Posted By: The American Journal of Human Genetics, 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 Max (maxdudek.bsky.social) to discuss his recent paper “Characterization of non-coding variants associated with transcription-factor binding through ATAC-seq-defined footprint QTLs in liver.”
AJHG: What motivated you to start working on this project?
MD: This project began as I rotated in the lab of Christopher (Casey) Brown, PhD. Casey was a leader of the Genotype-Tissue Expression (GTEx) consortium, and his graduate student at the time, Brandon Wenz, had generated the massive, multi-donor assay for the transposase-accessible chromatin using sequencing (ATAC-seq) dataset used in this paper – an extremely valuable resource. While Brandon’s thesis work involved uncovering the genetic components of chromatin accessibility, Casey suggested the alternate approach of “footprinting” for my rotation project. Based on Casey’s previous work, the discovery of “footprint-inferred” quantitative trait locus (QTLs) seemed like the obvious direction to head in. His charm and guiding mentorship made the decision to join his lab easy. Sadly, only a few months later, Casey passed away suddenly. It was a joy to be able to work with him, and I’m sure he would be thrilled to see this project completed with my current co-mentors, Struan Grant, PhD, and Laura Almasy, PhD, and appearing in his favorite journal.
AJHG: What about the paper/project most excites you?
MD: In my view, the biggest strength of our footprint quantitative trait loci (fpQTL) method is the ability to fine-map disease-causing variants at a much higher resolution than traditional QTL studies. While genome-wide association studies (GWAS) have found thousands of genetic mutations associated with disease, interpretation is challenging because risk-increasing mutations tend to be inherited together with nearby variants. This means that in GWAS, we observe several disease-associated variants in each region, without knowing which one is actually causing the increase in disease risk. To find these “causal variants”, we need to perform functional experiments like ATAC-seq to understand exactly where in the genome gene regulation is happening. The footprinting method that we used differs from traditional ATAC-seq analysis in that it can precisely pinpoint regulatory activity at base-pair resolution by identifying where transcription factors are binding. By comparing samples across many donors, our manuscript maps which variants alter transcription factor binding, and by extension, implicates variants that are likely causing disease-associated dysregulation. In addition, I’m also excited about the chance this gives us to understand the regulatory “grammar” in non-coding regions by analyzing the sequence motifs disrupted by these variants.
AJHG: Thinking about the bigger picture, what implications do you see from this work for the larger human genetics community?
MD: My hope is that this work encourages future projects to explore similar methods, which can discover functional variants at base-pair resolution.
AJHG: What advice do you have for trainees/young scientists?
MD: Learn how to plot data effectively. Create each figure to communicate just one or two points and make it as simple as possible, without hiding relevant patterns in the data. Make your axis labels large and descriptive, and in scatter plots, make it clear what a point is representing. Also, force yourself to be extra social at conferences! You never know where your next collaboration or project idea will come from.
AJHG: And for fun, tell us something about your life outside of the lab.
MD: I’m a sucker for word puzzles (New York Times Crossword, Connections) and puzzle video games (Portal, The Talos Principle, The Witness). I am also a very occasional jazz pianist.
Max Dudek, BS, is a PhD Candidate at the University of Pennsylvania.