Genes, environment, and DNA sequence

Although canine DNA research has improved, it still lags behind human research

Although canine DNA research has improved, it still lags behind human research.
Although canine DNA research has improved, it still lags behind human research.

One of the reasons science is so successful as a method for understanding nature is it allows our models of the world to evolve over time as new discoveries are made. Rather than faithfully adhering to the immutable recorded opinions of sages in times past, science and science-based medicine challenge and alter conventional understandings based on new ideas and new evidence.

One of the most interesting and significant shifts in biomedical science has been the change in our understanding of how genes are influenced by environment, and even how such influences can be inherited without changes to the DNA sequence of our chromosomes.

In the last half century, the field of epigenetics has emerged as a transformative collection of ideas and methods that has widespread influence on how we understand the relationship between genes and environment, and how we can potentially influence this relationship. Like all new and complex areas of science, however, the field of epigenetics has provided inspiration and new marketing opportunities for promoters of pseudoscience.

An overview

In broad terms, epigenetics is the study of how environment and behavior can influence gene expression, and the resultant impact on health. However, this general definition covers a vast territory of complex and detailed biology that is far from fully understood.

Much of the focus of the field is currently on how modifications of DNA, other than base-pair sequences, changes can influence gene expression. Such modifications include the addition and removal of methyl groups on specific chromosome locations (call CpG sites), modification of the histone proteins providing structure to the chromosomes and influence gene expression, and changes in the type and number of microRNA and other non-coding RNA, as well as other mechanisms.1 Doubtless, there is much yet to learn about these and other epigenetic mechanisms before we can confidently understand and alter health through these pathways.

The evidence that epigenetic factors have a significant impact on health and longevity is strong. Much of this comes from animal model research, especially the ubiquitous rat and mouse studies. However, there is a growing body of epigenetic research in humans, which offers fascinating insights into the potential of epigenetics to impact health.

One of the earliest illustrations of this potential was the discovery that starvation conditions experienced by pregnant women in Holland during World War II had lifelong health effects in their children, including increased risk of diabetes mellitus, schizophrenia, and other health problems.

These health effects were associated with changes in DNA methylation patterns, and likely represent the impact of prenatal undernutrition on health outcomes decades after birth.2,3 This is a truly astounding example of how disease risk can be influenced by alterations in gene expression induced by environmental factors.

Smoking evidence

A more proximate example of the influence of environment on epigenetic markers is the influence of smoking on DNA methylation. The methylation patterns of chronic smokers are markedly different from those of people who have never smoked. However, the true potential of epigenetics is illustrated not just by this evidence for epigenetic damage from a toxin, but by the fact these changes are reversible when people stop smoking!4

Epigenetics is not just a step on the immutable path between environmental risk factors and disease; it is also a measure of how behavioral and environmental variables can influence health in both negative and positive ways.

As always, the available evidence for dogs is considerably less robust, but the epigenetic research we do have shown similar patterns. Environmental stressors harming health have been shown to influence DNA methylation and other epigenetic markers in dogs.

Other variables associated with poor health, such as age and obesity, also have measurable effects on such markers in dogs. And many epigenetic changes associated with the development of specific diseases, such as cancer, occur in dogs in patterns similar to those seen in humans and other animals.5-7 The potential to use epigenetics to understand and influence health risks in dogs is clear. However, there is much work yet to do to realize this potential.

Much of this basic epigenetic research is ongoing. There is, for example, a database of genetic and epigenetic data for various tissues from healthy dogs, BarkBase, which is modeled on those used in human research.8 There have also been studies looking at the specific epigenetic changes associated with neoplasia in dogs and comparing these to those found in other species.

The Morris Animal Foundation has partnered with Loyal, a canine aging company I work for, specifically to investigate the relationship between epigenetic markers and the occurrence of cancer in golden retrievers.

This work will help us to understand the genesis of specific types of neoplasia and the role of environmental risk factors, and it may lead to new therapies. Drugs to alter DNA methylation, for example, are already approved for use in human cancer patients, and some of these are being studied in canine oncology.7,9

The tick tock of aging

Another interesting area of research is the epigenetic clock. DNA methylation patterns are known to change with age, and it is possible to use these patterns to determine the chronological age of individuals. More importantly, it is suspected DNA methylation and other epigenetic markers may be a representation of biological age, the impact of aging on health, and resilience, which varies between individuals and is not solely determine by how long a person or a dog has been alive.

Several studies have developed such clocks for dogs, and there is ongoing work to improve this technology and make it potentially useful in clinical practice.10-12 The Dog Aging Project and several other groups are looking at the use of epigenetic clocks to assess biological age, predict longevity, and potentially assess the impact of therapies intended to mitigate the negative effects of aging on health.

Epigenetic research is also ongoing to identify environmental risk factors for behavioral problems, to better understand the evolution and domestical of the dog, to evaluate the impact of nutritional interventions of health, and in pursuit of many of the other potential insights and benefits epigenetics can offer. There is great potential in this work, but there is also the inevitable danger of excessive and unreasonable enthusiasm associated with any new and exciting field.

Our nascent and limited understanding of epigenetics is already being used to justify unscientific, unproven, and even potentially dangerous practices, from raw diets and other dietary interventions to supplements, herbal remedies, and many other alternative therapies.13

Epigenetics is similar, in this way, to the field of quantum mechanics. Very few people have a serious and deep understanding of quantum physics. For most of us, it is just a phrase associated with counterintuitive and magical phenomena, such as spooky action at a distance and quantum tunneling. Given we don’t really understand what these are, it is easy to take the term and use it as a rationalization for other counterintuitive and magical phenomena that aren’t real, such as energy healing and telepathy.

Similarly, because epigenetics shows us that genes are not destiny and can be influenced by the environment, it is tempting to use this as a rationalization for any intervention we fancy. However, the complexity of epigenetics and the limits of our current understanding. The fact that starvation or fasting or other dietary interventions can alter epigenetic markers and health outcomes in the lab or in natural experiments like the Dutch Famine doesn’t automatically validate claims that carbohydrates harm dogs or that raw meat and “superfoods” prolong health and lifespan through epigenetic mechanisms. Such claims skip over important scientific work and simply assume their own conclusions without demonstrating them scientifically.

The burgeoning field of epigenetics opens up some truly amazing possibilities, but we must balance our optimism with skepticism and being willing to put in the hard work of rigorous scientific research to unlock the true potential in this field.

Brennen McKenzie, MA, MSc, VMD, cVMA, discovered evidence-based veterinary medicine after attending the University of Pennsylvania School of Veterinary Medicine and working as a small animal general practice veterinarian. He has served as president of the Evidence-Based Veterinary Medicine Association and reaches out to the public through his SkeptVet blog, the Science-Based Medicine blog, and more. He is certified in medical acupuncture for veterinarians. Columnists’ opinions do not necessarily reflect those of Veterinary Practice News.

References

  1. Hyde LK, Friso S, Choi S-W. Introduction to Epigenetics. Princ Nutr Nutr. January 2020:129-139. doi:10.1016/B978-0-12-804572-5.00017-3
  2. TJ R. Epidemiological evidence for the developmental origins of health and disease: effects of prenatal undernutrition in humans. J Endocrinol. 2019;242(1). doi:10.1530/JOE-18-0683
  3. BT H, EW T, AD S, et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci USA. 2008;105(44). doi:10.1073/PNAS.0806560105
  4. McCartney DL, Stevenson AJ, Hillary RF, et al. Epigenetic signatures of starting and stopping smoking. EBioMedicine. 2018;37:214-220. doi:10.1016/j.ebiom.2018.10.051
  5. Yamazaki J, Meagawa S, Jelinek J, et al. Obese status is associated with accelerated DNA methylation change in peripheral blood of senior dogs. Res Vet Sci. 2021;139:193-199. doi:10.1016/j.rvsc.2021.07.024
  6. Yamazaki J, Toyomaki H, Nakayama SMM, et al. Genome-wide DNA methylation analysis of dogs with high lead exposure living near a lead mining area in Kabwe, Zambia. Environ Pollut. 2021;286:117229. doi:10.1016/j.envpol.2021.117229
  7. Xavier PLP, Müller S, Fukumasu H. Epigenetic Mechanisms in Canine Cancer. Front Oncol. 2020;10:2353. doi:10.3389/fonc.2020.591843
  8. Megquier K, Genereux DP, Hekman J, et al. BarkBase: Epigenomic Annotation of Canine Genomes. Genes (Basel). 2019;10(6):433. doi:10.3390/genes10060433
  9. Rius M, Lyko F. Epigenetic cancer therapy: rationales, targets and drugs. Oncogene. 2012;31(39):4257-4265. doi:10.1038/onc.2011.601
  10. Wang T, Ma J, Hogan AN, et al. Quantitative Translation of Dog-to-Human Aging by Conserved Remodeling of the DNA Methylome. Cell Syst. 2020;11(2):176-185.e6. doi:10.1016/j.cels.2020.06.006
  11. Thompson MJ, vonHoldt B, Horvath S, Pellegrini M. An epigenetic aging clock for dogs and wolves. Aging (Albany NY). 2017;9(3):1055-1068. doi:10.18632/aging.101211
  12. Horvath S, Lu AT, Haghani A, et al. Epigenetic clock and methylation studies in dogs. bioRxiv. March 2021:2021.03.30.437604. doi:10.1101/2021.03.30.437604
  13. Dodds WJ, Laverdure D. Canine Nutrigenomics : The New Science of Feeding Your Dog for Optimum Health.; 2015. https://www.worldcat.org/title/canine-nutrigenomics-the-new-science-of-feeding-your-dog-for-optimum-health/oclc/890808034&referer=brief_results. Accessed October 27, 2018.

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