Inside AJHG: A Chat with Tony Capra and Will Bush

Posted By: Sarah Ratzel, PhD, Science Editor, AJHG

Each month, the editors of The American Journal of Human Genetics interview an author(s) of a recently published paper. This month, we check in with John A. (Tony) Capra and Will Bush, to discuss their paper, “Comprehensive Analysis of Constraint on the Spatial Distribution of Missense Variants in Human Protein Structures.

Tony Capra, PhD, left, and Will Bush, PhD, right

AJHG: What caused you to start working on this project?

Tony: The roots of this project go all the way back to when I was in graduate school. As a graduate student, I studied how quantifying evolutionary patterns in protein sequences and structures between species could help us understand their functions (e.g., Capra et al. 2009). Then, I transitioned to working on the genetics of recent human evolution and didn’t think much about proteins for several years. When I started my own lab, a colleague came to me with a question about the function of a protein-coding variant in a human protein. As lead author Mike Sivley and I mapped the evolutionary conservation of this variant and its 3D neighborhood across species, we realized that it was silly not to include the wealth of information about genetic variation within human populations in these analyses as well. Around the same time, my colleague Will Bush had a similar idea. Once we got together and implemented a pipeline to map a few variants into protein structures, there was nothing (except lots of debugging!) to stop us from doing it comprehensively. More than 4 million variants later, we had this paper.

Will: I have had a long fascination with structural biology, and have focused much of my work on genomic analyses that are informed in some way by the biological context where variation occurs. This project started for me when multiple studies were published using technologies that explicitly target coding variation, which point to protein-level thinking. Around this time, I met Tony with expertise in protein evolution, and this project felt like the perfect way to start a new collaboration.

AJHG: What about this paper most excites you?

Tony: This paper is a great example of how looking across fields can help solve hard problems. Once we had mapped protein-coding variants into 3D structures, we needed to find a way to quantify whether their spatial patterns exhibited evidence of constraint. After several failed attempts, we realized that this problem had a lot in common with questions that field ecologists commonly ask about the distribution of individuals across physical ranges. A bit of reading revealed the Ripley’s K framework for evaluating and comparing spatial distributions of observations. We had to adapt the methodology for our application, but making this connection to a problem in another field provided the foundation for our solution. I like that an approach from ecology helped us to re-establish a strong link between human genetics and structural biology.

Our results also illustrate why data sharing is so important. By putting two big publicly available databases together, we were able to learn something new about how genetic variants are constrained in 3D space. It would not have been possible without the efforts and foresight of the groups that collected and maintain protein structural data (the Protein Data Bank) and genetic variation data (gnoMAD, COSMIC, TCGA, and ClinVar). Thank you to all of them!

Will: Like Tony, I am excited about the potential of modeling genomic data in a totally different way! The field of geospatial analysis has grown dramatically over the last few years, so using Ripley’s K just scratches the surface of the potential approaches that could be applied in this context. Given all the data that is available for research, the idea of data integration has become quite popular, but there are often many methodological hurdles to combining data of different types or from different domains in a coherent way. I’m excited that our work contributes in this area, and I echo Tony’s thanks to all the wonderful resources that provided the data we used in this work.

AJHG: Thinking about the bigger picture, what implications do you see from this work for the larger human genetics community?

Tony: This paper provides a framework that I believe will improve analysis strategies in both human genetics and structural biology. Both fields have seen substantial increases in the amount of data available over the past 15 years, and our work illustrates the potential to extract insight from the integration of patterns of human genetic variation with 3D structures. We have many new ideas about fully leveraging this combined point of view.

I hope that the human genetics community will recognize that structural biology has many powerful tools that can help us with variant interpretation. However, our results demonstrate that getting the full benefit of the structural perspective requires considering the complex 3D context of variants. This goes beyond the basic structural information, like secondary structure, that is often included in variant pathogenicity predictors.

We also think that we human geneticists have a lot to teach structural biologists, especially about the flexibility and dynamics of their structures. But that’s a topic for another paper!

Will: Beyond our key findings, I hope that this work will inspire other ways to think of the genome in 3D! Chromatin conformation studies are now producing spatial maps of DNA within the nucleus, and we know that these patterns influence gene expression.  Long non-coding RNAs fold into complex forms to achieve their functions – many possibilities exist!

AJHG: What advice do you have for trainees/young scientists?

Tony: Talk to diverse scientists (and non-scientists). This will help you make unexpected connections between fields. Much of the motivation for this project came out of the fact that my office happens to be on the same floor as the Vanderbilt Center for Structural Biology. Different fields have powerful datasets and methods that have direct relevance to important problems (like variant interpretation). The challenge is finding them and then figuring out how they fit together! It is much easier to be creative when you have a broad knowledge of what is state-of-the-art in different fields.

Will: Keep your work organized and persevere. Mike Sivley is a meticulous note-taker, so it was easy at any given moment to go back to prior results and put everything together. Taking good notes is also a great way to know what questions you are asking, and to push through until you have an answer. With any project, there is a time when multiple setbacks make you question the whole endeavor. Looking back over notes from an entire project is the best way to see how much you’ve learned in the process, and that can be a strong motivator to push forward.

AJHG: And for fun, tell us something about your life outside of the lab.

Tony: I secretly want to be a bartender. I suspect this is because I watched too many re-runs of Cheers when I was young. I also hate getting to work before noon.

Will: I intentionally schedule my meetings with Tony before noon, and I really love a good bourbon, especially from Tony’s bar.

Tony Capra, PhD, Assistant Professor at Vanderbilt University, has been an ASHG member since 2012. Will Bush, Assistant Professor at Case Western Reserve University, has been an ASHG member since 2005 and served on the Society’s Communications Committee from 2012-17.

Help Secure $2 Billion More for NIH!

Posted By: Derek Scholes, ASHG Director of Science Policy, and Jillian Galloway, Science Policy Analyst

Take Action Now

On Monday, the Office of Management and Budget rolled out the President’s budget request for Fiscal Year (FY) 2019. Although Congress ultimately determines federal spending, the President’s budget sets the tone for the nation’s domestic and international priorities. The proposed budget for the Department of Health and Human Services (see page 40) suggests $34.8 billion for the National Institutes of Health (NIH). While this represents an increase over the current funding for NIH, most institutes at the NIH funding genetics research would see their funding cut. In response, ASHG President David Nelson issued a statement expressing disappointment and the Society’s enthusiasm for working with congressional leaders to sustain ongoing investments in biomedical research.

U.S. Capitol (Credit: National Park Service)

With the FY 2019 announcement coming from the White House this week, you might assume that Congress has finished its work for funding FY 2018. But you’d be wrong! After several months of debate and delay, and a couple of brief government shutdowns, Congress is finally entering the home stretch. As you may have heard, last Friday Congress passed legislation allowing spending caps on federal programs to increase by $296 billion. The passage of this legislation also established a deadline of March 23 for Congress to determine how much funding to allocate to each federal agency in FY 2018, including for NIH. Therefore, now is the time to contact your members of Congress about why sustained federal funding for human genetics research is so important.

The FY 2018 funding story to date has been complicated, so let’s briefly recap what’s happened so far. Congress was unable to pass legislation to establish FY 2018 funding for federal agencies by the September 30, 2017 deadline established by law. Since then, Congress has been passing a series of Continuing Resolutions, or CRs, to allow the government to continue to function. These have been necessary because Congress has been unable to reach agreement on overall levels of funding in FY 2018 and what the funding of each agency should be. The passage of last week’s budget agreement between Republicans and Democrats marks a significant hurdle in overcoming this impasse.

For NIH specifically, there are two alternative proposals on the table for FY 2018. House appropriators have proposed $35.2 billion for the agency, an increase of $1.1 billion over the FY 2017 funding of $34.1 billion. A Senate proposal goes further, supporting a $2 billion increase to $36.1 billion. Over the past several months, ASHG and its partners within the Federation of American Societies for Experimental Biology (FASEB) have been working with the larger biomedical research community in making the case for a $2 billion increase. These numbers stand in stark contrast to the Administration’s proposal to cut funding for NIH by an unprecedented $7 billion cut to $26.9 billion.

To secure the $2 billion increase for NIH, your Senators and Representatives need to hear from you now! Please go to our Advocacy Center to send a personal appeal to your elected representatives about the impact of federal appropriations on your research and/or institution, urging them to support a $2 billion increase for NIH. Your story matters: Emphasizing the important role federal funding makes to your genetics work is imperative for making the case, more generally, for scientific discovery as a national priority. Take action today and make sure your voice is heard on Capitol Hill.

For more information on ASHG programs in policy and advocacy, visit the Policy & Advocacy page.

Judging DNA Day Essay Submissions: A Look Inside the Process

Posted by: Dennis Drayna, PhD, NIDCD, National Institutes of Health

Dennis Drayna, PhD, NIDCD (photo courtesy Dr. Drayna)

I’ve served as a judge for the DNA Day Essay Contest for a number of years now. Every year, I look forward to seeing the efforts of high school students across the world who are grappling with an interesting problem in contemporary human genetics.

This year’s essay question asks students to argue if consumers should or should not have direct access to predictive genetic testing. The results of their efforts vary, of course, but I never cease to be amazed at the level of sophistication displayed by many of them. If you have concerns about society drifting toward less trust of scientific knowledge, you’ll find many of the essays reassuring. All of the entrants’ efforts bolster the view that evidence-based critical thinking is alive and well among today’s motivated and ambitious young people, some of whom will constitute the future generation of our Society’s leaders.

One of the biggest changes I’ve noticed is the evolution in the students’ use of online resources. The traditional scholarly style, with ample use of references to relevant papers in the peer-reviewed literature, always represented a very high standard for students of high school age. The best essays always bore evidence of liberal use of PubMed, and they still do. However, Wikipedia provided an easier entry into this process, and as Wikipedia became a richer and more detailed resource, students began to avail themselves of it. Less ambitious efforts then began to show evidence of using simple Google searches, which themselves have become more effective over time. Some of the less stellar efforts now seem to rely on social media as an information source. Here, I find the chance to provide comments or feedback one of the more satisfying aspects of the judging process.

I have always volunteered as a Round 2 judge, and as far as I’m concerned, the less glamorous part of judging is done for us in Round 1, when the lower quality essays are removed before we Round 2 judges see them, so we’re typically distinguishing between fairly good, very good, and outstanding essays. I’ll admit that as a researcher who does very little teaching (and zero grading of exams or essays), judging these essays doesn’t feel much like any of my regular obligations. And, the workload is very manageable (made easier by the rubric), the website is intuitive and easy to navigate, and it’s always satisfying to contribute to the efforts of ASHG.

If you want to give back a little, judging ASHG DNA Day essays is an easy way to do it. And if we can provide a little support for developing the scientific workforce of the future, so much the better.

Dennis Drayna, PhD, is Chief of the Laboratory of Communication Disorders and Chief of the Section on Genetics of Communication Disorders at the National Institute on Deafness and Other Communication Disorders, part of the NIH. A longtime member of ASHG, he has served as a judge of DNA Day essay submissions since 2014.

Interested in judging DNA Day essays this year? Email to sign up.

AJHG Welcomes Its New Editor: Q&A with Bruce Korf

Posted By: Staff

A warm welcome to Bruce R. Korf, MD, PhD, new Editor-in-Chief of The American Journal of Human Genetics (AJHG)! We chatted with Dr. Korf about his vision for the journal, which he also described in an editorial in this month’s AJHG.

Bruce R. Korf, MD, PhD, Editor of AJHG

ASHG: What excites you about human genetics research today?

Bruce: Human genetics encompasses an enormous range of research activity. We are in a golden age of gene discovery, including the identification of genes that underlie rare disorders and revealing genetic contributions to common disorders. From my own perspective as a medical geneticist, it’s exciting that disorders we used to only be able to diagnose are now potentially treatable as we uncover the genetic mechanisms and underlying pathophysiology.

There is also fascinating research into human origins and history, independent of medical implications. As a reader of the Journal I did not previously focus on this type of work, but now as AJHG Editor, I am finding this work to be really interesting – these papers bring together ideas we can all relate to.

ASHG: How do you view AJHG’s role in advancing the field?

Bruce: AJHG is the place for geneticists to showcase their best research. It’s a forum to publish findings of broad interest in genetics, and has long been trusted for its scientific rigor, integrity, and careful review of manuscripts. It’s also a resource for the next generation of geneticists, to both encourage and educate early-career scientists and trainees.

As we learn more about ways to diagnose and increasingly, to treat genetic conditions, the Journal can be involved in publishing papers that demonstrate the clinical utility of these interventions – to show that they actually improve outcomes in a cost-effective way. Findings published in AJHG also help highlight the value of publicly funded research: this important work produces new knowledge that leads to better health care and outcomes.

ASHG: ASHG members receive a free subscription to AJHG and are exempt from publishing fees. What other benefits does AJHG offer members?

Bruce: When you’re reading AJHG, you’re looking at the final product of an intense team process. Our staff and editorial board share a strong sense that the papers should represent as carefully vetted a story as possible, which happens at every step from submission to review to acceptance and editing of manuscripts. AJHG and Cell Press put in a lot of effort to ensure reliability of the findings we publish.

The Journal can also serve as an educational forum, for example to help trainees understand the background of why and how a study was put together.

As AJHG is the Society’s journal, we would welcome members’ advice and suggestions on what we can do better, do more of, etc.

ASHG: Are there new areas of emphasis where you’d like to see more submissions?

Bruce: Genetics has advanced tremendously in recent years, and conditions that we could previously only identify can now be treated. I would love to see more submissions on treatment, from preclinical testing to even reporting of clinical trials.

Cancer genetics is another area of interest. Historically, many cancer papers published in AJHG have emphasized germline and Mendelian changes associated with cancer risk. I would like to see more submissions on somatic cancer genetics in addition to work on inherited predisposition to cancer.

ASHG: You’ve also expressed interest in addressing genetics questions that affect society more broadly. Tell us about that.

Bruce: Advances in genetics are bringing up ELSI-related questions, such as how to responsibly use genetic information and how to protect genetic privacy. We look to ASHG to serve as a voice of reason and thoughtful analysis, weighing in on important issues of the day through Society statements. Beyond those statements, I would like to see more Commentaries from individuals in the genetics community, which provide a venue to share personal opinions and generate thoughtful discussion.

Meet 2018 President David L. Nelson

Posted By: David L. Nelson, PhD, ASHG 2018 President

Happy New Year!

I am truly honored to serve as your 2018 ASHG president. I have been involved with the Society for some 30 years – including serving on the Program Committee and as Board Secretary, on the editorial board of The American Journal of Human Genetics, and most recently as AJHG Editor – and am looking forward to working with you in this new role.

David Nelson, PhD, presents at the ASHG Business Meeting in October 2017.

During that long involvement, human genetics has changed in exciting ways, and the science continues to advance at a pace that is challenging to keep up with. It’s vital that ASHG evolves to keep pace with its members, and a key focus for the upcoming year is to better understand and more effectively address members’ needs. This will involve both reflecting changes in the field and taking an active role in its continued progress. Recognizing the penetrance of genetics into other areas, I look forward to forging partnerships with related fields and organizations.

Our varied programs reflect our values as scientists and geneticists. Every fall, the Annual Meeting gets to the core of our purpose as a Society: to bring the genetics and genomics community together to exchange ideas, methods, findings, and approaches. Our increasing involvement in policy and advocacy addresses the growing prominence of genetics in broader society. And our educational programs for trainees and K-12 students reflect our commitment to the next generation and future of our science.

In 1974, when I took a course in human genetics as a senior undergraduate using Curt Stern’s classic textbook, understanding the complete set of genes that compose humans was a far-off dream, limited by technologies yet to be discovered or invented. Within 25 years, the dream was fulfilled, and the field is now making significant headway toward therapeutically correcting mutations in humans. It has been an immense privilege to have contributed to some of these advances and to have been able to highlight the work of others through AJHG.

What will the next 25 years hold? ASHG must continue to be at the forefront of educating the public as we wrestle with the implications of these advancements, just as it has been from its beginnings in the 1940s. Discoveries will continue to present our field with challenges in education and advocacy, and the members of ASHG will be vital for meeting those challenges.

David L. Nelson, PhD, is 2018 President of ASHG. He is a Cullen Foundation Professor of Molecular and Human Genetics at the Baylor College of Medicine, Associate Director of the BCM Intellectual and Developmental Disabilities Research Center, and Director of the BCM Integrative Molecular and Biomedical Sciences Graduate Program.


Behind-the-Scenes: Developing the DNA Day Essay Question

Posted By: Evelyn Mantegani, BA, ASHG Education Coordinator

For teachers and students participating in the DNA Day Essay Contest, each year’s question seems to appear on the website out of thin air. While that would be simpler for us on the Question Committee, it wouldn’t be any fun.

20180118_DNAday-logoOur goal every year is to craft a challenging, thought-provoking, and current question. We often have a hard time narrowing down our choices because of our excitement for the potential answers from students, and turn to a variety of resources to help.

Soon after celebrating DNA Day on April 25, we launch into discussions for the next year’s question. This year’s Question Committee included myself, the rest of the Education Department, our former Genetics & Education Fellow Teresa Ramirez, and our former Executive Vice President Joe McInerney. First, we look over questions from previous years to determine what worked and what didn’t. We consider a question to be less successful if there are fewer submissions or it has a concept too difficult for students to grasp. We then look through a list of potential questions that has been built up in recent years. We pick our favorites, alter some, add on to others, and brainstorm new questions based on what is new in genetics. What follows is weeks of discussion about how to shape our top choices to be both challenging and accessible to high school-aged students around the globe.

This part of the process is often the most difficult, as we try to figure out how to get the wording perfect. When satisfied, we send three pilot questions to a group of teachers to vote and critique via survey. We ask questions like whether students would understand the question prompt and whether they would be interested in the question topic. Our pilot group of teachers are longtime contest participants who have submitted more than four essays each year over the past five years and are from public and private schools, as well as from various states and countries. Based on their vote, our 2018 question, which asks students to argue if consumers should or should not have direct access to predictive genetic testing, was chosen as the winner.

Now that we have finalized the question, we are excited to see the responses. I think this year’s question will be especially thought-provoking because direct-to-consumer genetic testing is becoming increasingly popular and accessible. And now, it’s on to the contest.

ASHG Members: If you would like to participate as a judge in this year’s essay contest, look out for a recruitment email in February. Please keep in mind that you must be a current ASHG member to judge DNA Day essays. If you have any questions, please email

Students and Teachers: We are now accepting essay submissions via the DNA Day website. The deadline is March 9.

Evelyn Mantegani, BA, is Education Coordinator at ASHG. For more information on ASHG’s programs for K-12 students and teachers, visit the education website.

Inside AJHG: A Chat with Barbara Evans

Posted By: Sara Cullinan, PhD, Deputy Director, AJHG

Each month, the editors of The American Journal of Human Genetics interview an author(s) of a recently published paper. This month, we check in with Barbara Evans of the University of Houston, to discuss her Commentary, “HIPAA’s individual right of access to genomic data: reconciling safety and civil rights.”

Through such Commentaries, AJHG encourages individuals in the genetics community to share their personal views on a policy issue. Distinct from journal editorials and official ASHG statements, it is our hope that these commentaries will help spur discussion within the field.

Barbara Evans, University of Houston (Credit: S. Chandler)

AJHG: How did you become interested in this topic?

Barbara: Last summer, I was getting a lot of calls from research participants who were having trouble exercising their HIPAA right of access to their own genomic data. The HIPAA Privacy Rule is a U.S. federal privacy law. It grants people a right to obtain copies of data about themselves that is stored at HIPAA-regulated facilities. Since 2013, the Privacy Rule protects genetic data and, since 2014, its access right extends to data stored at HIPAA-regulated labs. People heard that they have a right to see their data, so naturally they wanted to see it. Many were being told “no.” Law professors play an informal role as society’s help line for questions about the laws we write about. I write about HIPAA, so I’m like the canary in the coal mine if a new HIPAA problem is emerging: my phone starts to ring. I checked around, and other HIPAA lawyers were getting those same calls from frustrated research participants. “Strange…why now?” we wondered. It seemed worth looking into—which, for a Law Prof, means you write an article. This is the article.

AJHG: What about this topic most interests/concerns you?  

Barbara: Regulatory lawyers are like primary-care docs: when someone shows up with a regulatory problem, you order a battery of diagnostic tests. The first test you run is to trace back in legal history till you find the statute (the Act of Congress) that gave rise to the regulation. Like most people, I always assumed that HIPAA’s access right must flow from the HIPAA statute. That’s true, but with a fascinating twist. As it relates to genetic information, HIPAA’s access right flows from a mandate Congress laid down in the Genetic Information Nondiscrimination Act of 2008. It’s a civil right! That fact has impacts that my commentary explores.

What concerns me most? Under the U.S. system of law, one of the worst ways things can go wrong in a democracy is if government agencies, which are supposed to protect people, take actions that deprive people of their civil rights. Your right under HIPAA to see your own genetic information is a federally protected civil right. That limits the range of actions regulators like the U.S. Food and Drug Administration and the Centers for Medicare and Medicaid Services, which regulates clinical labs, can take to block people’s access to their own genomic data. My commentary hopes to spark a dialogue about ways to address valid safety concerns about individual data access, without violating people’s civil rights.

AJHG: Tell us a bit more about the bigger picture—for scientists and the general public.

Barbara: Using people’s genomic data in research offers huge benefits to society, but it exposes people to privacy risks and other threats to their civil rights. Dating back to the dawn of the information age in the early 1970s, Congress has approved policies that let researchers use people’s data to advance public health and research. The quid pro quo is that Congress has consistently stood by the idea that if researchers have broad access to your data, then you should have broad access, too. Doesn’t that seem fair?

People who want to block individuals’ access to data need to appreciate that, over the past 50 years, Congress gave this matter a lot of thought and commissioned multiple ethical analyses. What they found is that if you want to take people’s access away, you can do so. But in return for taking people’s access away, you would then need to severely curtail researchers’ access to people’s data as an alternative way to protect people’s civil rights. So which world do you want? In World 1, researchers and people both have broad access to the people’s data. In World 2, neither group has access. Those are the two ethical options. It’s just not ethically defensible to have a World in which researchers have broad access to people’s data, but the people do not.

AJHG: What advice do you have for trainees?

Barbara: If your job doesn’t excite you and make you feel useful most of the time, get another job. Risks work out more often than we are led to believe. Take them. You hold your talents in trust, and you have a fiduciary duty to shepherd your talents to a green pasture where they can thrive.

AJHG: And for fun, tell us something about your life outside of the office.

Barbara: It’s generally tranquil, but last year was anything but with Hurricane Harvey, 52 inches of rain, fences down, and administering a portfolio of family interests across Texas. The saving grace is the lack of speed limits on rural Texas highways and discovering—in the fullness of middle age—the joy of really fast cars.

Barbara Evans, PhD, JD, LLM, is an Alumnae College Professor of Law and a Professor of Electrical and Computer Engineering at the University of Houston.