by Emily Hasser | Dec 22, 2020 | Disease Genetics, Evolution
Main Takeaways:
- Genetic mutations that lead to uncontrolled cell proliferation can cause cancerous tumors. Random genetic mutations occur at every cell division. As more cell divisions accumulate, there are increased chances for a cancer-causing mutation. While one would expect that larger organisms would be at an increased risk for cancer because they accumulate greater amounts of cell divisions, this is not the case for elephants and whales.
- Several hypotheses may explain this paradox: shorter telomeres, negative selection against hypertumors, and variation in the TP53 gene. Read below for more detail.
In the United States, the National Cancer Institute estimates that about 1.8 million new cancer diagnoses and approximately 600,000 cancer-related deaths will occur in 2020 [1]. Furthermore, about 39.5% of people can expect to receive a cancer diagnosis at some point in their life [1]. Although cancer has many possible causes, downstream genetic mutations ultimately drive the development of cancer [2].
In multicellular organisms, genetic mutations don’t just affect a single, isolated cell, but can be passed on to many cells in the organism through cell division as the organism grows. Random genetic mutations occur at every cell division, and some of these can lead to uncontrolled cell proliferation resulting in the growth of tumors that can become cancerous. As an organism grows larger and lives longer, more cell divisions will occur in its body over its lifetime. One might expect that larger organisms would accumulate more mutations due to increased numbers of cell divisions and that there should be more chances for tumor growth. However, mortality due to cancer in large animals with long lifespans is not higher than in humans: this discrepancy is known as Peto’s Paradox [3]. If organisms the size of whales had up to 1,000 times the cancer risk than humans, as we might expect given the increased number of cell divisions and random mutations, it would be very unlikely for them to reproduce before succumbing to cancer.
Several hypotheses have been proposed to account for Peto’s Paradox, using data collected from large animals such as whales and elephants [3,4]. Studying cancer in wild mammals presents unique challenges due the lack of accessibility to populations and inability to control factors such as environmental exposures. However, whales, porpoises, and dolphins are all cetaceans, which is a group of wild animals that has been extensively studied [4]. Except for a few cases linked to environmental pollution, cancer in whales rarely occurs [3,4]. This makes them a great model organism for studying Peto’s Paradox. Since these organisms do not appear to have a high risk of cancer, it is suggested that their cancer prevention mechanisms are likely more effective than those of smaller organisms. Other researchers maintain that the rate of cancer development is the same, but cancer may not be as lethal in larger organisms. Here, I will describe hypotheses explaining Peto’s Paradox involving telomeres, hypertumors, and the tumor suppressor gene p53, in the order of least to most investigated.
Telomeres
Telomeres may play a critical role in cancer suppression in large organisms. Similar to how shoelaces have plastic aglets to prevent fraying, telomeres are repetitive DNA sequences located on both ends of each chromosome to prevent DNA damage [5]. Telomeres protect the important stretches of the genome located in the middle of the chromosomes and have recently become a hot topic in research due to possible implications in aging and cancer [5].
Telomeres (pictured in purple) gradually shorten each time a cell divides.
Telomeres deplete with every round of DNA replication. When the telomeres become too short, the cell becomes senescent, entering a dormant state in which it doesn’t divide. Researchers hypothesize that shortened telomeres in large organisms with long lifespans could explain their reduced cancer incidence [3]. Reducing the number of times an individual cell divides would reduce the opportunities for a mutation in an oncogene or tumor suppressor gene to occur. With fewer previous divisions for mutations to accumulate, the cell has a decreased risk of developing cancer. The exploration of telomere modifications as an explanation for Peto’s Paradox has just begun, and further research is needed to investigate the possibility.
Hypertumors
Another new hypothesis proposed to explain Peto’s Paradox is promising, but has only been illustrated in silico, or through a computer simulation. Researchers suggest that in larger animals, malignant tumors have a fitness disadvantage compared to benign tumors [4]. In a population of cancer cells with various phenotypes, natural selection may favor aggressive “hypertumors” that piggyback off the vascular growth of parent tumors. Acting as parasites, these hypertumors deplete the parent tumor’s resources and eventually destroy it. Unlike in small organisms, tumors need to reach a substantial size to have consequences in large organisms. Therefore, hypertumors have plenty of time to develop and damage the original tumor before the original tumor grows to a lethal size. As a result, cancer may still be more common in large organisms, just less lethal [4]. Additional research investigating tumor growth in living whales is needed before any concrete conclusions can be drawn.
TP53
Variation in TP53 has been identified as another possible explanation for Peto’s Paradox [3,6]. As a tumor suppressor gene, TP53 helps control cell growth, and mutations in the TP53 gene have been found in up to 50% of human cancers. The p53 protein expressed by this gene has primary roles in cell cycle arrest, DNA repair, and apoptosis. Mutations in the TP53 can lead to reduced expression of p53 and the uncontrolled cell growth that is a hallmark of cancer [7].
Imagine the cell cycle as the process of loading laundry into your washing machine. You’ve put the clothes and detergent in and started the wash cycle when soapy water suddenly starts seeping out of the crevices. Your instinct in this situation is probably to stop and turn off the washing machine to investigate the problem. Likewise, cell cycle arrest occurs when the cell notices that something is wrong, and all duplication processes stop to identify the problem. If you notice a fraying, broken wire poking out from behind the wall, you will probably choose to call an electrician instead of risking a do-it-yourself fix. In the cell cycle, p53 recognizes DNA damage and activates DNA damage response pathways to initiate DNA repair. Sometimes, your machine might be too broken to fix, and you must resort to removing it from your house and heading out to buy a new one. In a cell, the analogous process is apoptosis, where a severely damaged cell is marked for destruction and effectively killed before it can do further damage or proliferate.
To investigate the relationship of p53 and Peto’s Paradox, genome-wide studies were conducted, synthesizing data from 61 animals with a range of sizes [6]. These animals included large species such as the Asian elephant and woolly mammoth. Researchers found that as species evolved to be bigger, they acquired more copies of TP53, the gene that encodes the p53 protein. While humans only have one copy of the TP53 gene, the elephant genome contains 20 copies of TP53, resulting in greater production of p53 protein. This increase may be responsible for protecting these large organisms from developing cancer [6,8]. The role of p53 has evolutionary implications because when p53 evolved as a way to regulate the cell cycle, it fortified the system in place to ensure DNA was replicated correctly and cells with mistakes were killed before the issue could spread.
Although many explanations have been proposed to account for Peto’s Paradox, more research is necessary to elucidate the precise molecular basis of the paradox. Mouse models currently dominate studies in cancer research, but they are small organisms with short life spans. Although these characteristics are useful when researchers want to conduct a study over an organism’s lifetime, they also mean that the mouse model is not the ideal model for studying cancer suppression. Expanding the study of cancer to a more diverse variety of organisms would allow for a more complete understanding of the underlying mechanisms.
Understanding Peto’s Paradox is not only important for conservation scientists and wildlife zoologists; it also has implications in human medicine. Peto’s Paradox provides an interesting opportunity for potential research that may provide insight into cancer treatment. Determining the mechanism behind cancer resistance in large animals could reveal powerful techniques to develop novel treatments for human cancers by targeting telomere length, p53 expression, or hypertumors.
References
[1] Cancer Statistics. National Cancer Institute. https://www.cancer.gov/about-cancer/understanding/statistics. Accessed December 20, 2020.
[2] Griffiths AJF, Miller JH, Suzuki DT, et al. An Introduction to Genetic Analysis. 7th edition. New York: W. H. Freeman; 2000. Mutation and cancer. Available from: https://www.ncbi.nlm.nih.gov/books/NBK21809/
[3] Caulin AF, Maley CC. Peto’s Paradox: evolution’s prescription for cancer prevention. Trends in Ecology & Evolution. 2011;26(4):175-182. doi:10.1016/j.tree.2011.01.002
[4] Nagy JD, Victor EM, Cropper JH. Why don’t all whales have cancer? A novel hypothesis resolving Peto’s paradox. Integrative and Comparative Biology. 2007;47(2):317-328. doi:10.1093/icb/icm062
[5] Are Telomeres the Key to Aging and Cancer. Learn.Genetics Genetic Science Learning Center. https://learn.genetics.utah.edu/content/basics/telomeres/. Accessed November 15, 2020.
[6] Sulak M, Fong L, Mika K, et al. TP53 copy number expansion is associated with the evolution of increased body size and an enhanced DNA damage response in elephants. eLife. 2016;5. doi:10.7554/elife.11994
[7] Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol. 2010;2(1):a001008. doi:10.1101/cshperspect.a001008
[8] Abegglen LM, Caulin AF, Chan A, et al. Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans. JAMA. 2015;314(17):1850-1860. doi:10.1001/jama.2015.13134
by Hanley Kingston | Apr 28, 2020 | Evolution
Main Takeaways:
- Neurological diseases and disorders that strike during young age present some fascinating questions. 1) Is there a link between a genetic predisposition to these conditions and a propensity for genius or creative talent? 2) How have these often debilitating conditions remained so common, when many evolutionary models suggest the genetic risk factors for these diseases would have been eliminated through evolution?
- New research shows that many early-acting hereditary neurological diseases are caused by similar types of genetic mutations. The occurrence of these mutations is common, but the exact location of each mutation can be unique to a small number of families. It is the commonality with which these mutations occur that explains the commonality of neurological diseases and disorders like schizophrenia, bipolar disorder, and autism, largely independently of the “genius connection.”
- Humans may be unique in their propensity to develop such mutations.
The most basic principles of evolution dictate that serious genetic diseases that affect the young are rare because their sufferers are often less likely to have children and, therefore, less likely to pass along the disease-causing mutation(s). But common neurological diseases and disorders like schizophrenia, bipolar disorder, and autism long confused evolutionary geneticists by defying this principle. For instance, although most people with schizophrenia do not have children, the disease remains both highly heritable and common: striking about one in every hundred people.[1]
These conditions are fascinating, not only for their hard-to-explain abundance, but because of another well-known paradox – an apparent excess of savantism and creative genius among people affected by these neurological conditions, as well as among their family members. But while early hypotheses suggested that such cases might offer unique insight into the genetics and evolution of human cognition, the findings were often soured by preconceived notions about class and intelligence, from a 1970 study that observed that “close [male] relatives of psychotic individuals have a significantly increased probability of being considered persons of eminence” to more recent studies that crudely use occupation and college major as proxies for creative talent.[2]
Captivated by the possibility of a connection between genius and neurological disease, however, early research proposed that a long-understood evolutionary phenomenon called balancing selection, might explain the commonality of schizophrenia and autism. In balancing selection, inherited parts of the DNA that cause disease in some people are able to last throughout many generations by benefiting others. Sickle Cell Disease is a well-known example. People who have two copies of a mutation in the hemoglobin-beta gene (one from each parent) suffer from the life-threatening disease. People who carry just one copy, on the other hand, have few of the associated negative health effects but do have enough of the sickle-shaped blood cells to make their blood resistant to infection by malaria-causing parasites. By affording resistance to a different disease, the mutation for sickle cell increases its own odds of making it into the next generation and bucks the forces of evolution that would otherwise largely eliminate it. The authors of the 1970 study on schizophrenia and eminence postulated a very similar mechanism – the existence of at least one genetic mutation that could cause schizophrenia in people who inherited it from both parents but which increased creative talent in people who inherited only the one copy.[2]
As genetic causes of many diseases were solved through advanced genetic techniques, however, it became clear that most neurological diseases were not quite like Sickle Cell Disease in that not everyone with the disease had a mutation in the same gene. In fact, very few common diseases, neurological or otherwise, can be explained by the same mutation in each person.
Most common diseases are caused by a combination of many common variations between different people’s DNA (termed genetic variants).[3] Everyone carries around some pieces of DNA that increase their risk of diseases and others that decrease their risk. In certain families and, therefore, certain individuals, the risk-increasing pieces for a given disease are especially common, and they are more likely to develop the full-blown disease. This is the genetic mechanism that best explains asthma and cardiovascular disease and has proven roughly accurate to explain late-onset neurological conditions like Parkinson’s and Alzheimer’s. Because Parkinson’s and Alzheimer’s usually occur in late adulthood, however, they have little effect on the likelihood of having children and their commonality is not paradoxical, as it is for diseases like schizophrenia, where we would not expect harmful variants to persist throughout generations. Among other popular explanations, we return to balancing selection, which can also apply to diseases caused by multitudes of common variants if the common variants are beneficial to the people who dodged the full-blown disease. The variants, scattered throughout the genome, are hypothesized to act like vitamins or drugs: they’re helpful, to a point – but detrimental in too high a dose.
Balancing selection explains many aspects of human physiology, but as an explanation of the persistence of common neurological disorders, the theory has recently suffered several major blows. Most seriously, there is little indication that genius of any variety yields any advantage from an evolutionary standpoint. Selection depends on the number and health of your children and is largely indifferent to Who Is Who lists.[4] This does not mean that the “mad genius” connection is not real or that it has nothing to tell us about the evolution of the human brain; recent research suggests that the link between schizophrenia and creativity, if present, has been overblown, but there’s likely some link between bipolar disorder an IQ and savantism, while rare, is overrepresented in autistic individuals.[4,5,6,7,8] While modern research remains mixed on whether there is a connection between neurological disorders and specific skillsets, it is almost definitely not the driving force behind the prevalence of these diseases.
Recent research finally explains common neurological conditions in a way that is consistent with long-established principles of evolution. Like sickle cell disease, these conditions are often caused by a single mutation in each person, but unlike sickle cell disease, it is not the same mutation in each person.[9] Like a boat flooding as fast as it is bailed out, every generation, new mutations pop up randomly in different spots in different unlucky people.
The impact of common rare mutations is not unique to neurological disease. Cancer-stricken families are often uniquely unlucky in that the mutations they share are very uncommon outside of their family, although hereditary cancers as a whole are sadly abundant. Medical practice is just starting to recognize the importance of considering these distinct mutations in classifying and treating cancers. Similarly, Schizophrenia disease-causing mutations are scattered throughout the genome, yet they cluster by the types of biological pathways they fall into.[9] Similarly, researchers have been able to subclassify cases of autism – a hugely broad umbrella diagnosis – by their rare mutations, finding subsets of ten or twenty patients from around the world who share the same mutations and who show pronounced similarities in appearance, mannerisms, and health.[10] These studies are also resolving a third paradox of neurological disease – a tendency for families to experience high levels of more than one prognostically distinct neurological disease. It turns out that the genes in which the disease-causing mutations occur are often the same genes that give rise to mutations causing other neurological conditions like depression, bipolar disorder, autism, epilepsy, and schizophrenia.[ 11,12]
On its face, this conclusion seems less than extraordinary: neurological disorders are common because our brains are complex and typical function depends on a large percentage of our genes working properly; however, this simple finding has much to teach us about the evolution of the human brain.[9] How did humans get to be so sensitive to these mutations? Our genome may be uniquely fragile. While humans are not special in our number of genes – we have fewer than some fleas – we are unique in the number of segments in our DNA that have nearly exact copies in separate parts of our genome. Certain areas of the genome are hotspots for co-opting these duplicated segments and occasionally merge them into novel genes. Creating new “patchwork” genes in this way may have given us a cognitive edge over other primates; however, the consequence of having parts of our genome that almost exactly match other parts is that sometimes the replication machinery in the genome gets confused between the two regions and causes errors, like failing to copy part of the DNA or copying a part too many times. These errors can result in both common and rare diseases that are often neurological in nature.[13,14] The errors that occur between duplicated regions look distinct from the types of errors that cause diseases like sickle-cell or the genetic variants that increase the risk of Alzheimer’s disease. This new research suggests neurological diseases may be a price we pay for evolving the most advanced brains in the animal kingdom.
References:
- Keller, M. C. (2008). The evolutionary persistence of genes that increase mental disorders risk. Current Directions in Psychological Science, 17(6), 395-399.
- KARLSSON, J. L. (1970). Genetic association of giftedness and creativity with schizophrenia. Hereditas, 66(2), 177-181.
- https://en.wikipedia.org/wiki/Common_disease-common_variant
- Greenwood, T. A. (2016). Positive traits in the bipolar spectrum: the space between madness and genius. Molecular neuropsychiatry, 2(4), 198-212.
- Pearlson, G. D., & Folley, B. S. (2008). Schizophrenia, psychiatric genetics, and Darwinian psychiatry: an evolutionary framework. Schizophrenia bulletin, 34(4), 722-733.
- Folley, B. S., & Park, S. (2005). Verbal creativity and schizotypal personality in relation to prefrontal hemispheric laterality: A behavioral and near-infrared optical imaging study. Schizophrenia research, 80(2-3), 271-282.
- Keller, M. C., & Visscher, P. M. (2015). Genetic variation links creativity to psychiatric disorders. Nature neuroscience, 18(7), 928-929.
- https://www.spectrumnews.org/features/deep-dive/extraordinary-minds-the-link-between-savantism-and-autism/
- Walsh, T., McClellan, J. M., McCarthy, S. E., Addington, A. M., Pierce, S. B., Cooper, G. M., … & Stray, S. M. (2008). Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. science, 320(5875), 539-543.
- Sebat, J., Lakshmi, B., Malhotra, D., Troge, J., Lese-Martin, C., Walsh, T., … & Leotta, A. (2007). Strong association of de novo copy number mutations with autism. Science, 316(5823), 445-449.
- https://www.spectrumnews.org/news/schizophrenia-prevalence-may-threefold-higher-people-autism/
- https://www.nimh.nih.gov/news/science-news/2018/suspect-molecules-overlap-in-autism-schizophrenia-bipolar-disorder.shtml
- Sharp, A. J., Hansen, S., Selzer, R. R., Cheng, Z., Regan, R., Hurst, J. A., … & Fitzpatrick, C. A. (2006). Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nature genetics, 38(9), 1038-1042.
- Mefford, H. C., & Eichler, E. E. (2009). Duplication hotspots, rare genomic disorders, and common disease. Current opinion in genetics & development, 19(3), 196-204.
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