Biology of Genomes 2018: The Past and Future of Genomics

Posted By: Emily C. Glassberg, PhD Candidate, ASHG Communications Committee

A few weeks ago, I attended the 31st annual Biology of Genomes (BoG) meeting at Cold Spring Harbor. In addition to highlighting the amazing research that comprises the current state of genomics, this meeting highlighted the storied past and bright future of the field. The enthusiastic participation of attendees, both at the meeting and on Twitter, shows incredible energy and momentum as we try to understand the genome’s role in biology, evolution, and disease.

20180607_BoG
Attendees network at Biology of Genomes 2018 (Credit: Constance Brukin; copyright CSHL)

Genomics Present

The seven scientific sessions covered functional genomics, medical genomics, computational genomics, and evolutionary genomics, as well as genome engineering. Seeing this varied body of work at a single meeting clearly demonstrates that theory, experiment, high-throughput screening, and countless forms of new technology and data analysis all play central roles in shaping our current understanding of the human genome.

And, while the human genome was the primary subject of study, non-human genomes got coverage as well. Highlighted research included the genomes of near relatives, like Neanderthals; to those of best friends, like dogs; to those of model organisms, like yeast. Crowd favorites included Jaemin Kim’s and Elaine Ostrander’s talks using dogs as a system to learn about the genetic basis of complex traits (for the science as well as the adorable pictures).

The scientific programming also included two keynote speakers, Wendy Bickmore and David Page. Bickmore discussed her group’s work on how 3D chromatin structure relates to the mechanism by which enhancers – particularly long-range enhancers – interact with promoters to regulate gene expression.

Bickmore’s emphasis on the need to assay enhancer function in vivo was echoed elsewhere at the meeting. In particular, Emma Farley spoke about high-throughput measurements of enhancer function in the model chordate Ciona. In combination, these talks sparked a conversation about whether current computational models are looking in the wrong places when it comes to predicting enhancer activity and specificity.

Page presented his group’s work on the evolution of sex chromosomes with an eye to understanding sex differences in health and disease. Page’s question of whether and how males and females “read their genomes differently” connected to broader questions that recurred throughout this year’s meeting –  how do we understand the genome dynamically? When and how does the same genome lead to different outcomes?

The ways in which the genome and its downstream effects change over time and space is a big open question, and this year’s BoG showcased many approaches to tackling it:

  • Ben Strober and Jonathan Griffiths both used time-course gene expression data to track how gene regulation changes throughout cellular differentiation and development.
  • Jake Yeung shared an example of dynamic chromatin interactions and rhythmic promoter-enhancer contacts that are connected to circadian rhythm.
  • Christina Leslie presented work on how the chromatin state of tumor specific T-cells changes during cancer progression and how that influences disease treatability.

And that’s just a sample of the exciting work in this space! While we don’t yet have clear answers to these questions, the research discussed at BoG reveals a landscape that is complex, nuanced, and fascinating. What a great time to be in genomics!

Genomics Past

In addition to discussions spanning the range of the current field of genomics, BoG included a brief talk in memoriam of molecular and developmental geneticist John Sulston, who passed away on March 6, 2018. Dr. Sulston was well known for his seminal work in the now-model organism C. elegans, as well as his role in the Human Genome Project. Eric Lander also toasted Jim Watson for his role in the Human Genome Project, and to celebrate his 90th birthday. Lander and other BoG organizers later apologized for the toast, as it was seen by many in the community as minimizing Watson’s history of racist and sexist commentary.

Genomics Future

And, finally, no meeting would be complete without a vision for the future of the field.

A panel on the Ethical, Legal, and Social Implications of genomics research included four perspectives on the promises and pitfalls of germline genome editing. While there is considerable excitement around using CRISPR to cure genetic disease, many issues remain regarding proof of safety as well as ensuring equal access to the technology. Following a lively discussion during the question-and-answer, the consensus seemed to be that germline genome editing is a distant future. In the meantime, we can focus on the application of currently available options, like genetic screening and assisted reproductive technologies.

The National Human Genome Research Institute (NHGRI) also engaged researchers in its current strategic planning initiative, which began in February 2018 and will be completed in 2020. NHGRI is collecting input on priority areas to help the institute live up to its mantra, The Forefront of Genomics.

Of course, the scientific discourse at Biology of Genomes isn’t limited to the talks. The three lively poster sessions were great opportunities to exchange ideas. And many spirited discussions took place during the coffee breaks, over the traditional Cold Spring Harbor banquet, and down at Blackford bar. All told, there’s a lot to look forward in genomics!

Emily C. Glassberg is a PhD Candidate in the Department of Biology at Stanford University. She serves on ASHG’s Communications Committee and has been an ASHG member since 2014.

#ASHG17 in the Shoes of a Trainee

Posted By: Monika Schmidt, Chair, ASHG Training & Development Committee

On any given day of the ASHG Annual Meeting, I find myself in a predicament: What’s next on the schedule? Should I attend the exhibitor talk in the CoLab theater, visit interesting posters, or seek advice at the Careers in Academia panel?

No matter how carefully I plan my schedule ahead of time, the meeting always has more to offer than I could possibly take advantage of: exciting talks, posters, trainee events, workshops, exhibitor presentations, and naturally, social events. This year’s meeting in sunny Orlando was no exception, and in my role as Chair of the Training and Development Committee (TDC), I hardly had a moment to sleep.

20171030_Monika-Disney
TDC members Lauren Tindale, Monika Schmidt, and Julie Jurgens take a moment to enjoy Orlando’s non-genetics attractions. (courtesy Ms. Schmidt)

I kicked off my experience early on Tuesday, October 17, by presenting to ASHG’s Board of Directors all the fabulous work the TDC has done over the past year. Despite being a bit nerve-wracking, this was hugely rewarding – there is so much support for trainee professional development and mentorship from the ASHG community. These two themes reverberated over the rest of the meeting.

Professional Development and Networking at #ASHG17

Developing networking skills benefits from lessons and practice. Recognizing this, ASHG teamed up with The Jackson Laboratory to develop the multi-week Conference to Career Program, which included a dedicated section on networking skills for national meetings.

Following the Conference to Career in-person session, the TDC hosted Peer Networking Trivia – an ideal event to put networking lessons into practice. 2017 marked the third year the TDC hosted this event for trainees; it was rewarding to watch new friendships form as trainees commiserated over the challenging genetics trivia questions. Naturally, it’s much easier to get chatting when a topic is presented for discussion, and so the Tweetup, Opening Reception, and various evening exhibitor events presented new situations for trainees to practice their networking skills. I thoroughly enjoyed meeting trainees at these receptions, chatting about their vision for future initiatives, and of course, singing along with NIH Director Francis Collins on guitar.

Mentors at ASHG: Many Ways to Connect

Between scientific sessions in the mornings and afternoons, trainee mentorship became the focus of my lunch hours. The TDC hosted two panel discussions this year: Careers in Academia and Careers in Industry. The panelists’ responses to trainee questions were thoughtful and thorough, which meant that I and my TDC colleagues spent a lot of time live-tweeting the discussions using our newly-introduced hashtag: #ASHGtrainee. Panelists hung back after the sessions to answer questions one-on-one, providing another networking opportunity.

On Thursday, the TDC launched our inaugural myIDP (Individualized Development Plan) session, led by Philip Clifford. I was blown away by the incredible turnout and high level of engagement with the material presented. This session led trainees on an introspective journey aided by their peers, and asked them to examine their values, strengths, weaknesses, and interests. The goal of the session was to help trainees define career paths that suit their personalities, needs, and wants. With a room abuzz with discussion, 75 minutes was undoubtedly too little time, and the TDC will be looking to expand the session at future meetings.

While the TDC-led lunchtime sessions were happening, ASHG staff were hosting the Trainee-Mentor Luncheons and newly introduced Round Table Discussions. These events focused on establishing trainee-mentor relationships and providing a more intimate setting to ask advice of a successful genetics professional. I myself am still in contact with the mentor who shared lunch with me in 2014. On the note of keeping in touch with mentors or networking contacts: remember that the mentors and Trainee Leaders at ASHG really care for your success as a trainee – we want to hear from you! Your emailed question or LinkedIn request (with an introductory message, of course) are welcome. So, take 30 minutes today to thank the mentors who spent time with you for their advice – you might just get a better response than you expected, and you’ll be on your way to building a network of professional contacts!

20171030_Monika-RR-session
TDC members Douglas Dluzen (far left) and Monika Schmidt (far right) with speakers at a trainee-organized invited session on rigor and reproducibility in genetics. (courtesy Ms. Schmidt)

The final trainee event of ASHG 2017 combined the best of mentorship and networking in an evening reception, Career Paths in Genetics. As a mentor at the TDC table, I and other TDC members were thrilled to answer questions from trainees about what being an ASHG Trainee Leader entails, and how the position provides an opportunity to advocate for trainees within the Society and at a federal level via FASEB. I also took a break to just ‘be a trainee’ per se, and heard a thrilling story about patenting BRCA1 from the intellectual patents mentor, discovered a whole new potential career path in scientific administration, and was offered very sage advice by a mentor from academia on maximizing upon my abilities post-PhD.

Reflecting on ASHG 2017

Every year I return from the Annual Meeting with renewed motivation for my research and a reading list as long as my arm, as is to be expected of any stimulating conference. I also came home hopeful that fellow trainees heard the same messages that I did over the five days in Orlando: it’s always the right time to say hello and explore potential new connections, pursue a new experience to build your skills, learn about yourself, and see what the world of genetics has to offer.

Monika Schmidt, BSc, is the 2017 Chair of ASHG’s Training & Development Committee, and has been part of the TDC since 2015. She first joined ASHG in 2014, the same year she started graduate studies.

Interested in a leadership position like Monika’s? Apply for 2018 Trainee Leadership Opportunities by Monday, November 6. For questions about these opportunities and other trainee issues, contact Monika on Twitter using #ASHGtrainee or by email

Advances in the Genetics of Alzheimer’s Disease at AAIC 2017

Posted By: Timothy J. Hohman, Assistant Professor of Neurology, Vanderbilt Memory & Alzheimer’s Center

I just returned from the Alzheimer’s Association International Conference (AAIC) in London. AAIC always covers an amazing breadth of the most recent advances in research and clinical care for Alzheimer’s Disease (AD), and this year placed a particular emphasis on biomarkers. More specifically, the focus was on how we can integrate the growing availability of in vivo biomarkers of AD neuropathology into diagnostic criteria for research, and into screening procedures for clinical trials.

20170731_TimHohman
Timothy J. Hohman, PhD (courtesy Dr. Hohman)

The Potential of Biomarkers

Philip Scheltens, MD, PhD, from the VU University Medical Center in the Netherlands kicked off the meeting with an impassioned lecture on the present landscape of biomarkers in AD, and the future potential of biomarkers in screening, diagnosis, targeted treatments, and disease prevention. AD is characterized by two primary neuropathologies: extracellular plaques composed of the amyloid-β protein and neurofibrillary tangles composed of hyper-phosphorylated tau. Over the past ten years, there has been a growing emphasis on measuring these proteinopathies in vivo, including the development of positron emission tomography tracers for amyloid and tau, and the development of assays to measure these proteins in cerebrospinal fluid. In 2011, the National Institute on Aging and the Alzheimer’s Association convened four work groups to develop new research criteria for diagnosis that integrated biomarkers of amyloid deposition into the clinical criteria for dementia. This year’s conversations focused on taking steps towards diagnosis and screening that relied solely on biomarkers.

Dr. Schelten’s emphasis on the future of biomarkers set up a somewhat heated panel presentation laying out a new NIA-AA research framework to investigate Alzheimer’s disease. Led by Clifford Jack, MD, the proposed framework would place a greater emphasis on biomarkers of the two primary proteinopathies, while also emphasizing the measurement and characterization of neurodegeneration. The panel has provided the opportunity for the community to give feedback directly to the workgroup as they continue to refine the proposed framework. Certainly, this will be a critical issue in AD research in the coming year and has important implications for clinical trials, study design, and (eventually) clinical care.

Functional Pathways, GWAS Findings, and AD

This is a genetics blog, though, so let’s get into the genetics! The primary keynote session on the genetics of AD was given by Julie Williams, PhD, from Cardiff University. Dr. Williams provided an overview of where we currently stand in unraveling the genetic architecture of the disease, and called for an increased emphasis on uncovering functional pathways that underlie the known risk loci. Dr. Williams argued the innate immunity and inflammation are fundamental pathways in AD pathogenesis, and that the causal pathways of sporadic AD may be fundamentally distinct from familial forms that operate strictly through an amyloid pathway.

Research presented throughout the conference re-emphasized the importance of innate immunity, including new risk loci in common variant and rare variant analyses completed by the Alzheimer’s Disease Genetics Consortium that implicated innate immune pathways (e.g., LILRA5).  Additionally, many of the functional genomic approaches emphasized the importance of macrophage and monocyte expression in predicting AD, including 14 genes implicated in a genetically regulated transcriptomic analysis by Towfique Raj, PhD, from the Icahn School of Medicine.

20170731_hashtags
Data parasites and data philanthropists both have important roles to play in using big data to study Alzheimer’s. (courtesy Dr. Hohman)

Given the growing emphasis on biomarkers throughout the field of AD, it was also encouraging to see substantial growth in the size of endophenotype analyses, including a GWAS of cerebrospinal fluid biomarkers of AD by Yuetiva Deming, PhD, analyzing data from over 3,000 individuals. Simon Lovestone, PhD, gave an additional “big data” plenary lecture in which he laid out how large-scale European collaborations integrating electronic medical record data and other big data resources will change the way research is completed. He called on #DataParasites (those who perform secondary analyses on existing datasets) to make use of rich data resources to identify new treatment targets and #DataPhilanthropists (data providers) to continue to step up and provide open access to collected data. Large scale data collection, data sharing, and secondary data analysis are becoming central components of AD research.

Varied Approaches to #EndALZ

There were many other areas of focus: from advances in neuroimaging and large-scale omics, to a growing emphasis on sex differences, racial disparities, and pathways of resilience, and a growing acceptance of the heterogeneity in the neuropathological presentation of the disease. If you are interested in AD and want to learn more from a variety of perspectives, this is a fantastic conference to attend. The field of AD is necessarily interdisciplinary and this conference is a fantastic representation of that diversity. Multiple perspectives, approaches, and treatment pathways will be needed to beat this devastating disease. After another year and another great conference, I’m hopeful and inspired to keep working to #EndALZ. Join us!

Timothy J. Hohman, PhD, is an Assistant Professor of Neurology at the Vanderbilt Memory & Alzheimer’s Center. He has been part of the ASHG community since 2013.

Teens’ Nuanced Views about Genetic Testing, at ESHG 2017

Posted by: Michael Dougherty, PhD, ASHG Director of Education

What do adolescents think about genetic testing – in particular, clinical recommendations to defer genetic testing for adult-onset conditions? We are beginning to have an answer, thanks to a research collaboration involving ASHG, Geisinger, and Sarah Lawrence College. Late last month, I had the opportunity to present our initial analysis at the 2017 European Human Genetics Conference (ESHG 2017) in Denmark.

20170613_ESHG-copenhagen
Nyhavn waterfront, Copenhagen, Denmark. (Credit: Michael Dougherty)

First, for those who haven’t been to Copenhagen, it’s a beautiful city that I highly recommend. Deep history, friendly people (almost all of whom speak excellent English), and the convenient mass transit that is so typical of Europe. Walk along the canals or climb the external staircase to the top of Vor Frelser’s Kirke (Our Savior’s Church). An hour north of Copenhagen, Kronborg Castle, which is the model for Shakespeare’s Elsinore in Hamlet, is an especially nice day trip. If you’re adventurous, try the Danish national meal, ‘stegt flæsk,’ a delicious crispy pork dish, which came with the following warning in our restaurant’s menu: “Ask your waiter before ordering”! But now, back to the research.

Little is known about how adolescents view genetic testing, especially the psychosocial impacts of the benefits and harms frequently discussed by experts, yet clinical practice often involves decisions that may affect them. Our research used data from ASHG’s annual DNA Day Essay Contest entries to characterize adolescents’ views.

ASHG’s 2016 DNA Day Essay Contest question asked high school students to identify an adult-onset genetic condition and to defend or refute the recommendation in ASHG’s 2015 position statement to defer genetic testing until adulthood. Over 1,200 essays from 45 U.S. states and 22 non-U.S. countries were assessed using thematic, mixed-methods analysis. Students identified 100 conditions, but 75% chose one of five more familiar disorders, including Huntington disease, hereditary breast and ovarian cancer (e.g., BRCA), and Alzheimer’s. Across all conditions, roughly equal numbers of students chose to defer testing as to not defer.

We then dug deeper to examine students’ choices regarding specific conditions, such as testing for a BRCA predisposition to breast and ovarian cancer (BRCA) and for Alzheimer’s disease (AD), which differ considerably in medical actionability. Here some statistically significant differences began to emerge. With AD, nearly two-thirds of students chose to defer testing, whereas with BRCA, fewer than half chose to defer.

The reasons students gave to justify their decisions were sophisticated and often matched those reflected in clinical guidelines and ethical discussions. Reasons to defer often included risk of psychological harm to the minor or the uncertainty of predictions arising from test results (e.g., ApoE4). Reasons not to defer included the benefits of alleviating uncertainty and preparing for increased surveillance (e.g., early, regular mammograms).

The rich data provided in the students’ essays will be mined for additional insights that may inform the development of future recommendations, but even now it appears clear that the decisions of mature adolescents should be taken seriously by clinicians.

Michael J. Dougherty, PhD, is Director of Education at ASHG. This research collaboration’s work was presented at ESHG 2017 as a poster and featured in the meeting’s Best Posters Session.

Reflecting on APHMG 2017

Posted by: Kathryn Garber, PhD, Chair of the ASHG Communications Committee

I’m just back from the annual meeting of the Association of Professors of Human and Medical Genetics (APHMG), and, as always, my head is swimming with ideas. For those not familiar with APHMG, it is a group that promotes human and medical genetics education in graduate and medical schools across North America. It’s a meeting where we spend most of our time talking about teaching and learning, but the fact that we are all geneticists means that we have a common understanding of the science we need to teach. We also discuss more practical issues of program design and oversight, particularly for medical students, residents and fellows.

20170530_APHMG-recap_pirate
APHMG 2017 attendees take a break from presentations for a pirate ship excursion. (courtesy Dr. Garber)

The focus of this year’s meeting was adult learning. Hope Ricciotti from Beth Israel Deaconess Hospital kicked things off with some valuable hints on interacting with millennial learners, including ideas on how to structure feedback to members of the “trophy generation”, who often aren’t used to negative feedback. Kadriye Lewis from Children’s Mercy Hospital in Kansas City then put adult learning in perspective through illustrations of different learning theories and their implementation. Next, Sarah Farrell and members of her team from Apple Education demonstrated tools and resources for use in education, including eBooks and courses that can be created or used by faculty, and apps that can foster interactivity in the classroom.

The second day of the meeting had a scientific focus on big data. Mike Murray from Geisinger described their approach to return of results to participants in their population-based GenomeFIRST project. He was followed by Sarah Elsea from Baylor, who discussed the use of large scale metabolomic profiles to identify inborn errors of metabolism. Finally, Piero Rinaldo from the Mayo Clinic argued passionately that we should stop using reference cutoffs to interpret biomarkers for metabolic disease, and should replace this approach with an assessment of the likelihood that an individual’s biomarker profile is more consistent with a normal or disease profile, based on large numbers of previously tested samples.

As usual, the annual meeting also included workshops by three special interest groups (SIGs), each one focused on a different set of trainees: medical genetics residents, medical students, and clinical laboratory fellows. I attended the medical student education workshop, which this year was co-sponsored by the Association of Biochemistry Educators (ABE). This allowed us to focus on topic integration across the undergraduate medical curriculum, and we had a productive small group session in which biochemists and geneticists worked together to develop teaching cases that integrate the two subjects. Later in the day, we brainstormed the inclusion of ethics in integrated medical curricula, as well as approaches to bringing the basic sciences into the clinical curriculum.

For me – and I think for many others – the most valuable part of the APHMG meeting is getting to know people who are teaching genetics at medical schools and hospitals across the country. We share ideas, create materials together, and establish collaborative projects that continue throughout the year. One of the key products of these interactions in recent years has been the sharing of resources that can be used broadly within the SIGs, including cases, assessments, evaluations, competency frameworks, and curricula. The Genetics Education Resource Exchange houses a number of these resources focused on undergraduate medical education. If your institution is an APHMG member, you can access this valuable resource. (Full disclosure: I was a member of the group that initiated this resource and was the founding curator of the resource exchange, a job that now belongs to Andrew Sobering from St. George’s University.)

If you want to meet and learn from people who are passionate about genetics education, this is the place, and I encourage you to join this supportive and collaborative group at our meeting in Santa Fe next spring. As you can see in the picture of our pirate ship excursion, we also make time for fun. Now, I’m off to take all of the great ideas that were sparked at the meeting and work on my syllabus for next semester.

Kate Garber, PhD, is an Associate Professor at Emory University. She is involved in designing and implementing human genetics training for physician assistants, genetic counselors, and medical students. Read more about Kate’s career.

A Genetic Counselor’s Perspective of ACMG 2017

Posted by Karen Hanson, MS, MBA, CGC, Health Professional Education Programs Manager at ASHG

Last month, I had the opportunity to attend the American College of Medical Genetics and Genomics (ACMG) 2017 Annual Meeting. As a genetic counselor working on health professional education at ASHG, one theme stood out to me: the rapid integration of whole genome/exome sequencing (WGS/WES) into clinical practice.

20170407_ACMG-recap_Karen.JPG

Karen Hanson (right) and Director of Education Michael Dougherty, at the ASHG booth in the ACMG Exhibit Hall.

Apparently, we are sequencing everyone – sick people, healthy people, adults, children, babies, and fetuses. The inspiring talk by William Gahl, MD, PhD, NHGRI, NIH about the work of the Undiagnosed Diseases Network (UDN) reminded us all of why we (researchers, clinicians, laboratorians) entered this field. This session showcased what could be thought of as the most traditional use of WGS/WES in the clinic: using advances in genomic sequencing to improve diagnostic outcomes in patients with suspected genetic disease. It’s now less likely that patients and families will struggle without a diagnosis for years.

Infants born with congenital anomalies or metabolic disease are also benefiting from rapid sequencing technologies that allow their physicians and families to quickly treat and manage them. And it’s not just ‘sick’ babies that are being offered sequencing. Several clinical trials are looking at the efficacy and outcomes of sequencing ‘healthy’ newborns. For years, the genetics community has talked about when the day would come that all newborns have a ‘genetic’ barcode (consider that the movie Gattaca turns 20 this year!). Newborn screening programs have already expanded to include dozens of carefully selected disorders, and WES almost seems like a logical next step. However, in at least in one clinical trial, the majority of parents of healthy newborns who were offered WES declined testing. So maybe we are not quite ready yet.

Another session was devoted to genomic sequencing in ‘healthy’ adults. The current scientific atmosphere certainly seems right for this, when you consider the advances in sequencing technology, the rapid growth of variant databases, and the push for personalized medicine. It did occur to me that we haven’t really worked out the ethical and logistics dilemmas we encounter through WGS/WES of ‘unhealthy’ individuals. However, to paraphrase Les Biesecker, MD, FACMG, NHGRI, genome sequencing is here and it’s not going away. The dilemmas associated with sequencing ‘healthy’ people are not new – variant classification, not enough genetic professionals, health provider education, and access to diverse and underserved populations. But overall, the intention is good – to use genomic technology to improve health and patient care. Which for me begs at least one question: who’s going to manage all these ‘patients’? After all, we will all be ‘patients’ after we get our WGS test results.

So, as a genetic counselor working on health professional education at ASHG, I think of all this as job security. My job – our job as geneticists – is cut out for us. We need to educate our medical workforce and all the rest of the ‘patients’ out there about genomic medicine. And who better to do it then those of us who have been and still are in the trenches.

Karen Hanson, MS, MBA, CGC, is Health Professional Education Programs Manager at ASHG. Read more about ASHG’s educational programs for health professionals.