Inside AJHG: A Chat with Stephen Kingsmore

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 Stephen Kingsmore to discuss his paper “A randomized, controlled trial of the analytic and diagnostic performance of singleton and trio, rapid genome and exome sequencing in ill infants.”

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Stephen Kingsmore, MD, DSc, holding his patient, Maverick Coltrin. The photo was taken in April 2018 at the Frontiers in Pediatric Genomic Medicine Conference.

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

Stephen: We’ve been working on implementing rapid whole genome sequencing in infants in intensive care units since 2011. We have two Guinness world records for fastest time to genetic diagnosis (the current benchmark is 19 hours). In the first 35 infants we tested, we saved two lives by changing therapy from that based on the clinical diagnosis to that based on the molecular diagnosis. Ever since then, we’ve been on a mission to understand how to make this reality in every intensive care unit in the world.

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

Stephen:  Randomized controlled trials are very exacting. This is just the second randomized controlled trial of clinical genome sequencing! You’re never sure whether a clinical trial will really test the desired hypothesis. I was most excited that we clearly showed that ultra-rapid whole genome sequencing, with fastest time to diagnosis, was best for seriously ill infants in intensive care units (ICUs). As with every previous study, I now know how to redo the current one!

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

Stephen: This manuscript is part of a growing body of evidence that demonstrates that infants in ICUs with diseases of unknown etiology benefit from rapid whole genome sequencing by virtue of the consequent implementation of precision medicine. We anticipate that 30,000 infants per year would benefit from this in the U.S. The current study was unique since almost one half of infants in ICUs were eligible for enrollment. As a result, we found that genetic diseases are much more common than previously expected.

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

Stephen: Think about a career in genomic medicine – the genomic medicine tsunami is coming and we’ll need every genetic counselor and medical geneticist to deliver this new type of care. For the first time, genomics will save lives day in, day out.

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

Stephen: I’m reading the Bible in a year. I’m 2/3 of the way through and it yields specific thoughts for each day, as well as continually adjusting my thinking to the bigger, long-term picture. It started as a chore and now is a vital part of my day.

Stephen Kingsmore, MD, DSc, is the President and CEO of Rady Children’s Institute for Genomic Medicine at Rady Children’s Hospital. He has been a member of ASHG since 2007.

Genomic Medicine at the Population Level: Your Questions Answered 

Posted By: Alissa Ortman, Associate Director, ASHG Digital Programs

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In September, ASHG and The American Journal of Human Genetics (AJHG) hosted a webinar to discuss large-scale, national studies that have been launched to collect phenotypic and genomic data on large populations. They also discussed how the data from that work should be shared around the world. If you missed it, you canwatch the recording or read this blog that summarizes the event.

This topic generated numerous audience questions, not all of which were able to be answered. Fortunately, the All of Us Research Program communications team was able to answer some of them after the webinar.

Attendee Question: When will All of Us start recruiting from smaller cities across the country? Example: I live in Tallahassee, FL. and am interested in joining.

All of Us: Recruitment is now open nationwide at https://www.joinallofus.org/en. Meanwhile, the program is gradually expanding its reach to collect physical measurements and samples from more participants in different areas across the country and will invite more participants to schedule a visit in time.

Attendee QuestionHas any uninterpreted genomic data (not results) been returned yet to any All of Us participants? If so, how much? If not, when is that anticipated to begin?

All of Us: No, not yet. We have not yet begun genetic analyses, either genotyping or whole genome sequencing. Participants will be able to request access to their raw genetic data in time. Our plans and timeline for the return of information are currently under development and will be subject to review by our Institutional Review Board.

Attendee Question: Do you anticipate expanding the data All of Us will return to participants—specifically, in line with recent FDA guidance around pharmacogenomics?

All of Us: Over time, the program plans to return various types of information. Genetic results will likely include information about ancestry and traits, pharmacogenomics, and findings tied to 59 genes associated with risk of specific diseases for which there are established medical guidelines for treatment or prevention. The specific details about what the program will return and when are under discussion and will be reviewed by our Institutional Review Board.

Attendee QuestionIt is great that genomic data is being used in novel ways for diagnosis of rare, even new diseases. However, what efforts are being made to make novel treatment options available to the individual patients?

All of Us: The mission of the All of Us Research Program is to accelerate health research and medical breakthroughs, enabling individualized prevention, treatment, and care for all of us. We hope novel treatments will be discovered based on the data available through the program and understand that these options then need to get to the folks who need them most. In August 2019, All of Us awarded $4.6 million in initial funding to Color, a health technology company, to establish the program’s nationwide genetic counseling resource. Through this funding, Color’s network of genetic counselors will help participants understand what the genomic testing results mean for their health and their families.

Attendee QuestionWill any training sessions be available for how to use the cloud data of All of Us Project?  

All of Us: Once the Research Hub is made available to all researchers (anticipated for 2020), All of Us will announce plans for upcoming training sessions on how to use the platform.

Thank you to our webinar sponsor, Illumina, whose sequencing and array technologies are fueling advancements in life science research, translational and consumer genomics, and molecular diagnostics. For more information, please visit illumina.com or contact their population genomics team at populationgenomics@illumina.com.

 

Inside AJHG: A Chat with Heidi Rehm

Posted By: Sarah Ratzel, PhD, Science 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 Heidi Rehm to discuss her paper, “Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network.”

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Heidi Rehm (photo courtesy of Dr. Rehm).

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

Dr. Rehm: We (Broad Institute and Partners Laboratory for Molecular Medicine) as well as Baylor College of Medicine were funded to provide genomic sequencing and interpretation support for Phase 3 of the eMERGE program.

AJHG: What about this paper most excites you? 

Dr. Rehm: Understanding our genomes will require large scale data sharing, harmonization and analysis across many research and health systems. This paper represents key steps in harmonizing and scaling genomics in the context of real-life healthcare systems.

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

Dr. Rehm: We hope that our work sets the groundwork for more clinical laboratories standardizing the intake of genetic testing orders and output of clinical reports for consumption by electronic health systems which we hope will be embraced as we all try to best integrate genomics into the practice of medicine.

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

Dr. Rehm: Clinical genomics is an exciting field with tremendous growth happening. Come join us!

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

Dr. Rehm: I have two teenagers, so life outside the lab right now is mostly following them around to sports events and college visits. Most weeks I get to play at least one game of ultimate Frisbee in the evening when I’m not traveling. And of course a favorite family activity is watching John Oliver as the only way to survive the current political climate in the U.S.!

Heidi L. Rehm, PhD, FACMG, is Chief Genomics Officer in the Department of Medicine for Massachusetts General Hospital, and Medical Director of the Broad Institute Clinical Research Sequencing Platform. She has been an ASHG member for over 20 years. 

Inside AJHG: A Chat with Jennifer Posey and Jim Lupski

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 Jennifer Posey (@poseypod) and Jim Lupski to discuss their paper “Paralog Studies Augment Gene Discovery: DDX and DHX Genes.”

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This photo of current and former lab members celebrates 30 years of discoveries in the Lupski lab. (courtesy Dr. Lupski)

 

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

Jenn and Jim: This project developed from several of the lessons we’ve learned through our work in the Baylor Hopkins Center for Mendelian Genomics. In collaboration with our Drosophila colleagues (Hugo Bellen, Shinya Yamamoto, Michael Wangler), we had learned that Drosophila genes with multiple human orthologs are 8-fold more likely to be associated with Mendelian conditions in humans (Yamamoto S, et al. Cell (2014)159:200-214).

Other key collaborations led to the elucidation of DHX30 and DDX3X as genes associated with neurodevelopmental disorders (Lessel D, et al. Am J Hum Genet (2017)101:716-724; Wang X, et al. Ann Clin Transl Neurol (2018)5:1277-1285) bringing the DExD/H-box RNA helicase gene family into focus as a candidate set of paralogous genes with which we could test our hypothesis that a paralog-focused gene-first approach would reveal novel candidate disease genes associated with overlapping phenotypic features.

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

Jenn & Jim:  Many of our research participants were first recognized clinically as having a rare condition with clinical features that were molecularly unexplained.  This focus on clinical features – or phenotypes – can often drive ‘phenotype-focused’ research analyses to identify relevant genes. While successful as an approach to novel disease gene discovery, the richness of clinical features, and the clinical variability amongst individuals sharing the same causative gene, can be lost.

Turning this approach on its head, we instead took a gene-first approach to interrogate a large cohort of participants with varied phenotypes to objectively identify clinical features associated with rare variants in DExD/H-box RNA helicase genes. We were struck by the observation that both clinical features common to a majority of individuals with rare variants in these genes (neurodevelopmental delay), as well as unique features that were observed in only a subset of individuals (genitourinary disease), were revealed by this approach.

We were also pleased to see the involvement of the international community facilitated by GeneMatcher (https://www.genematcher.org/), and the matching of multiple stakeholders, including families, physicians, and researchers interested in this gene family. GeneMatcher also led to another successful collaboration with our colleagues at the University of Washington Center for Mendelian Genomics and fomented gene discovery.

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

Jen & Jim: A gene-first approach and family-based genomics is turning out to be a very powerful way to gain an entry point into disease biology, and at the same time, stimulate molecular diagnoses for families.

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

Jenn & Jim: Work hard and diligently to understand disease biology in human genetics. Collaboration and international team-building benefits all stakeholders.

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

Jenn & Jim: Life outside the lab is enriched by the colleagues and collaborators and families with whom we are so fortunate to spend time.

There is a curious parallel between the inspiration derived from art and artists’ expressions of their individuality and the drive we share to understand how genetics and genomics impacts each individual’s personal health. Tableside conversations become even more interesting with international travel, good foods from all over the world, and shared experiences.

Jennifer Posey, MD, PhD is an Assistant Professor of Molecular and Human Genetics at Baylor College of Medicine. James Lupski, MD, PhD, DSc (hon) is the Cullen Professor of Molecular and Human Genetics and Professor of Pediatrics at Baylor College of Medicine. A longtime ASHG member, he was the recipient of the 2002 Curt Stern Award and the 2018 McKusick Leadership Award. 

Inside AJHG: A Chat with Natalie Telis

Posted By: Sarah Ratzel, PhD, Science 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 Natalie Telis to discuss her paper, “Public Discussion Affects Question Asking at Academic Conferences.”

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Natalie Telis, PhD (courtesy Dr. Telis)

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

Dr. Telis: At one of the first conferences I went to, I realized after a day that I was the only woman who’d asked a question. And I remember thinking, “That’s weird, right?”

But then I second guessed it. I said, well, there were maybe 10 questions today. If 1 in 10 people in the audience are women, that participation is actually representative. What information would I need about this conference to discover whether this is representative participation?

Part of being a computational biologist is that you have a skill set that applies to computational problems — not just biology problems. So I started drawing on that skill set to try to learn more about this problem, and things kind of evolved from there!

AJHG: What about this paper most excites you? 

Dr. Telis: I am really excited about the opportunity to explicitly set goals, and then to use these techniques to measure whether our interventions get there. If our goal is to increase proportionate participation, it’s easy to say: “Well, having 50% of people in the room be women will help us get there.” But does that actually come to bear? We can test that question now (and learn that it doesn’t work that way). That can help us build powerful interventions to change culture and reshape access for underrepresented groups in science more broadly.

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

Dr. Telis: The human genetics community is still grappling with questions about representation and participation across the board, not only for women scientists but across intersectional categories. I do hope that raising these questions in a scientific way has contributed to more discussion around inclusion and representation. We definitely still need to ask, what do we want our community to look like, and how do we get there?

This work provides a precedent and hopefully a computational framework for testing that. And that’s a critical infrastructure we need to develop as we attempt to create change.

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

Dr. Telis: Any question is an opportunity to hone your scientific skills. Asking questions about questions didn’t seem like human genetics to me, but the computational techniques I’ve learned were ultimately what I used to solve that problem. Being a scientist is an opportunity to live and work on the edge of what is known — bring that curiosity in the face of uncertainty with you wherever you go!

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

Dr. Telis: I don’t really believe in New Year’s resolutions or setting a goalpost (especially because I always miss them), so instead this year I started trying to numerically track things I want myself to do more of. So I’m surprised and shocked and very proud to say I’ve read 27 books so far this year! Making space for all that fiction reading, not just paper reading, has made me more refreshed, inspired, and creative in my research.

Natalie Telis, PhD, is a Staff Scientist at AncestryDNA. She has been an ASHG member since 2014.

Recap: ASHG-AJHG Webinar on Polygenic Risk Scores

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

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Eimear Kenny, PhD (provided by Dr. Kenny)

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?

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Sekar Kathiresan, MD (courtesy Dr. Kathiresan)

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.

Conclusions

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.”

Next Webinar:

Exploring the Responsibility to Recontact

Inside AJHG: A Chat with Lluis Quintana-Murci

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 Lluis Quintana-Murci (@quintanamurci) to discuss his paper “Impact and Evolutionary Determinants of Neanderthal Introgression on Transcriptional and Post-Transcriptional Regulation.”

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Lluis Quintana-Murci (far right) with the members of his lab, including Martin Silvert and Maxime Rotival (courtesy Dr. Quintana-Murci)

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.