Inside AJHG: A Chat with Tychele Turner

Posted By: Sara Cullinan, PhD, Deputy 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 Tychele Turner to discuss her paper “Sex-based analysis of de novo variants in neurodevelopmental disorders.”

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Tychele Turner, PhD (courtesy Dr. Turner)

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

Tychele: Since my early graduate studies, I have been interested in understanding the etiology of autism, and in particular, I have been intrigued by the observed sex bias in autism. It has been well established that there are more males (~80% of individuals with autism) than females with autism. Over the past ten years, evidence has been accumulating for a “female-protective effect” whereby females with autism more often than males with autism have variants of interest that are rare variants of large effect.

During my postdoctoral work with Dr. Evan Eichler, I received an Autism Science Foundation fellowship to further explore this effect. While many groups had focused on a pooled male and female approach, we chose to look at it in reverse, in the thousands of sequenced parent-child trios with neurodevelopmental disorders that have been published to date and are now in our de novo variant database. The greatest reason we began to work on this project is because sex bias is a common feature of many disorders and we want to help to determine why this occurs so as to inform future studies into the genetic architecture of human disease.

AJHG: What about this paper/project most excites you? 

Tychele:  One of my favorite aspects of the paper is that we utilized a discovery/replication cohort approach to identify genes with significant excess in neurodevelopmental disorders. While this has been a common approach in genome-wide association studies it has been uncommon in studies of de novo variants. This was very helpful to us in identifying genes of high confidence. Related to this, as a person who enjoys thinking about numbers, I was excited that we were able to study so many sequenced parent-child trios from the literature (~9,000 families and ~27,000 individuals) as a discovery cohort.

This highlights a real benefit of data sharing in our genetics community. In addition, we were beyond grateful to GeneDx for providing us with replication data (~19,000 families and ~57,000 individuals) for the genes we initially identified as significant in our discovery cohort.

Since we were determined to find out if there were differences in gene discovery in males and females and the possible genes that could be sex-biased, we found it was critical to have this two-stage (discovery and replication cohort) analysis. Probably the most striking result in the paper, to me, was that our gene discovery in ~3,000 females was similar to our discovery in ~6,000 males and that the X chromosome genes reaching significance were only found in females.

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

Tychele: There are a few implications of this study for the human genetics community. It provides lessons learned about the sex bias in human disease and also emphasizes why the NIH has generated policy around the inclusion of sex as a biological variable. While our study focuses on neurodevelopmental disorders, we think the findings provide insight into other phenotypes as well. Our study highlights the importance of studying the rarer class (in autism it is females) to identify rare variants of large effect.

First, we find that study of the rarer class enables greater gene discovery and in studies where funding or sample sizes are limiting, it may be beneficial to prioritize the rarer class individuals. Second, we show that there are a few genes that are significant in only one sex and those genes primarily reside on the X chromosome. Third, we find that the genes we discovered converged to one network involved in chromatin biology.

When you look at the gene set, surviving replication, you realize that they could have almost all been identified by only focusing on females. This suggests that useful biological insights can be derived from a study of the rarer class. There is much work that remains in understanding how sex bias occurs in disease, but we think this study provides one way to think about this issue.

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

Tychele: Remember that all scientists struggle from time to time, and that even when you think you know how someone’s career has gone, you often do not know the struggles they have faced. Find a good network of mentors both inside and outside of your department. Most importantly, if there is something you are passionate about scientifically, pursue it. There’s no limit to what you can do, and you never know when or where the next great scientific breakthrough will be!

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

Tychele: One of my favorite things to do outside the lab is to read books from the library. It is fun to take some time to “go on adventures” through literature, and you don’t even have to leave “home”. I also enjoy spending time with my family in Michigan.

Tychele Turner, PhD, is an Assistant Professor in the Department of Genetics at Washington University School of Medicine. She has been a member of ASHG since 2013.

Get to Know Maurice Godfrey, Geneticist and Educator

Posted By: Evelyn Mantegani, Public Education & Engagement Specialist, ASHG

Maurice Godfrey, PhD, is a member of the Genetics Engagement & Education Network and co-chair of the ASHG Public Education & Awareness Committee. In his role, Dr. Godfrey judges entries to the DNA Day Essay Contest and facilitates the ASHG High School Workshop, an activity held in conjunction with the Annual Meeting in which members bring hands-on activities to local schools. He began his career in bench science and more recently works with Native American communities by bringing lessons in health and science, including human genetics and career opportunities.

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Maurice Godfrey (center) leads students through a genetics activity. (courtesy Dr. Godfrey)

ASHG: How did you begin your involvement in public education and engagement?

Dr. Godfrey: My real involvement came when I had young children. Teachers would say, “I heard from this teacher what you did. Can you come to my school?” So, it became an avocation to do that. I had a really extraordinary experience mentoring a high school student who is now a practicing physician. He was the first person in his family to go to college, then he went to medical school, and he went to his number one choice in residency and fellowship. You provide opportunities and give people a chance to go find their way in science.

ASHG: What’s the most rewarding part of your volunteer experiences?

Dr. Godfrey: Having lived in both the bench science world and now this outreach world, you get much more immediate positive, feedback when you’re working with students and communities. When you’re doing bench research, you’re doing hundreds of experiments before one breakthrough, and that may take a long time. When you’re working with a student and see them light up because they’ve just gotten something that they didn’t know, that’s really rewarding.

ASHG: What’s the best memory you have of one of your educators when you were a student?

Dr. Godfrey: [My high school anatomy teacher] was a stickler and was very, very focused. He set a very good model of how you have to be very methodical with science. Then, I had a college professor who made us write every lab report in the same format as a journal article. I had a great genetics professor in college, too. I’m still in touch with him.

ASHG: What’s the best piece of advice for other volunteers, especially those who are just starting out?

Dr. Godfrey: Be very patient, don’t give up, don’t expect dramatic results at first, be very respectful of the communities you’re in, keep things simple, and make them fun. Don’t lecture, try to get things that can be hands-on, and make them relevant to the area.

ASHG: What’s the one thing you want the public to know about human genetics?

Dr. Godfrey: [First], It’s really important for people to know how similar we all are when it comes to our genetics. [Second], with advancing technology in genetics, there are a lot of questions that will be coming up. Where do you draw the line with making manipulations in plants so you can feed more people, versus in people so you can “design” better people? Is that where we want to go? It’s a fine line between ‘are we going to treat genetic diseases’ versus ‘are we going to “enhance” traits in people’?

Social Issues at the Annual Meeting: Perspectives on Germline Gene Editing Regulation

Posted by: Eve Granatosky, PhD, 2018-19 Genetics & Public Policy Fellow

Recent advances in human gene editing research have sparked widespread conversation in the international scientific community about the benefits, risks, limitations, and ethical considerations associated with editing technologies. ASHG collaborated with the National Academies of Science, Engineering, and Medicine to bring this dialogue to members, at the “Perspectives on Germline Gene Editing Regulation” forum at the 2019 Annual Meeting.

The National Academies, along with the Royal Society of the United Kingdom, leads the International Commission on the Clinical Use of Human Germline Genome Editing. The Commission is currently developing a framework for considering issues around germline genome editing, which would govern the use of the technique if and when society decides that such use is appropriate. A similar effort – the Expert Advisory Committee on Developing Global Standards for Governance and Oversight of Human Genome Editing – is currently underway at the World Health Organization (WHO). Both groups are writing reports articulating their recommendations for germline editing. Leaders from these projects convened in Houston to outline their progress so far and to engage in a discussion, moderated by Charles Rotimi, PhD, with ASHG attendees.

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Dr. Dzau addresses attendees at the Perspectives on Germline Gene Editing Regulation forum at ASHG 2019.

Victor J. Dzau, MD, President of the National Academy of Medicine, outlined previous international efforts that shape the Commission’s goals and scope. He noted that the November 2018 announcement of the first “CRISPR babies” was a wake-up call for experts to take stronger, more definitive action to confront the realities of a world where human germline editing was not only possible, but happening. In an interview with ASHG TV, Dr. Dzau said, “This forum is timely, because as both of these studies are ongoing, it’s a perfect place for the community to come together to talk about this, and to be aware of what we’re trying to do.”

Kay E. Davies, PhD, co-chair of the Commission, described her group’s mission and efforts thus far, which include the first of three planned commission meetings. She presented several prompting questions that the Commission hopes will guide the community in providing useful feedback to the group.

Kazuto Kato, PhD, a member of the WHO Expert Advisory Committee, shared that the group plans to leverage the global presence of the WHO to make appropriate international, national, and regional recommendations on governance mechanisms for human genome editing. He also noted that some nations, including his home country of Japan, were beginning their own conversations and projects on human genome editing.

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Forum attendees heard from international genetics leaders before being invited to voice their own perspectives.

The second half of the forum was dedicated to open conversation on germline gene editing regulation. Major themes included the need for any reports to be flexible and adaptable to future developments in the field, the need to represent a variety of geographic and demographic perspectives in international discussions, and the tensions between encouraging scientific and medical progress while exercising appropriate caution.

Dr. Rotimi and the panelists were enthusiastic about the level and quality of discussion and expressed interest in following up with the ASHG community next year as their groups’ work continues. As the forum concluded, Dr. Davies remarked,  “I look forward to the workshop next year when both reports will be out, and we’ll have another opportunity to address some of these issues because they’re so important for everyone in this room and everyone in the world…I’m an optimist too but there’s going to be a lot of hard work.”

Couldn’t make it to this session? Check out the recording!

Eve Granatosky, PhD, is the 2018-2019 Genetics and Public Policy Fellow, and is currently completing her third fellowship rotation in ASHG’s Policy and Advocacy Department.

Ensuring Diverse Representation in Your Invited Session Proposal

Posted By: Teri Manolio, Chair, 2020 Program Committee

Invited session and workshop proposals for the ASHG 2020 Annual Meeting are now open, and I’m looking forward to working with the Program Committee to assemble an exciting, wide-ranging scientific program in the coming months. Human genetics and genomics are progressing in a variety of new directions, with clinical implementation of many basic science advances on the horizon – and in many cases, already taking place.

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Teri A. Manolio, Chair, 2020 Program Committee (courtesy Dr. Manolio)

As host of the world’s largest human genetics and genomics meeting, ASHG and our Program Committee work hard to ensure the meeting has something for everyone. An important part of that is addressing diversity and inclusion among members and meeting presenters – as noted in our strategic plan, ASHG strives to be a recognized leader in valuing, driving, and embodying diversity in genetics and genomics.

An Inclusive Presentation Stage

Scientifically and professionally, the field benefits from a broad range of perspectives. Interpretation of research results is often a matter of judgment and thus influenced by our individual perspectives and open to our biases. An inclusive environment results in a more balanced viewpoint and, often, more robust and generalizable results. To encourage diversity and inclusion in the Invited Sessions, this year’s submission form asks organizers to describe specifically how they are addressing the important topic of diversity.

We on the Program Committee hope to see session proposals that address diversity in all its forms. We urge session organizers to invite presenters and moderators from a broad mix of institutions and geographical locations, representing a variety of laboratories and disciplines. We will also pay attention to demographic diversity, as persons of different ethnic and cultural backgrounds bring important and unique perspectives. We encourage organizers to address this proactively by describing how presenters and moderators self-identify. In addition, ASHG is an incubator of the next generation of scientific luminaries, and we encourage session organizers to include trainees and other less experienced scientists among their presenters and moderators.

Diversity of Genetic Data

In addition to diversity among presenters and moderators, I have long tried to promote diverse research cohorts that include data from ancestral populations around the world. Despite the inclusion of persons of diverse ancestry in more recent studies, there has been a tendency for researchers to focus analyses on their largest subpopulations, which are almost always of European ancestry.

To learn about the influence of genetic differences on human health and disease, we need to study people who are genetically different, with appropriate consideration of the potential for confounding by other factors related to population differences. How ironic that as a scientific community we strive to understand global genomic variation, yet so often limit ourselves to studying just one-sixth of the world’s population.

We encourage session organizers to emphasize diversity of populations studied in assembling topics for their proposals, and to describe how their proposed session will support ASHG’s strategic goal of valuing, driving, and embodying diversity in genetics and genomics.

The Program Committee and I look forward to receiving and reviewing this year’s slate of Invited Session and Workshop proposals! For more information, check out tips to craft a competitive invited session and guidance on building a cohesive invited workshop. Submissions are due December 12.

Teri Manolio, MD, PhD, is 2020 Chair of the ASHG Program Committee.

Social Issues at ASHG: Invited Session on “DNA in the Public Sphere”

Posted By: Eve Granatosky, PhD, and Sammy Katta, PhD, Genetics and Public Policy Fellows

In addition to showcasing a wide array of excellent scientific programming, the ASHG 2019 Annual Meeting featured several interesting discussions on topics at the intersection of science, policy, and bioethics.

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This session brought together experts from multiple fields to discuss the use of genetic information outside of traditional laboratory and clinical settings. Credit: Elena Ghanaim, NHGRI

One such session was “DNA in the Public Sphere: How Genomic Information is Used and Protected Outside of Research and Medicine,” which brought together experts in genealogy, anthropology, forensics, and law to discuss how genetic information is integrated into their work. The session included:

  • CeCe Moore, DNA Detectives and Parabon Nanolabs
  • Amy McGuire, JD, PhD, Baylor College of Medicine
  • Kate Spradley, PhD, Texas State University
  • Jennifer Wagner, JD, PhD, Geisinger Health
  • Cristina Kapustij, MS, National Human Genome Research Institute (co-moderator)
  • Sara Katsanis, MS, Northwestern University (co-moderator)

Behind the Scenes

Eve had an inside look into the makings of this session during her Genetics and Public Policy Fellowship rotation in the Policy and Program Analysis Branch (PPAB) at NHGRI (read more about her fellowship experiences). She worked with PPAB Branch Chief Cristina Kapustij to shape the overall scope of the session, brainstorm and invite potential panelists, and draft the proposal for the session. She had a great learning experience considering which speakers would be interesting to ASHG attendees and how their different expertise and perspectives would contribute to the discussion.

Engaging with Attendees

CeCe Moore opened the discussion by outlining facts and myths about her work as an investigative genetic genealogist, and expressed concerns that changes in public databases’ policies requiring users to opt in to searches will make it more difficult to both accurately identify likely suspects and avoid unfairly targeting innocent, uninvolved persons. Amy McGuire spoke about how general mistrust of government shapes perceptions of using genetic databases, and noted that current policy provides no oversight for bad actors and violations of public trust. Kate Spradley discussed the challenges of identifying postmortem human remains found near the border given their varied nationalities, and emphasized that international collaboration and transnational agreements on the use of genetic data would be immensely helpful to her work. Jennifer Wagner concluded by walking the audience through legal precedents surrounding the use of DNA outside of research, and emphasized the lengthy process involved in enacting new regulations or law.

In a live poll during the session, about 200 attendees shared their interests, reactions to the topics presented, and ideas for continued conversation related to regulation, privacy, security, and engagement.

  • 48% had heard from the media about DNA databases being used in criminal investigations. Despite the prevalence of immigration-related stories in the national news, only 2% of respondents had heard that DNA data is used in this context.
  • 28% of respondents said that they would add their raw genomic data to a public database knowing that it might be used by law enforcement. 42% said they would not add their data, and the remaining 30% were unsure.
  • 59% of respondents either felt positively or somewhat positively about the creation of a universal DNA database for solving crimes and investigating deaths, while 33% felt negatively and 8% were unsure.
  • 45% of respondents said that DNA testing should not be used on migrant families to verify claimed relationships, while 28% believed that it should be used and 27% were unsure.
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Moderator Cristina Kapustij invites session attendees to participate in the Poll Everywhere live survey. Credit: Elena Ghanaim, NHGRI

Session attendees also commented on how the genetics community should connect with the public on the use of genetics in the public sphere. Top answers were:

  • Being clear and open about how DTC companies can use genetic information
  • Maintaining transparency in how DNA can be used in all facets of society and encouraging the public to be engaged with enforcing this transparency
  • Hosting and participating in conversations with non-scientists in community spaces
  • Developing guiding principles for the use of DNA outside of research and medicine

Earlier this fall, ASHG released a perspective describing the society’s core principles about privacy protections that should apply to all genetics and genomics research. Many of the themes in ASHG’s perspective also arose during this session. Attendees generally agreed about the importance of considering the context and potential benefits and risk of the use of genetic data, and that transparency, confidentiality, and individual decision-making about data use should be prioritized in all contexts.

Continuing the Conversation

Sammy, who recently began her first fellowship rotation at PPAB, found the panel to be a fascinating introduction to some of the less-publicized policy implications of genetic testing. She will be sharing the panelists’ perspectives and the audience’s responses with the NHGRI community through a poster at the institute’s upcoming annual symposium. She hopes attendees at the session and the symposium will feel more informed about these policy issues, and encourages them to continue discussing with their communities how DNA is used in the public sphere.

Eve Granatosky, PhD, is the 2018-2019 Genetics and Public Policy Fellow, and is currently completing her third fellowship rotation in ASHG’s Policy and Advocacy Department. Sammy Katta, PhD, is the 2019-2020 Genetics and Public Policy Fellow, and is completing her first fellowship rotation at NHGRI.

How I Work: Marsha Michie

Posted by: Anna Miller, PhD student, Case Western Reserve University

We sat down with ASHG member Marsha Michie, PhD, Assistant Professor of Bioethics at the Case Western Reserve University School of Medicine, to learn more about her research on the ethics of biomedical research and practice.

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Marsha Michie, PhD, Case Western Reserve University School of Medicine (courtesy Dr. Michie)

ASHG: Tell us about your position and how it fits into your institution and its goals. 

Dr. Michie: I am a social scientist and empirical bioethicist, meaning that I conduct research on topics related to the ethics of biomedical research and practice. My main areas of interest are the translation of genetic/genomic and related technologies from research into clinical care, and the impact of genetic information on patients and families, particularly in the perinatal period. I also teach and mentor students and trainees in topics related to bioethics.

ASHG: How do you keep up with the latest in genetics science and use this in your work?

Dr. Michie: I subscribe to quite a few news sources and blogs in genetics, including GenomeWeb and news from ASHG and ACMG. Because so much of my research is about how new genetic technologies are developed and used, I keep in touch and collaborate with genetic scientists, clinicians, and genetic counselors to make sure I am up to date and have a clear understanding of the newest developments in the field.

ASHG: What are your favorite genetics websites and Twitter feeds?

Dr. Michie: GenomeWeb, TheDNAExchange.com, StatNews, @hail_CSER, @GA4GH, @eshgsociety, @GeneticCouns, @GenethicsForum, @GeneticsSociety, @TheACMG

ASHG: What are you currently reading/thinking about?

Dr. Michie: I was just funded by NHGRI to study how parents prepare for a child with a genetic condition after they receive prenatal test results. I’m also working a lot on ethical issues around CRISPR, especially ways to incorporate the views of patient communities into ethical guidelines, and am spending a fair amount of time looking into infant and maternal mortality.

ASHG: What everyday thing are you better at than everyone else? What’s your superpower?

Dr. Michie: I’m pretty good at calming other people (students, colleagues) down when they are nervous or anxious, and helping them see the big picture. If only I could apply that superpower to myself!

Marsha Michie, PhD, is an Assistant Professor of Bioethics at the Case Western Reserve University (CWRU) School of Medicine, and has been an ASHG member since 2013. Find her on Twitter at @marshamichie!

Anna Miller is a PhD student in Genetics and Genome Sciences at CWRU, and has been an ASHG member since 2019. 

Grant and Collaboration Success: Perspectives from ASHG and NSGC

Posted By: Nalini Padmanabhan, Director of Communications and Marketing, ASHG

On October 16, ASHG and the National Society of Genetic Counselors (NSGC) held a joint forum at the ASHG 2019 Annual Meeting. In the 90-minute session, titled Achieving Successful Collaborations in a Research Setting, moderator Maureen Smith, MS, CGC, and panelists discussed how researchers and genetic counselors can collaborate through grant funding.

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Presenters from ASHG and the National Society of Genetic Counselors shared approaches to research collaboration through grant funding.

Obtaining funding can expand your professional network and resources and improve your research portfolio, the panelists explained. Adam Buchanan, MS, MPH, CGC, kicked off the session by sharing his trajectory from genetic counselor training to a more research-oriented career. Along the way, he learned the value of starting with a real-life clinical need when articulating a research question and building out an approach to study it. Once the question has been identified, he said, important next steps include brainstorming with colleagues, assembling a research team and preliminary data, choosing a funding mechanism, and writing and revising specific aims.

Team science and a mutually respectful approach were also key themes for the next presenter, Robert Green, MD, MPH. “I have always relied on the competence of genetic counselors,” he said, describing aspects of a genetic counseling background that make counselors particularly effective as research project managers. These include strong writing and interpersonal communication, a clinical care mindset, and a deep knowledge of genomics.

Toni Pollin, MS, PhD, CGC, shared specific tips for obtaining research funding as a genetic counselor. A combination of knowledge, feedback, and good planning are critical, she explained, placing special emphasis on choosing collaborators widely and wisely. Even if difficult to hear, feedback from mentors and colleagues helps those seeking funding to strengthen their knowledge – and in so doing, strengthen their grant applications. To successfully incorporate this feedback, it is important to start early and allow plenty of time for revisions.

Rounding out the session, Ebony Madden, MSGC, PhD, walked attendees through the NIH grant review process, citing points along the way where conversation with a program officer can be especially helpful. Though they are not directly involved in scoring grant applications, program officers know the intention and goals behind funding opportunities, Dr. Madden explained. Reaching out to them can help applicants identify (and highlight) the most promising aspects of their own work, as well as respond effectively to feedback when resubmitting an application.

Missed the session and want to learn more? This session was recorded and will be available online after the Annual Meeting.