Genomic medicine has been traveling at warp speed ever since the 2003 completion of the Human Genome Project, a global initiative to sequence the entire human genome. The profound impact of being able to “unzip” a person’s DNA to reduce, reverse, or mitigate many chronic diseases was not lost on the early genomic researchers. To use this tool to construct truly preventive medicine programs has been the promise and dream of genomic medicine. During the past 13 years, genomic testing has expanded beyond the lab bench to the clinic, and continues to grow at an exponential pace.
In recent years, genomic medicine has reached a tipping point. Healthcare professionals in the U.S. and around the world are using the concepts and principles of the “omics” revolution to personalize prevention and treatment strategies. However, the technology and information are evolving so rapidly that it is challenging for clinicians to find the time and resources to learn and assimilate the new information and integrate it into clinical practice. One of the biggest challenges is in learning the terminology that accompanies this new scientific discipline, and reconciling it with the concepts learned in genetics courses in medical or graduate school.
The terms “genetics” and “genomics” are often used interchangeably, even among scientific and clinical experts, contributing to the confusion that exists today. While genomics is a branch of genetics, it is important to understand the distinctions that exist between the two, and how they affect health and disease. In a nutshell, genetics operates in the realm of prediction, and genomics in susceptibilities.
In a clinical sense, genetics is the study of single genes or parts of genes and their effects on a person’s development, disease risk, or response to drugs, which is collectively referred to as a person’s phenotype. A single gene conferring a unique phenotype is generally referred to as a “monogenic” approach, since the focus is on a single gene. In contrast, genomics is the study of the function and interactions of all the genes in the genome. Compared to genetics, genomics can be complex and confusing. Based on our professional experience interacting with clinicians, it takes time and practice to see how using this new tool can impact a person’s chronic disease risk.
The classic definition of genetics is the study of heredity—how the characteristics and traits (phenotypes) of a living organism are transmitted from one generation to the next. This occurs via deoxyribonucleic acid (DNA), a double helix molecule in the cell’s nucleus that is organized in units called genes, the basic unit of heredity. Many of the early principles and rules of heredity were discovered by Gregor Mendel, an Augustinian monk and scientist. His seminal research with pea plants in the mid-1800s laid the foundation for modern-day genetics.
Genetic mutations can range from a change in a single base pair to entire chromosomes, and typically follow well-established penetrance and inheritance patterns. Although genetic disorders are individually rare, in aggregate they account for about 5 percent of all human disease. Geneticists can use a person’s genetic architecture or genotype to predict with considerable accuracy the impact and heredity risk of a rare, single gene mutation found in the germline. Inherited disorders, such as Tay Sachs disease, hemophilia, and cystic fibrosis fall into this category. Genetic testing enables identification of mutations that are linked to specific diseases, with development of appropriate screening and treatment protocols. In most cases, there are no proactive steps available to mitigate or prevent the effects of the mutation.
Genomics is the “new kid on the block” compared to genetics, and became possible only in the last couple of decades due to technical advances in DNA sequencing and computational biology. Ninety-five percent of all diseases are associated with common gene variants called single nucleotide polymorphisms (SNPs). These chronic diseases are multifactorial, polygenic disorders that result from interactions between gene polymorphisms and environmental factors.
Gene polymorphisms are changes in DNA nucleotide sequences that can lead to changes in gene function. A substitution of a single nucleotide in the DNA sequence of a gene can have varying effects, depending on the location. It may impact the functionality of the protein produced, alter protein synthesis on a quantitative level, or have no impact at all. In addition, a gene SNP can confer an advantage to the phenotype or it can be deleterious. Genomic polymorphisms do not follow the specific and predictive patterns that are seen with genetics.
In contrast to genetic mutations, single gene polymorphisms typically have a small effect on phenotype. Multiple gene SNPs in a biochemical pathway or biological system can have an additive effect, and can also interact with gene SNPs in other systems.
Adding to the complexity, environmental factors can interact with the effects of single or multiple gene polymorphisms in a biochemical or metabolic pathway. Therefore, a chronic disease process represents the unique interaction between a person’s gene SNPs and environmental factors, which can vary from person to person, and by gender, ethnicity, and region of the world. The genomic diversity necessitates epidemiologic retooling to effectively address the current epidemic of polygenic, multi-factorial chronic diseases of the 21st century.
As our exploration of the human genome continues to advance, we will develop an even greater understanding of the complexity of DNA. Today, the lines between genetics and genomics are starting to blur, once again shifting our current genetic paradigm. Rather than segregating genetics and genomics into discrete entities, more scientists are seeing them as part of a continuum (see figure 1), with rare, single gene disorders in the germ line with high penetrance on one end of the spectrum, and common, low penetrance gene variants or SNPs from multiple locations interacting with environmental factors and leading to complex diseases on the other end. In between there is now a gray area that has yet to be named. Advances in genetic research are enabling greater insight into the mechanisms associated with some genetic mutations, and revealing that local cellular environment may play a greater role than was previously thought.
Take the inherited form of breast cancer caused by BRCA1 gene mutations. These are classically considered genetic mutations, with defined inheritance and penetrance patterns. Not every woman with a mutation gets breast cancer, so researchers have been asking if there could be something else at play.
Recent studies suggest that the microenvironment associated with the BRCA1 breast cancer cells may play a role in its development. It is well established that BRCA1 mutations result in a loss of function, and lack of DNA repair has been thought to be the main mechanism behind cancer development. In a recent study in rats by Gorrini et al, additional mechanisms have been identified, including regulation of oxidative stress response. Cell signaling involving Nrf2, a master regulator gene of the endogenous antioxidant cascade, has been shown to be impaired by the BRCA1 mutation. In tandem, nutrigenomic research has revealed that impaired antioxidant response through a gene SNP in Nrf2 can increase the risk for breast cancer. Numerous bioactive compounds including sulforaphane and resveratrol can modulate the Nrf2 gene function, mitigate the impact of a gene SNP in Nrf2, and potentially reduce breast cancer risk. It is an unanswered question as to whether applying these genomic principles to a woman with a BRCA1 genetic mutation may be able to influence its impact.
The future of personalized genomic medicine is exciting. For clinicians who wish to dive into clinical genomics, it is critical to have a solid foundation and understanding of its core concepts. This starts with knowledge of the basic terminology, as well as of the similarities and differences between the old paradigm of genetics and the new branch of genomics. With these differentiators in mind, genomic testing can become a powerful tool in a clinician’s toolbox to personalize disease prevention and treatment strategies for a patient population that increasingly wants and needs an individualized approach.
All About The Human Genome Project (HGP). https://www.genome.gov/10001772/all-about-the–human-genome-project-hgp/
Richards, S, Aziz, N, Bale, S, et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May; 17(5): 405–424.
Khoury, MJ. Genetics and genomics in practice: The continuum from genetic disease to genetic information in health and disease. Genet Med 2003:5(4):261–268.
Gorrini, C, Baniasadi, PS, Harris, IS et al. 2013. BRCA1 interacts with Nrf2 to regulate antioxidant signaling and cell survival. J. Exp. Med. Vol. 210 No. 8 1529-1544.
About the Authors
Dr. Roberta Kline and Dr. Joe Veltmann have extensive experience in conventional, functional and integrative medicine, with over 20 years combined experience using genomic medicine in clinical practice. They are cofounders of Genoma International, offering comprehensive genomic testing and genomic medicine education to clinicians. They also offer personalized genomic medicine consulting to patients worldwide through their practice, the GENESIS Center for Personalized Health.