The following is the script for a talk I gave about my research at Duke's GRADx event. Consider this a well-edited first draft for the many talks to come!
--Dr. James Neel
In 1962, geneticist Dr. James Neel, an MD PhD working from the Department of Human Genetics at Michigan University, proposed a controversial hypothesis in the field of population genetics. Now, Dr. Neel was quite the academic globetrotter, having been the first to establish the genetic basis for sickle cell anemia from a family study of African Americans in 1949, and later initiating a study that examined the mutational effects of atomic radiation on survivors of Hiroshima and Nagasaki, so he could speak on this matter with some authority.
--Thrifty gene hypothesis
His hypothesis, dubbed the thrifty gene hypothesis, suggests that some populations, particularly those that have experienced food scarcity and famine throughout history, have evolved to be more efficient in storing and utilizing energy. In times of famine this efficiency represented a survival advantage, but in a modern environment, where food is abundant, that efficiency causes obesity, hypertension, and type 2 diabetes.
Now, given how complicated human genetics are, why on earth would you use a worm to study this?
--Transparent and genome, hermaphrodites
As this picture demonstrates, the nematode roundworm Caenorhabditis Elegans is transparent under a microscope, so we can observe the effects of our genetic experiments at a cellular level. These experiments are also made easier by the fact that the genome of C. Elegans is much shorter and better understood than the human genome. Most wild C.elegans can produce both sperm and eggs themselves, making them hermaphrodites, so there’s no need to make sure these animals mate in captivity.
--Hermaphrodites, no captivity, short life span = generational
The full life cycle of C elegant takes only about three days when conditions are stable, allowing us to also observe the effects of our experiments across generations and at the population level.
--Intro to Dauer
But C. Elegans are unique in their starvation response, and it plays an important role in their life cycle. When the larval worm’s food source is depleted and the animals are crowded, C elegans larvae activate an alternate life cycle and molt into a larval stage called the “dauer” larva. This morphological transition is initiated by the anticipation of starvation. They can live in this state of arrest for up to 4 months.
--L1 arrest
C. elegans larvae can also reversibly arrest development earlier, during the first larval stage (L1) in response to hatching without food. “L1 arrest” (also known as “L1 diapause”) occurs without morphological modification but is accompanied by increased stress resistance.
--Map of C elegans strains
C. Elegant shares humanity's propensity for globetrotting, as you can see here. Each of these pins represents a location where a diverse wild strain of C elegans was gathered in the field. So there's a lot of natural variation in how these animals handle starvation, just like humans.
--Overall goal, pathways, nat var. address thrifty gene hop
By identifying specific genes and metabolic pathways in C. elegans that are associated with energy storage and utilization, and the natural variation of this process between strains, we can address the thrifty gene hypothesis.
--Introduce GWAS
In humans, we often use statistics to try and find the regions of the genome that are associated with a trait of interest in something called a Genome-wide association study, or GWAS. We take genetic samples from people with and without the trait, and identify the genetic markers that they carry. Then, again with statistics, we can identify regions of the genome that are associated with the trait of interest, and zoom in to identify SNPs that are the most likely to be causal for the trait.
--Conclusion
In C. elegans, this is a little more complicated because these statistical models were built around the human genome. And this is where my work is now, adapting these tools for use in C. Elegans, so that we can harness their unique biology to gain insight into our own physiology. Thank you!
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