Variant Effects Seminar Series: past, present and future

Recently, the Variant Effect Seminar Series (VESS) marked its 100th speaker. As we look to next 100, we chat with two of its original presenters, Mafalda Dias and Jonathan Frazer. Discover how VESS has influenced their journey, their connection to the 100th speaker, Ezequiel Galpern, and what’s next for them.

In 2021, Mafalda and Jonathan were postdocs in the lab of Debora Marks within the Systems Biology Department at Harvard Medical School. They were pioneers for VESS, presenting in Episode 3 of the seminar series.

We asked them about how they became involved with VESS, the impact it’s had on their work and find out where it's taking them next.

VESS was brand new when you presented. How did you come to be involved?

“We were just taking our first steps into modelling variation for human disease genetics, leveraging constraints across diverse species to learn about variants that might be involved in human disease. That was probably the genesis of a lot of our work now.

We’d been interested in AVE (the Atlas of Variant Effects Alliance) since the very beginning. The whole mission and community, the fact that it brings so many different perspectives on the problem, and different stakeholders together under the same umbrella. That’s something that has been very important for our work. It was natural for us to be interested in the seminar series as well, since that’s a great way of showcasing the new work going on in the community.

Nowadays, there's a very strong computational element to this community, but back then, it seemed that much of the community were coming from the deep mutational scanning side of things. We were very keen to get involved and start more dialogue between the computational and experimental groups, because we're ultimately trying to achieve similar things.”

You mentioned that your VESS presentation has informed your current work. Where has it taken you since then?

“A large focus of what we do is developing probabilistic models of the effect of genetic variation. Those models span a broad range of questions, from rare disease diagnosis – which is probably the work that's most mature – through to models for predicting future onset of disease. We’re also studying more generally the genetic architecture of disease, including now more complex traits. That's something that our group has moved towards in recent years, studying genetic factors in non-coding regions as well, both in the context of rare disease and common disease.

We're also increasingly working with other omics, other biomarkers. We're interested in thinking about blood proteomics as a kind of endophenotype, almost like an intermediate layer between genetic variation and disease status. We are considering how we can use blood proteomics as a way to explore the disease landscape from another perspective.

Another area where the lab has been growing is conservation genomics. We can build clinical quality models for humans, so now we’re developing those for many different endangered species and using those to try and sort of inform breeding programs, improve monitoring of wild populations, things like that. Being able to do this has been something of a surprise for us and it has opened up some fantastic collaborations and been a wonderful experience.”

Did you already see the potential in VESS when you spoke, and has it achieved what you anticipated?

“It’s absolutely amazing how much reach the seminar series gets! In a sense, it should be expected, because the community is very broad with a lot of different interests.

It’s not just the people in the room, but also the number of on-demand views the talks get. When you compare that to a conference presentation, for example, VESS is fantastic.

The seminar series gained traction quite quickly. That’s probably because it’s such a wonderful learning resource, giving researchers a window into what the community is doing.

We were thrilled and honored to be giving one of those early talks and I think we knew then that it was special. So, it is no surprise that the series has now had 100 speakers.”

Are you still invested in VESS?

“We were incredibly excited to present to that community back then. And we’ve been involved ever since – both with AVE more broadly and with VESS.

Within AVE, we are active within the Analysis, Modelling and Prediction (AMP) workstream and were part of the organizing committee for the 2025 Mutational Scanning Symposium in Barcelona, which was a fantastic meeting with an enormous amount of collaboration.

With VESS, we always recommend our students and postdocs should watch all the previous VESS episodes. It's a fantastic way to train people in the field.”

Our 100^th VESS speaker was Ezequiel Galpern – a postdoc in your lab. Did you know he was applying to speak at VESS?

“No, but we’ve always encouraged all our students and postdocs to attend the seminar series and to try to be involved in it and we encouraged Ezequiel to give a talk. The work Ezequiel is doing spans the AVE community, so it felt apt for him to be the 100^th speaker.”

Do you see VESS still being as important and relevant for the next 100 speakers and beyond?

“Very much so! We really enjoy the focus on the PhD students and postdocs who are actually doing the work. That's also what differentiates it from some of the other seminar series, because you hear first-hand from the people delivering the result. That’s so important and something that should be preserved.

Will you come back to VESS and do a ‘what came next’ talk about your work from then to now? 

“Definitely! What was nice about that talk that we gave originally was it was really the first steps of us starting to think about developing models for clinical applications.

Looking back now, that area has matured and moved faster than we expected, with things like the guidelines, which have changed how these models are used in the clinic. They're now considered strong evidence, whereas they used to be considered weak evidence. Now, we routinely collaborate with clinicians, so the clinical side of variant effect prediction has come a tremendous way since 2021. It would be great to present again and share that progress with everyone!”

[Editor’s note: Watch this space for a new VESS talk from Mafalda and Jonathan later this year!]