfer through marine food webs, posing an unknown ecological risk and biogeochemical impacts."
The combined analysis procedure used by the research team provides a far more integrative view of distribution of microplastic particles in the interior of an ocean gyre as well as their biological impact.
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🧬Mutation “Hotspots” in Cancer…
University of California - San Diego. "Mapping mutation ‘hotspots’ in cancer reveals new drivers and biomarkers." ScienceDaily. ScienceDaily, 9 February 2022. <www.sciencedaily.com/releases/2022/02/220209112102.htm>.
Erik N. Bergstrom, Jens Luebeck, Mia Petljak, Azhar Khandekar, Mark Barnes, Tongwu Zhang, Christopher D. Steele, Nischalan Pillay, Maria Teresa Landi, Vineet Bafna, Paul S. Mischel, Reuben S. Harris, Ludmil B. Alexandrov. Mapping clustered mutations in cancer reveals APOBEC3 mutagenesis of ecDNA. Nature, 2022; DOI: 10.1038/s41586-022-04398-6
🐄Sea Cow Genome Shows Links To Humans?
EurekAlert (2022) https://www.eurekalert.org/news-releases/942933
Le Duc, D., Velluva, A., Cassatt-Johnstone, M., Olsen, R., Baleka, S., Lin, C., Lemke, J., Southon, J., Burdin, A., Wang, M., Grunewald, S., Rosendahl, W., Joger, U., Rutschmann, S., Hildebrandt, T., Fritsch, G., Estes, J., Kelso, J., Dalén, L., Hofreiter, M., Shapiro, B. and Schöneberg, T., 2022. Genomic basis for skin phenotype and cold adaptation in the extinct Steller’s sea cow. Science Advances, 8(5).
🪥Missing Plastics Uncovered…
PHYSORG. (2022) Gisele Galoustian, Florida Atlantic University. https://phys.org/news/2022-02-scientists-uncover-plastics-deep-ocean.html
Shiye Zhao et al, Large quantities of small microplastics permeate the surface ocean to abyssal depths in the South Atlantic Gyre, Global Change Biology (2022). DOI: 10.1111/gcb.16089
Left Image Credit: Members of the Pelagia cruise 64PE448/Florida Atlantic University