Drrrrrr. Alasdair MacKenzie

I feel a burning desire to go to talks. Of any type. I could go to one about sports or about order and organization. But it is true that the science talks are my favorite and this week I had the luck of being able to go to one. I say good luck because despite the fact that the University of Aberdeen is very active in events and conferences of all kinds (and they are free!), they do not always coincide with the free schedule of each one.

The guest of this conference was Dr. Alasdair MacKenzie, also a professor at the University of Aberdeen of Genetics, Frontiers of Molecular Medical sciences and Developmental Genetics. In short, he is crazy about genetics. His research career is based on the regulatory variation, epigenetics and human disease, and aims to decipher how conserved areas of non-coding DNA can finely regulate the expression of some genes.

The talk took place on March 12 at the Aberdeen Science Center, from 7:00 p.m. to 8:30 p.m., which was part of British Science Week. In one of the chairs in the room was a white-haired man sipping tea, which turned out to be Dr Alasdair MacKenzie himself. He was a tall, big man, with clear eyes and with a constant need to specify that he was Scottish because of his way of speaking. He started the talk with a "thank you verrrrrrry much y'all for coming". No, this gentleman was not Australian, but "thank YOU Drrrrrr for being here".

The talk was titled "Tales from the Dark Side: the" junk "genome and human disease." A subject that personally amazes me but I lose myself immediately because nothing is known about it. Anyway, Dr. MacKenzie made the talk easy to follow and we were all attentive, because of his accent and the fact that he was good at telling bad jokes.

Dr. MacKenzie began explaining that only 1.5% of the entire human genome are genes that encode proteins. Shocking because a tiny crustacean, called Daphnia pulex, far exceeds the number of genes that we have. Therefore, it seems that we are composed of quite a few genes to have a superior brain to other animals, to be so sophisticated and blah blah blah. So, what is the rest of the genetic material that are not genes? It is not known very well, and for that reason until now it has been called "junk genome" or "dark side". Uuuuuuu, everything very mysterious, but during the past years it has been seen that perhaps it is much more important than it was thought. The more complex an organism is, it seems that it has more "junk genome" and fewer genes. Therefore, the explanation to which many experts have come is that a large percentage of this DNA has to serve as regulators and gene enhancers. If you haven’t lost so far, my most sincere congratulations. If not, you have to investigate on the internet.

It all started when the Human Genome Project was launched in 1990, a scientific investigation that aimed to sequence the human genome in order to understand better what is written on our chromosomes. The project cost nothing more and nothing less than 3.000 million dollars (for many would be enough to buy more than a pair of boots if we get exquisite) and lasted 13 years. It is until now the largest biomedical research project in history. However, the results obtained from this study were quite scarce. The most important conclusion was that the human genome is made up of 24.000 genes. Oh, and that in the population there are around 10 million variations of a single base, also called SNPs, where most are in areas of non-coding DNA (sip of coffee to understand everything, and move forward). To see if certain SNPs were related to a greater predisposition to develop a disease or were simply linked to a phenotype, another study called GWAS (genome-wide association study) was conducted. The basis of this study was to compare SNPs of healthy individuals with SNPs of individuals who presented a pathology (obesity, diabetes, hypertension, and many others). In this way SNP arrays were developed, which studied the differences of hundreds of SNPs of many people at the same time. The result of the arrays is a dodgy image that seems to be completely pixelated. However, once again, the results were not very clear, since most SNPs were not highly related to the onset of a disease. A shame. Moreover, the SNPs related to pathologies only gave a small predictive value of their development.

Dr. MacKenzie and his group study gene misexpression in generating susceptibility to conditions that include anxiety, obesity and alcohol abuse (problems that we all know about, huh?), among others, and we have seen that the Galanin gene (GAL) is directly related to dietary preferences and mood. In experiments with murine models where the GAL gene is overexpressed, it has been seen that they suffer more anxiety, obesity and desire to drink alcohol. It is clear to us, we do not want too much GAL.

Dr. MacKenzie et al. used comparative genomics to analyze the area of ​​the chromosome where the GAL gene is located. They saw that there was a region just before GAL that was highly conserved in many mammalian species (see figure below). They wondered if this non-coding region could be an enhancer that activated or deactivated the expression of GAL. To answer this question, they used gene editing techniques such as CAS9/CRISPr technology to knock out these cis-regulatory regions. The result was that the knock down of the enhancer had a significant effect, causing GAL expression to decrease.

Figure from Mcewan et al., 2019 showing the conserved sequence that might acts as an enhancer for GAL.

With this contribution it seems that SPNs that affect the activity of enhancers, which are found in regions of non-coding DNA, can cause expression changes in GAL and significantly affect the phenotype, or in other words, affect the anxiety, obesity and alcohol abuse that each one expresses.

In summary, the GAL gene is regulated by a highly conserved region in mammals, which seems to act as an enhancer. Considering that most SNPs occur in non-coding intergenic zones, one might expect that some would be affecting an enhancer, which could cause the increase or decrease of GAL. If the SNP were increasing GAL expression, that person should, in theory, be more likely to develop anxiety, obesity and alcohol abuse. If you're still alive when you get here, congratulations. You deserve a reGALo (which in Spanish means gift), but not too many, because apparently they are not so good.

Happy week!

References:

- Mcewan, A., Hay, E., Davidson, C., Turnbull, Y., Marini, P., Wilson, D., … Mackenzie, A. (2019). CRISPR disruption and UK Biobank analysis of a highly conserved polymorphic enhancer suggests its role in anxiety and male alcohol intake, 44(0).

- Richardson, T. G., Minica, C., Heron, J., Tavare, J., Mackenzie, A., Day, I., … Wynick, D. (2014). Evaluating the role of a galanin enhancer genotype on a range of metabolic, depressive and addictive phenotypes. American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, 165(8), 654–664.

- Shanley, L., MacKenzie, A., McGuffin, P., Davidson, S., Lear, M., Barrett, P., … Hing, B. (2011). Differential Activity by Polymorphic Variants of a Remote Enhancer that Supports Galanin Expression in the Hypothalamus and Amygdala: Implications for Obesity, Depression and Alcoholism. Neuropsychopharmacology, 36(11), 2211–2221.