Genetics for you
Mini Medical School #6
December 5, 2015
Presented by Stephanie Taylor MD PhD
History of genetics:
Many of you are familiar with Gregor Mendel, who lived in the mid-19th century. He was an Augustinian friar who did significant genetic research. You may not know that he initially started his research with mice. Apparently his superiors felt that keeping mice in his monk’s cell was unseemly. In addition the fact that he was propagating mice by mating was also unseemly for celibate friar. His superiors suggested he work with another less human organism and he retreated to the safety of the lowly garden pea. His work was lost in obscurity until it was rediscovered in 1905. This work formed the foundation of modern genetic teaching of autosomal dominant and recessive inheritance. This is probably what you remember from your years in high school taking biology. For example, the gene for blue eyes is thought to be recessive. Two individuals with blue eyes should only have blue-eyed children. However a parent with brown eyes who carried a recessive gene for blue eyes married to another brown-eyed parent also carrying the recessive blue eyed gene, would have 25% possibility of having a blue-eyed child. We now know that inheritance is much more complex, even with a simple model such as eye color.
Watson and Crick published a paper proposing the double helix model of DNA in 1953. It’s not well known, however, that they got significant assistance from reviewing Rosalind Franklin’s x-ray crystallography data strongly supporting the double helical structure of DNA. Rosalind Franklin was a very gifted young scientist who did not get along well with her supervisor. While she was away from the laboratory, her supervisor showed her research to Watson and Crick providing critical insight on the correct 3-D configuration of the DNA helix. She is now getting the recognition that she deserves. Unfortunately Rosalind Franklin died very young of ovarian cancer and never shared the Nobel Prize with Watson and Crick.
The next major advance in genetics was nucleotide sequencing which began in 1977. It was originally a very slow and expensive process. Technology continued to improve and the human genome was sequenced in 2003 to much fanfare. This took a massive effort over a long period of time to sequence one person’s genetic code. Even though sequencing the human genome was a significant advance we still only knew about one individual. We knew the code but we did not know how the code was regulated. To learn more about this will need to look at a short video describing the process of translating the DNA code into a protein. This is called The Central Dogma.
Using the knowledge-Rare disorders
Let’s see how this knowledge has been applied. We will look at genetic research on rare disorders and direct to consumer genetic testing for ancestry and health risks. We will then move on to epigenetics-the regulation of the genome, pharmaco-genomics, nutri-genomics and the inheritance of acquired characteristics.
Rare disorders are a very fruitful field of study because there is often an identifiable underlying metabolic dysfunction that causes a significant disease. Understanding these rare dysfunctions often adds important details to our understanding of normal metabolism. Populations that are relatively small and have some degree of consanguinity have a higher frequency of rare mutations. A familiar example, is the BRCA gene which is much more common among Ashkenazi Jews than other Caucasians from Northern Europe. In the United States, the Amish population, which is quite small, also has a higher frequency of rare disorders.
The Clinic for Special Children in Pennsylvania is an extraordinary institution that is created for and supported by the Amish population. The clinic does cutting edge research, diagnosis and specific therapy for children with genetically determined diseases. If that was not extraordinary enough, the clinic is supported primarily by the Amish community annual craft fundraiser and private charitable grants. The Amish community donated the 2 ½ acres for the clinic site, gave the lumber and raised the building themselves. The advantage of community outreach and early intervention is illustrated in this family history. The older brother came to the clinic at four years of age already significantly disabled by his disorder. The metabolic defect was identified and after consultation with experts in the field he was successfully treated with a relatively common over-the-counter supplement called betaine. He recovered some neurological function, but remains partially disabled. His sister, born two years later, was treated immediately at birth and is entirely normal as long as she takes her supplement. This illustrates the importance of early diagnosis and intervention in metabolic genetic disorders. The gratifying part of this particular story is that the treatment is relatively easy and inexpensive once the diagnosis is established.
Significant discoveries beneficial to the larger population can come from studying relatively rare genetic variants. The Amish population has an unusually high frequency bipolar disorder, a source of tremendous suffering in the community. Careful investigation of affected persons identified a gene segment that may be a candidate for therapy. The function of this section of the DNA involves potassium movement across cell membranes and partially explains the cyclic nature of bipolar disease. Hopefully, further study will suggest a relatively simple and more direct treatment.
Using the Knowledge-Direct to consumer genetic testing
23 and me is the leader in direct to consumer genetic testing. 23 and me was founded by Linda Avey, Paul Cusenza and Anne Wojcicki in 2006. Their strength is the reliance on very large volumes of data (Metadata) and the computing power to perform deep analytics on that data. Right now they have over 1 million individual’s gene sequences. They have recently been FDA approved to reinstitute the health module and in the interim have been continuing to do their ancestry testing.
Testing is performed on a saliva sample results are obtainable in several weeks. It takes quite a while to amplify and sequence the DNA. This is done on highly sophisticated processing machines. Here is an entertaining short marketing summary of the journey of your DNA at 23 and me.
Even though your health report from 23 and me is somewhat constrained by FDA guidelines you do still have access to the raw data. The 23 and me website allows you to upload your raw data to other services. Dr. Taylor cannot endorse any of these sites but if you want to do your own independent research and are willing to assume the privacy risks they are reasonable options. This is an opportune moment to discuss privacy matters. When genetic testing was first developed many individuals refused testing because they feared discrimination by employers and insurance companies. Legislation was passed to prevent discrimination regarding employment and insurance coverage however that did not extend to life and disability health coverage. An additional concern is the possibility that your personal information could be hacked with the relatively small amount of information publically available on the Internet. This is a decision that you will have to make personally given your own unique situation.
Using the knowledge-Pharmacogenomics
Pharmacogenetics is the study of how your unique genetic constitution affects your response to prescription medications. It is a relatively new field combining pharmacology and genetics. Pharmacogenetics testing profiles an individual’s ability to activate and metabolize prescription medications. Individuals vary a great deal in their metabolic pathways. Knowing this information before prescribing a medication will help your physician prescribe a medication that will be both effective and have minimal side effects. This is the heart of The Precision Medicine initiative announced by Pres. Obama and funded for 2016. The tag line for this initiative is “the right drug, at the right dose, at the right time”.
Watch Jo Handelsman, Associate Director for Science in the Office of Science and Technology Policy, explain the Precision Medicine Initiative.
Here is a familiar example of a drug-gene interaction that is entirely preventable. Cholesterol-lowering medications, despite all being HMG CoA reductase inhibitors, are metabolized differently. For example, Lipitor is metabolized in the liver by the 3A4 and 3A5 P450 system, Lescol by the C29 P450 system and Crestor is not metabolized at all, and is excreted unchanged. Consequently an individual whose 3A4 or 3A5 system was slow would have an increased risk of side effects by taking Lipitor. Cholesterol in that individual would be better controlled with a drug such as Crestor which is not dependent on the 3A4 and 3A5 systems.
Using the Knowledge-Nutrigenomics
Nutri-genomics is the study of the effect of foods on gene expression, colloquially put: you are what you eat. The research focuses on understanding the interaction between individual nutrients and regulation of DNA expression. This is a vast topic but one familiar example that is quite compelling are the foods that influence cancer risk. Examples of protective foods are green tea, carrots, leafy greens, turmeric, blueberries, raspberries, cruciferous vegetables, tomatoes, grapes, plums, and berries. These foods respectively contain EGCG, beta-carotene, curcumin, delphinidin, isothocyanates, lycopene and resveratrol, and cumulatively confer significant protection against cancer.
Using the knowledge-The inheritance of acquired characteristics
Can you inherit memories?
There is very exciting recent research in both animal and human models demonstrating the transgenerational inheritance of experience. The most compelling research is done in mice, since several generations can be followed. In our example, mice are exposed to a strong odor and given a mildly painful stimulus. They associate the odor with a shock, and become afraid of the odor even when it is not paired with a shock. The olfactory receptor for this specific odor as well as the DNA code for expressing that receptor has been very well-characterized in the past. The mice continue to have a negative reaction to the odor even though the shock is been gone for a very long time. Of interest to you, is the observation that the fear of the specific odor is passed down to the next generation. Because it is possible that dysfunctional parenting may account for the offspring’s fear, the newborn pups were fostered to a mouse that had never been conditioned to be afraid of the odor. The offspring raised by foster parents still have the fear of the odor. Second generation mice born by in vitro fertilization using a fearful parents DNA also still had the fear of the odor. This suggests the presence of an inheritable modification of the DNA. Fortunately since this receptor and its code have been so well-characterized was possible to demonstrate a heritable change in the methylation of the DNA regulatory sequence which codes for that receptor. A more familiar example from human health is the inheritance of posttraumatic stress disorder. Many children of individuals who have severe PTSD have exaggerated fear responses, even though they have never been exposed to their parent’s traumatic situation. The children’s behavior was originally thought to be due to dysfunctional parenting but once again there is the research support for a heritable modification in the DNA. Additional research on these questions have been primarily carried out in mice however the implications to the human situation are compelling. It is possible to deconditioned the fear response and actually demonstrate changes on a molecular level in DNA methylation. Hopefully it will be possible to break the chain of suffering. The old adage that the sins of the father will be visited upon the future generations can be modified to include the sentence “unless we do something about it”.
As you can see, we are at the beginning of a big adventure in human health and genetics. I hope that this brief review has given you a foundation as well as a curiosity about future developments.