Posted By: Kylee Spencer, PhD, Assistant Editor, AJHG
Each month, the editors of The American Journal of Human Genetics interview an author of a recently published paper. This month we check in with Alex to discuss his recent paper “Disentangling mechanisms behind the pleiotropic effects of proximal 16p11.2 BP4-5 CNVs.”
KS: What motivated you to start working on this project?
For some time, I had thought that a comprehensive review of the pleiotropy associated with the 16p11.2 BP4-5 CNVs was missing. I was convinced that such a report would be useful to many geneticists and clinicians. The plethora of 16p11.2 published manuscripts and the multiplicity of linked phenotypes were making it difficult to get a clear picture of what was going on. While Chiara Auwerx and Zoltan Kutalik were immediately on board with my idea, our discussions pinpointed that our previous investigations on the effect of CNVs in unselected populations (Auwerx, Genome Med 2024; Auwerx Am J Hum Genet. 2022) could be exploited further. They could help us also understand how the 16p11.2 effects are brought about. Is it by direct or indirect pleiotropy (aka vertical or horizontal pleiotropy)? Does one phenotype trigger the others? Or alternatively, are copy number changes of different genes mapping to the interval causative of distinct pathologies? Mechanisms that are, of course, not mutually exclusive.
KS: What about this paper/project most excites you?
While we thought that answering those questions would be the perfect complement to the above-mentioned review, I am excited as we were able to answer them. The answers we got were not of a single color as we found multiple mechanisms at play. Emblematic of indirect pleiotropy, an initial increase in BMI was the harbinger of a large fraction of the 16p11.2 deletion-driven associations. Conversely, we identified using a matched-control approach multiple associations that were independent of the assessed mediators suggesting genuine direct pleiotropy of the region and demonstrating that the 16p11.2 BP4-5 syndromes are bona fide contiguous gene syndromes.
Even after thirteen years and our first mirror discovery (Jacquemont, Nature 2011), I am still thrilled when we come across mirror effects–when loss and gain of a genome interval have opposite effects. BMI, platelet count, and puberty timing are the most significantly associated traits with 16p11.2 cytoband dosage through a mirror model. Life is on the edge of having too much or too little of a good thing. Having two copies of a locus is the ideal middle-ground scenario.
KS: Thinking about the bigger picture, what implications do you see from this work for the larger human genetics community?
National health systems will fulfill their goals of precision and preventive medicine only if our community does its part. We, as human geneticists, have the responsibility to explain the mechanisms at play and identify the individuals most at risk. This will ensure that they are correctly followed. For example, the more than 370,000 Europeans and 190,000 North American carrying a deletion of the 16p11.2 BP4-5 locus should be monitored by dedicated teams to mitigate co-morbidities.
KS: What advice do you have for trainees/young scientists?
While Zoltán Kutalik and I came with ideas and guidance, let me be crystal clear that this article is the work of Chiara, now Dr. Auwerx, who we both had the privileged to co-mentor. My advice for trainees/young scientists is that, like Chiara, you should not stop nurturing your curiosity; you should challenge both yourself and your mentor(s). Success is around the corner, but it will only be reached with a lot of work and some sacrifices. Do not get me wrong, keep some free time to meet friends and do something you like (e.g. outdoor activities, playing music; Chiara loves to sail). These “breathing” moments will recharge your batteries. Personally, they are my first line preventive care, and after, I am more productive.
Never forget that science is fun … even when your experiment has failed multiple times or when your hypothesis has been shattered to pieces.
KS: And for fun, tell us something about your life outside of the lab.
I regularly go out birding and mammal watching. While I am a quite impatient person, to see some elusive species like Eurasian lynx I can spend hours quietly nestled under a tree. During my travels I have, for example, encountered wolves more than fifty times on four different continents and in eight countries.
Alexandre Reymond, PhD is a Professor in the Center for Integrative Genomics at the University of Lausanne in Switzerland.