For the second time in the past three years, we celebrated the DNA Day activities in association with the School of Health Related Professions (SHRP) Research Day, at the University of Mississippi Medical Center (UMMC). The goal was to present the ASHG to the students and the faculty of this medical center.
High school students presented research posters for judging and discussion containing illustrations, data, and study results, on topics including potential cancer therapy, population diversity, health disparities, and molecular modeling. The sound of students’ presentations was loud and added to the excitement. The students, a majority of whom are from Murrah High School of Jackson, Mississippi, were mentored by the UMMC faculty.
The students are in a program called Base-Pair, supported in part by funding from the Howard Hughes Medical Institute. Base-Pair was initiated over 25 years ago to help advance science education in the public schools of Jackson, Mississippi.
Just in time, I was able to include the names and photos of the 2019 DNA Day Essay Contest winners in the poster. The students were excited about the DNA Day Essay Contest. Some of them are thinking about participating next year. I presented a couple of quizzes just for fun and also to test their genetics understanding, one about the sickle cell gene and disorder, and another about genome editing. The students responded enthusiastically to the quiz. I promised to discuss the role of genetics in organ transplantation next year. Overall, the event was very educational.
Recently, there has been a re-emergence of gene patenting, an old issue that could impact the future of genetic research and medicine. On Wednesday, May 22, Senators Thom Tillis (R-NC) and Chris Coons (D-DE), along with Representatives Doug Collins (R-GA-9), Hank Johnson (D-GA-4), and Steve Stivers (R-OH-5) released text for a draft bill that seeks to reform Section 101 of the Patent Act. If passed, this legislation would effectively overturn the 2013 Association for Molecular Pathology (AMP) vs. Myriad Supreme Court decision, which ruled that our genomes are not eligible to be patented, as they occur in nature. Essentially, the bill would allow for the patenting of genes.
To provide a bit of history on the issue, back in 2009, AMP, along with the American Civil Liberties Union (ACLU), filed a lawsuit against Myriad Genetics, challenging the validity of Myriad’s patents on the isolated BRCA1 and BRCA2 genes. AMP argued that these patents created extraordinary burdens for researchers, as they skyrocketed the cost of related testing and prevented further innovation. ASHG and several other medical associations submitted an amicus brief in support of AMP’s claims. In March 2010, the case was heard before the United States District Court of New York, where the judge ruled that products of nature could not be patented.
Upon successful appeal by Myriad, the case was eventually heard by the Supreme Court. In 2013, the Supreme Court ruled that isolated genes were still considered products of nature, and were not eligible to be patented.
This AMP vs. Myriad ruling has played a large part in fostering an environment where researchers and clinicians are unencumbered by patent barriers.
Reacting to the news of the pending legislation, ASHG President-Elect, Anthony Wynshaw-Boris, MD, PhD, stated, “ASHG remains firm with our support of the 2013 Supreme Court ruling of AMP vs. Myriad that established that naturally occurring DNA is not patentable because it is a product of nature. It allows researchers to investigate the entire genome without fear of legal barriers and repercussions, helping to advance genetic discoveries and the development of new diagnostics and treatments for patients.”
This week, a two-part hearing titled “The State of Patent Eligibility in America” was held by the Senate Judiciary Committee’s Subcommittee on Intellectual Property, where Senators Tillis and Coons serve as Chairman and Ranking Member, respectively. In his opening remarks, Senator Coons stated that the bill does not intend to overrule the 2013 Supreme Court ruling, but instead hopes to draw the line for how much human intervention is needed to determine patent eligibility.
In his testimony, Charles Duan, Director of Technology and Innovation Policy at the R Street Institute, disagreed with Senator Coons’ claims, citing that the draft bill “provides that patent eligibility inheres in any ‘invention or discovery’ that arises ‘through human intervention.'”
Also amongst the panelists was Kate Ruane, Senior Legislative Counsel at the ACLU, who stated that the draft bill’s proposed revival of patent claims on genes would essentially violate the First Amendment, as it would deny scientists the ability to freely study and research genes. A third group of panelists will testify for a final hearing early next week.
ASHG will be following this impending legislation closely in the next coming weeks, and will alert ASHG members on any significant updates or grassroots advocacy efforts that may require your action and support. To stay up-to-date on the issue, be sure to subscribe to our monthly policy and advocacy email updates.
Posted By: Ann Klinck, Communications & Marketing Assistant, ASHG
With growing interest in polygenic risk scores (PRS) and questions arising about its clinical relevance, ASHG and The American Journal of Human Genetics (AJHG) hosted the webinar The Development and Application of Polygenic Risk Scores. The archived video is now available for viewing.
Bruce Korf, AJHG editor and webinar moderator, was joined by Eimear Kenny, PhD, Director of the Center for Genomic Health at the Icahn School of Medicine at Mount Sinai, and Sekar Kathiresan, MD, Director of the Center for Genomic Medicine at Massachusetts General Hospital, and Director of the Cardiovascular Disease Initiative at the Broad Institute.
Origins of Polygenic Risk Scores
With much research leading to the growth of PRS, Dr. Kenny believes the research paper The Correlation between Relatives on the Supposition of Mendelian Inheritance (1918) from R.A. Fisher was a huge contributor to the modern-day field complex trait genetics. Fisher defined the term variance, introduced the analysis of variance to partition observed variation into underlying casual factors, and theorized that several genes could contribute to variation using mendelian segmentation. This work led to understanding the genetic architecture and the prediction of complex traits.
Dr. Kenny went into further detail on the background of PRS, which you can see in the archived webinar (skip to 4:53).
What is a PRS?
A PRS is defined as “a genetic prediction of an individuals’ phenotype. It is calculated by summing across the products of a genome-wide association study (GWAS) effect sizes and number of trait-increasing alleles.” Dr. Kenny said that the ultimate goal of a PRS is to predict the phenotype in an out of sample individual who does not have a recorded phenotype.
So, Where Does GWAS Fit In?
Dr. Kenny emphasized that the explosion of GWAS was a tipping point for risk prediction and has expanded in both number of studies and size. GWASs provide evidence supporting Fisher’s theory that most heritable variation is due to thousands of genetic variants each with a tiny marginal effect.
In other words, the genetic architecture of complex traits is almost always highly polygenic. Essentially, the expansion of PRS and GWAS go hand-in-hand.
Where is PRS Being Seen in the Field?
PRS are influencing a variety of subject areas including epidemiology, statistics, public health, social science, and medicine. Dr. Kathiresan shared the real-world case of a 42-year-old male patient, who suffered a heart attack after being told six months prior that he had only a 1.7% chance of having a heart attack within the next ten years. In this case, other methods of predicting heart attack risk like cholesterol, triglycerides, or blood pressure were not helpful preventatives. As the current heart attack risk prediction model is largely driven by age, heart attack in people under 55 is difficult to predict.
“For early-onset disease, stratifying individuals based on inborn DNA variation is an important option, being as most diseases have an inherited component,” Dr. Kathiresan noted. What this could lead to is earlier interventions outside of lifestyle changes, like the use of a statin medication.
Essentially, over the last 15 years, it’s been found that using a polygenic risk model can identify other at-risk individuals. Dr. Kathiresan believes that in the next five years, polygenic risk will start to be incorporated when calculating a patient’s heart attack risk.
To hear more about the work on heart attack risk and other common complex diseases, check out the full webinar (skip to 35:02).
Representing the Global Population
Though there are millions of GWAS participants, most databases driving the GWAS and PRS research are of European ancestry, while only one-seventh of the world’s population has European ancestry. PRS can be adjusted for ancestry, but if based on current data, scores may not be as accurate for non-European populations.
Dr. Kenny described increasing diversity amongst genetic study participants as a multi-pronged issue (skip to 1:00:12). There are many efforts to recruit diverse populations, not only in ancestry, but in community type and socioeconomic status. Still, there is a lot of work to be done. Dr. Kenny believes that increasing diversity in the scientific community as a whole will allow labs to think about participant diversity more clearly.
Dr. Kathiresan agrees and pointed out that participant diversity is important for not only common disease genetics, but also for rare disease genetics in terms of who has been sequenced and the ability to then interpret rare variation.
PRS is a fast-moving area of interest but is just one developing approach to genomics and health, and there are many others such as transcriptional risk scores, epigenetics, and copy-number variation.
“I am optimistic about our ability as a field to really tackle these questions, problems, and challenges,” said Dr. Kenny in conclusion. “There are reasonable solutions, and we can pursue them. I’m hopeful we as a scientific community engage a lot more with the public, clinicians, and other stakeholders that think about these similar questions.”
AJHG: What prompted you to start working on this project?
Lluis: My laboratory is interested in the evolution of human populations and their long-standing relationship with infectious agents; half of the lab thus works on population genetics questions and the other half focuses more on population/systems immunology. In the context of this project, it all started back in 2016, when we found that Neanderthal introgression has affected innate immunity genes as a whole, and that some innate immunity genes (e.g., the TLR1/6/10 cluster) display extremely high levels of Neanderthal ancestry (Deschamps et al. Am J Hum Genet, 2016).
Later that year, we also found that Neanderthal introgression has been pervasive among regulatory variants (eQTLs), in particular those involved in responses to viral stimuli including influenza (Quach et al. Cell, 2016). The next natural question was then to explore how Neanderthal-introgressed variants in the genomes of non-Africans have affected more generally transcriptional and post-transcriptional regulation, focusing on promoters, enhances and miRNA-mediated regulation, in different tissues and cell types.
AJHG: What about this paper/project most excites you?
Lluis: Several things. First, although Neanderthal introgression has had relatively little effect on miRNA-mediated regulation, a mechanism that in general tolerates little variation and is highly evolutionary constrained, a few Neanderthal variants in a few miRNAs can exert a massive impact on downstream transcriptional programs. In general, I am fascinated by the fine-tuned “smart” way miRNAs function.
Second, I am excited about our results of enhancers, in particular the enrichment in Neanderthal ancestry we find in enhancers that are active in T cells (yes, sorry, I have a biased interest in all immune-related processes). What is even more interesting is that the excess of Neanderthal ancestry we observe in T cell enhancers is not due to increased Neanderthal introgression. Instead, it results from a higher human-Neanderthal divergence at these elements. This may reflect past adaptation in the Neanderthal lineage for this type of enhancers.
AJHG: Thinking about the bigger picture, what implications do you see from this work for the larger human genetics community?
Lluis: This work highlights once more the potential benefits of admixture between our ancestors and other human forms, such as Neanderthals or Denisovans. The latter were adapted to their environments, whereas our ancestors entering Europe or Asia were less adapted. In this context, acquiring advantageous variation through archaic admixture is a fascinating topic, with obvious consequences for the larger human genetics community. Indeed, such archaic admixture increasingly is being shown to affect molecular phenotypes such as gene expression or mechanisms of gene regulation (e.g., this study) and more generally, organismal phenotypes such as traits and diseases (e.g., skin pigmentation, sleeping patterns, allergies) in present-day human populations.
AJHG:What advice do you have for trainees/young scientists?
Lluis: Be open while doing research, be curious, be rigorous, exchange a lot with other trainees and PIs, read a lot, and MAINLY, have fun and be passionate! Meaning both in your working and non-working life. Enjoy the work, do not suffer from it! For me, this is rule number one. If you follow this rule, great findings will follow…and, yes, a bit of luck also helps.
AJHG: And for fun, tell us something about your life outside of the lab.
Lluis: I like to garden (actually, I can spend hours gardening), to bike, and, increasingly, to run. These three things really empty my mind and recharge my batteries. Also, I do need to go at least once per year to Mallorca (where I was born). Having lived there until I was 20 gave me a handicap for life: my need for sun and sea (and I live in Paris…). There’s nothing that relaxes me more than getting into the turquoise Mediterranean water and swimming!
I also love art exhibitions, almost exclusively modern art, and pop if possible! I spent last summer in NYC on a mini-sabbatical at Rockefeller University, and I really enjoyed the exhibitions there!
I also like to read. I can compulsively read historical biographies. When I enjoy somebody’s life, I can read 30 books about them even if most of them say the same thing. A recent example is the life of Princess Marie Bonaparte – a psychoanalyst and close friend of Sigmund Freud, whom she helped escape from Nazi Germany. I also love reading about contemporary politics: one of my preferred topics is the so-called “Spanish transition,” the period starting 1975-1980 when Spain transitioned from being under Franco’s non-democratic regime to being the modern, open-minded country that is today. Obviously, I like books about evolution, but then, that is more work-related again…
Lluis Quintana-Murci, PhD, heads the Unit of Human Evolutionary Genetics in the Department of Genomes and Genetics at the Institute Pasteur. He is a first year member of ASHG.
Posted By: Kiran Musunuru, 2019 Chair, ASHG Program Committee
As you are preparing your ASHG 2019 abstract, I wanted to take some time to share how the ASHG topics and subtopics are structured and guidance on how to select the right topic. Understanding this will help you score better during review and get your talk or poster in front of the right people.
How ASHG Topics are Structured
Each of the twelve topics covers a large portion of current research in human genetics and are organized to group the most similar abstracts together. The topics and subtopics form the basis of the abstract review and session building process and, eventually, the organization of the poster hall. Program Committee members are assigned to review an abstract topic aligned with their research expertise.
With an average of 3,500 abstracts submitted, it has been helpful to further divide the topics into subtopics based on organ systems and clinical phenotypes. The subtopics are the same regardless of the main topic chosen. When Program Committee members gather to draft the Platform Sessions in July, they will often use the subtopics to build cross-topic sessions covering the most exciting research.
Changes to the Topics to Keep Up with the Field
The topic/subtopic system was last reorganized in 2016. Given the pace of expansion in human genetic research, the Program Committee reviewed and revised the topics this year. The largest changes were the addition of two topics. “Precision Medicine, Pharmacogenomics, and Genetic Therapies” was added to address the rise in genetic therapy development in recent years. “Molecular Effects of Genetic Variation” expands upon the previous “Genome Structure and Function” topic, so that we may group together all the functional genetics and gene expression abstracts that were previously spread across several abstract topics. Look for the new topics as you browse posters in Houston.
Tips for Selecting the Right Topic
Selecting the correct topic for your research is important to make sure it is reviewed by the appropriate experts and programmed with similar abstracts in either an oral or poster session. Each topic is represented proportionally in the talks, so there is no advantage to selecting one topic over another. In fact, submitting to the wrong topic will likely result in a poorer score because experts from other fields may view your work as less compelling.
Before submitting your abstract, make sure you read the definitions for each of the twelve topics. Determine which topic is most likely to have closely related studies to yours, as that is likely the best fit. Taking a few extra minutes to find the right home for your abstract will help you achieve the best possible score and boost your visibility with relevant colleagues.
Kiran Musunuru, MD, PhD, MPH, 2019 Program Committee Chair, is an Associate Professor of Cardiovascular Medicine and Genetics, and the Director of the Cardiovascular Institute’s Genetic and Epigenetic Origins of Disease Program, at the Perelman School of Medicine at the University of Pennsylvania.
I recently returned from the ISB Biocuration 2019 conference in Cambridge, UK. To me, this year’s conference focused on two of the core goals of the International Society for Biocuration (ISB): one, to promote communication and exchanges between curators and two, to encourage best practices by providing documentation on standards and annotation procedures.
Communication and Exchanges between Curators
Many presenters encouraged sharing of database resources and curation materials so as not to duplicate efforts and to facilitate transparency. For example, Rolf Apweiler, director of EMBL-EBI, discussed the Alliance of Genome resources, an effort to locate all curations of model organisms on the same website in a standardized format. The Alliance is founded by FlyBase, Mouse Genome Database, the Gene Ontology Consortium, Saccharomyces Genome Database, Rat Genome Database, WormBase, and the Zebrafish Information Network and contains information about six model organisms. In a related vein, Niklas Blomberg, director of ELIXIR, pointed out that many of the curation resources used by the entire scientific community are reliant on grant funding, making their future existence unstable. He discussed how resources should be defined as Core Data Resources to potentially solicit permanent stable funding.
There were also interactive workshops each afternoon that further supported this idea of communication between curators. One workshop, in which I presented, discussed the efforts of the Gene Curation Coalition (GenCC). This Coalition is an international group of gene curation resources with the goal of harmonizing the terms for defining clinical validity of gene:disease relationships. Three GenCC member groups (ClinGen, Genomics England PanelApp, and Orphanet) each took turns presenting their gene curation strategies. Participants were able to discuss the similarities and differences between the approaches. The workshop ended with survey results from the scientific community about the gene:disease validity terms.
Documentation and Standards
The more time I spend as a curator, the more I understand the value of consistent curation language. This idea was heartily supported by presenters at the conference who encouraged use of ontologies and the idea that each curation resource should strive to abide by FAIR (Findable, Accessible, Interoperable, and Reusable) data standards. Varsha Khodiyar, data curation editor at the journal Scientific Data, discussed how Springer Nature is trying to support FAIR data sharing to help reduce irreproducible experiments. Sirarat Sarntivijai, ELIXIR interoperability platform coordinator, spoke about recommended interoperability resources, tools that could be used by curators, creators of websites, or even authors to make data FAIR.
Many talks about specific resources, such as SIGNOR/DISNOR, SwissLipids, and the BioGRID Interaction database, cemented the idea that resources are most useful when they use ontologies to categorize terms.
The four days of this conference were a fascinating and important glimpse into the world of curation resources. After attending, it is quite clear that many of these resources are critical to the scientific community and keep research moving forward, thanks to the hard work of all the biocurators. The poster sessions were intimate and allowed for thoughtful discussion, useful suggestions, and hopefully the start of budding collaborations. Workshops were very interactive, and it was clear that the curators harbor a passion for their field of work and the work of their fellow curators.
If you have ever done or are planning on doing any curation, I highly recommend you attend this conference. The 13th International Biocuration Conference takes place in Bar Harbor, Maine from May 17-20, 2020.
Marina DiStefano, PhD, is a member of the ASHG Communications Committee and a postdoc at Harvard Medical School. She has been a member of ASHG since 2018.
Posted By: Ann Klinck, Communications and Marketing Assistant, ASHG
Earlier this month, ASHG hosted a webinar titled Resilience and Wellness, which focused on strategies to maintain your mental wellness in the scientific workplace and improve your resilience to the challenges and setbacks we all face.
Sharon Milgram, PhD, Director of the Office of Intramural Training and Education (OITE) at the National Institutes of Health (NIH) reminded webinar listeners that to function at the highest capability, you must take your own well-being into consideration.
“Those who are resilient prepare to be resilient,” said Dr. Milgram. Developed through education, self-reflection, and practice, resilience can help a person navigate through adversity constructively. Here’s how:
People: Find people you can trust, who will give you energy when you feel stuck, and go to them to find compassion, a listening ear, or just companionship.
Process: Figure out what wellness practice or resources you can focus on that will help you in that moment.
Prepare: You cannot try to discover these things in a moment of crisis; you have to set yourself up for success.
Dr. Milgram also provided this helpful tool to identify characteristics of a resilient person.
Handling Our Inner Critic
To improve the way you view difficult situations or setbacks, analyze your self-talk. Are the stories you tell yourself harsher than they need to be? Consider whether you would say the things you tell yourself to a friend. Are you seeing the broader picture?
Destroying Cognitive Distortions
Dr. Milgram described cognitive distortions or automatic negative thoughts as “Characteristic ways that our mind convinces us of something that is really not true to reinforce negative thinking or emotions.” Some examples are:
All-or-nothing thinking: Your performance is either perfect or a complete failure.
Catastrophizing: You exaggerate the implications of a setback or mistake.
Mind reading: You make assumptions about what someone else is thinking.
Here’s how to tame them:
Journal to identify your most common negative thoughts.
Talk to mentors and peers.
Use your science voice to question them: Where is the evidence that this is the worst thing to ever happen in my life?
Be open to counseling when it’s unmanageable.
Never Feel Like an Imposter
Imposter fear is a type of cognitive distortion, qualified as “The feeling of phoniness in people who believe that they are not intelligent, capable, or creative despite evidence of high achievement.” Dr. Milgram pointed out that “If you are working towards a PhD in the sciences, if you are a postdoc, if you have been working as an undergraduate in a high-knowledge research environment, there is much evidence of high achievement already, though we often find ourselves feeling like fakes and phonies.”
Imposter fears include attributing success to luck or discounting your successes. You’re not alone! 70+% of individuals experience imposter fears at some point in their educational and work journey. Fight that feeling by practicing accepting praise and reminding yourself that impostor fears happen to everyone.
To Do Well, We Have to Be Well
Dr. Milgram provided a model of holistic self-care outlining four quadrants of wellness.
In her shared slide deck, you can find a wellness assessment for each quadrant. While everyone defines these quadrants differently, each needs to be fulfilled to feel well. Dr. Milgram reminded us we can’t fix everything at once, and to take time to work on one area instead of trying to change too many habits too quickly.
Watch the full webinar, or check out our Twitter account to see live engagement from listeners!