Why do some women with a specific oncogene develop breast cancer while others do not? Why do some people have a certain mutation but do not show the clinical manifestation of the mutation disease? The answer lies within the complex genetical architecture orchestrating transcription, translation and ultimately, life. To increase our understanding of this genetical symphony, scientists have turned to genetical genomics. Genetical genomics studies how differences in genotype leads to differences in gene expression levels. It can reveal locations on the genome correlating with differences in gene expression levels eventually underlying the differences we observe in an organisms phenotype, whether it is the length, age of death or even severity of mutation manifestation. It can help us to elucidate the role of the genetic background in phenotypic manifestation. As such, it is the better alternative to mutant screening in single genetic backgrounds.
For my MSc thesis I looked at a mutation in C. elegans, a nematode serving as a model organism for humans. This mutation, of a gene called bar-1, is known to play a role in tumour formation, metabolic diseases and neurological diseases such as Huntington and schizophrenia in humans. The signalling pathway to which it belongs has been thoroughly researched. But mutant screening has always been done in a single genetic background. My project tried to shed light on the question which role the genetic background plays in the manifestation of the mutation phenotype.
Data on phenotype and gene expression were already present. It was up to me to try to make sense of it by finding regions that correlate with observed difference in gene expression phenotypes using computational methods. For me this topic turned out to be a perfect fit, since my ambition for my MSc thesis was to work on a computational project, preferably on the topic of genetics. Although my list of potential chairgroups was quite long, I initially never considered the group of Nematology since it is not among the traditional Molecular Life Sciences thesis groups. It was thanks to a former worker of Nematology to whom I had explained my whish of doing something computational, that I ended up talking to one of the PI's of Nematology.
During my MSc thesis there was a lot of room and guidance for learning new skills. I had no experience with R, software for statistical analysis and manipulation of data, when starting my thesis. At nematology, my supervisor thought me the basics of R and coached me throughout the entire thesis allowing me to improve my programming skills. Learning a new programming language can be quite frustrating and involves many moments of wanting-to-throw-the-laptop-out-of-the-window and hours of puzzling what is wrong with the code to eventually find out that the mistake is a missing "(" at the beginning. But those frustrating moments and hard work more than payed off: when my thesis came to an end I was able to create scripts of my own in R. An skill that has proven to be very helpful in courses and research projects beyond my thesis project.
I also gained a lot of general knowledge concerning genetics, which I consider to be one of the more intriguing topics of biology. We discussed recent papers about human genome screening uncovering individuals with very severe mutations who do not show the clinical manifestation of that Mendelian mutation. How is it possible that these individuals are actually quite healthy? New theories, scientific rebuttals but also small progresses within the department were on the weekly menu. The biggest learning experience however, was probably the annual Zoölogy symposium that was held in November. Not only did I learn a lot about genetics thanks to the many presentations on a variety of topics, I also got the chance to present my own results. Shivering hands, feeling m heart beat up my throat and trying to keep a normal voice while I explained six months of work. I presented how we had found six regions on the genome, not located near the mutation itself, that correlate with the gene expression of many genes. These regions were specific for the mutated population. Furthermore we also found that some of these regions also correlate with diversity observed in mutation phenotype. With enthusiastic (young) scientist in the public asking encouraging questions this experience was very rewarding.
Looking back, I am very grateful for the opportunity to work on this project. I have gained a lot of general knowledge concerning genetics, learned a new programming language and I had the chance to present scientific work at a real symposium. An MSc thesis at Nematology might not be among the traditional thesis groups. But if you are looking for a challenge and up for learning new skills then Nematology should definitely be added to your list!