ASHG trainee newsletter writer Ryan Collins interviewed Beryl Cummings, member of the ASHG Program Committee, 2016 ASHG Charles J. Epstein Predoctoral Award Recipient, and PhD student in the Biological and Biomedical Sciences Program at Harvard Medical School (HMS).
ASHG: Can you give us a brief overview of your scientific background?
Ms. Cummings: I began my involvement in genome sciences during my freshman year at Duke University when I joined the Genome Revolution Focus program led by Dr. Hunt Willard. The Focus program at Duke provides students with an in-depth and interdisciplinary exploration of a particular topic (in my case, genomics) through thematically-linked seminar classes. Dr. Willard taught a seminar class entitled “Genomes, Biology and Medicine” that got me hooked on genomics. The summer of my freshman year, I joined the lab of Dr. Kristin Scott and stayed on for three years working on a project to elucidate the mechanisms involved in the inheritance of chromatin states at single-cell resolution in fission yeast.
I continued my heavy involvement in the Duke Institute for Genome Sciences and Policy, which really shaped my interests and career trajectory. I’m now a PhD student in the Program in Genetics and Genomics, which is a part of the Biological and Biomedical Sciences program at HMS. I joined the lab of Dr. Daniel MacArthur in the summer of 2015 and have since been working on using RNA sequencing (RNA-seq) to interpret genetic variation.
ASHG: Speaking of your RNA-seq work, congratulations on winning the Charles J. Epstein Predoctoral Award at last year’s ASHG Annual Meeting! Can you tell us a little bit more about the research you presented at the meeting this year?
Ms. Cummings: Thanks, I was thrilled to win the award! I presented our work exploring the utility of RNA-seq to provide molecular diagnoses for Mendelian muscle disease patients for whom prior exome and/or genome sequencing had failed to return a diagnosis. We were interested in exploring RNA-seq as a complementary diagnostic tool since it provides direct insight into transcriptional perturbations caused by genetic changes, and offers a layer of functional information beyond what we can discover with DNA sequencing.
In our study, we performed RNA-seq from muscle biopsies of 50 unsolved cases with severe neuromuscular disease for whom whole-exome and/or whole-genome had not returned conclusive genetic diagnoses. To identify putatively pathogenic transcriptional events, we used the skeletal muscle RNA-seq data from the Genotype Tissues Expression Project (GTEx) as a reference panel. We first faced the challenge of implementing proper quality control of patient biopsy-derived RNA-seq data against a panel of standardized controls from GTEx. After surmounting that hurdle, we next looked for aberrant splicing, allelic imbalance, and somatic variation unique to patients or groups of patients that were absent from unaffected controls. Importantly, the types of transcriptional abnormalities we investigated were all classes of events rarely detectable by genotype-based (e.g., whole-exome or whole-genome) data alone. In doing this, we were able to diagnose about 35% of our patients by validating candidate splice-disrupting mutations and identifying splice-altering variants in both exonic and deep intronic regions.
We identified the same de novo intronic mutation in COL6A1 that results in a splice-gain event in four patients with collagen VI dystrophy. This seemed unusual, so we genotyped the splice-gain-inducing variant in an independent cohort of undiagnosed collagen VI dystrophy patients and identified 27 additional patients with the variant. After validation against parental DNA, where available, we were able to estimate that approximately half of all of these COL6A1 splice-gain variants had arisen de novo in the affected individuals. Based on this screening, we estimate that up to a quarter of all cases clinically suggestive of collagen VI-related dystrophy but negative by whole-exome sequencing might be due to this recurrent de novo mutation, and thus this mutation represents the most common genetic cause of collagen VI dystrophy in the United States.
In summary, we found that RNA-seq could be very powerful in cases where there is no diagnosis from prior genetic analysis. We’ve since begun to incorporate RNA-seq into our diagnostic pipeline in the lab, and are already using it in our gene discovery efforts for muscle disorders as well as other Mendelian diseases.
ASHG: If you had to pick, what are your three favorite moments of your PhD experience so far?
Ms. Cummings: My favorite moment was giving a talk at the Biology of Genomes meeting in 2016 at Cold Spring Harbor. It was my first platform talk at a major conference and I was quite nervous. Thankfully, it went well, and I was elated afterwards! Two other favorite moments so far were being selected for the Epstein Award this year and, although not quite an individual ‘moment,’ I also enjoyed my rotations in the labs of Drs. Joel Hirschhorn and Steve McCarroll at HMS. I learned a ton in my first year of grad school and the rotations were one of my favorite parts of the whole experience so far.
ASHG: You recently joined the ASHG Program Committee. What motivated you to get involved in a leadership role in ASHG?
Ms. Cummings: I enjoy attending the ASHG Annual Meeting. It is totally overwhelming at first, but also incredibly exciting, and I wanted to play a part in organizing the event so I thought joining the ASHG Program Committee would be the best route.
ASHG: Why were you interested in joining the Program Committee in particular, rather than another ASHG Committee?
Ms. Cummings: In my opinion, the ASHG Annual Meeting is the biggest human genetics event of the year. It is the only conference that my whole lab attends. It’s also always an exciting time to present our work and learn about the latest research in human genetics. I therefore wanted to gain insight on the effort that goes into organization of such a massive and anticipated event like the ASHG meeting.
ASHG: What would you say to other trainees considering getting more involved in ASHG?
Ms. Cummings: If you feel comfortable in where you are with your training program (e.g., PhD, postdoc), definitely take the plunge and get involved! While I am still relatively new to the committee, I’ve enjoyed it so far. It is also a great way to interact with professors and other trainees outside of your institution.
ASHG: Beyond ASHG, are you involved in any other organizations or have any other leadership roles?
Ms. Cummings: Yes! Since undergrad, I’ve enjoyed being involved in programming and organization. I’ve dialed down my involvement in grad school to refocus more of my time on research, but I am on the Steering Committee for the Program in Genetics and Genomics at HMS. Apart from that, I’ve organized a day-long bootcamp course on the use of exome and RNA sequencing approaches for the diagnosis of Mendelian diseases for first-year grad students for the past two years. I am also a member of the local Duke alumni chapter that conducts college interviews. Finally, I enjoy taking breaks from science occasionally by playing intramural volleyball at Harvard.
ASHG: Any professional goals or plans after graduating you want to share?
Ms. Cummings: Many! Right now, I am focusing on new projects in my PhD, and hopefully will begin looking for a postdoctoral fellowship next year.
ASHG: Anything else you’d like to add?
Ms. Cummings: I’m an American citizen, but was born and raised in Izmir, Turkey, and came to United States for college and stayed for my PhD. I’m deeply saddened by the recent events that have prevented scientists from the same part of the world I came from to travel to the United States. I hope we will soon see these changes reversed so fellow scientists can freely travel to and from their home countries.