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.

Inside AJHG: A Chat with Susan Slaugenhaupt

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

Each month, the editors of The American Journal of Human Genetics interview an author(s) of a recently published paper. This month, we check in with Sue Slaugenhaupt to discuss her paper, “ELP1 Splicing Correction Reverses Proprioceptive Sensory Loss in Familial Dysautonomia”.

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Slaugenhaupt Lab (photo courtesy of Dr. Slaugenhaupt)

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

Sue: When I arrived at Massachusetts General Hospital as a postdoctoral fellow in 1991, one of the projects in Jim Gusella’s lab was focused on mapping the gene for familial dysautonomia (FD). Given my background in gene mapping, I became involved in the project and once we mapped the gene, I took over the project aimed at identifying the mutation. Once we cloned the gene and discovered that it was a mRNA splicing defect, I became fascinated by the idea of modifying splicing as a route to therapy, and my lab has worked on this ever since. I have known many FD patients and their families for over 25 years, and our work is driven by the desire to develop a disease modifying therapy for this devastating disease.

AJHG: What about this paper most excites you? 

Sue: Developing a mouse model for FD was a huge challenge since the disease is caused by a tissue-specific reduction of ELP1 protein. In 2016, we succeeded in generating a phenotypic mouse model and this paper describes the first trial of a potential therapy in our mouse. I am very excited that our treatment was able to increase the amount of ELP1 protein in the peripheral nervous system and, most importantly, rescue two of the most debilitating aspects of the disease, gait ataxia and kyphosis.

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

Sue: There are many efforts underway to generate therapies that target mRNA splicing, including small molecules, antisense oligonucleotides, and exon-specific U1 snRNAs. A significant fraction of human genetic disease mutations impact mRNA splicing, so this is an exciting time. These therapies are targeted at the molecular mechanism of disease, not at symptoms, and we are likely to see new treatments for many previously untreatable genetic diseases over the next several years.

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

Sue: Find a good mentor. One who cares more about your future and your career than their own. Look outside your own lab, and fight against the tide that keeps you locked in an unproductive situation too long.

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

Sue: I’m moving to a condo overlooking the beach next month and I can’t wait!

Susan Slaugenhaupt, PhD, is Scientific Director, Center for Genomic Medicine at Mass General Hospital Research Institute and Professor of Neurology at Harvard Medical School. She is a member of ASHG’s Board of Directors.

 

Inside AJHG: A Chat with Nancy Cox

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 Nancy Cox to discuss her paper “GRIK5 Genetically Regulated Expression Associated with Eye and Vascular Phenomes: Discovery through Iteration among Biobanks, Electronic Health Records, and Zebrafish.”

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Nancy Cox, PhD (photo courtesy Dr. Cox)

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

Nancy: I presented some of the preliminary studies from this work at a work-in-progress meeting at Vanderbilt, and Ela Knapik, who directs the zebrafish core here, saw the presentation and asked the question at the end, “Why don’t you knock out GRIK5 in zebrafish?” And so we talked afterward and agreed to collaborate on this project. I expected it to take forever — I was totally unprepared for how rapid CRISPR can be. But it has been a fantastic collaboration and we are working together on several additional really fun projects now.

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

Nancy: Trying to understand how polygenic contributions to disease work is challenging because the effect sizes for any individual variant are quite small. This was a different kind of discovery because we had used a gene-based method and found associations to a pattern of phenotypes, not just a single diagnosis. I think that helped to us to focus the follow-up to the zebrafish studies more broadly and think about how we might test for a relationship between vascular development and eye disease.

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

Nancy: I hope that people will begin to think more seriously about using very large-scale phenome information from electronic health records as an adjunct to genetic studies, which we can afford to do in only smaller numbers of individuals. The biobank at Vanderbilt is big — 250,000 subjects, but there are many more (millions) with quality phenome information but no DNA. Finding ways to use both should stretch our ability to make and extend discoveries.

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

Nancy: One of my mentors used to remind me on a regular basis that there is no shortage of interesting things to do in science — things that are so interesting they are hard to resist. But only a subset of those things are also important with respect to bigger picture questions or implications for other parts of biology. You have to continually ask yourself whether what you are doing is both interesting and important to insure that you are able to continue, and be funded, to do research that you find irresistible.

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

Nancy: I really love the music scene in Nashville! It is amazingly diverse, and we take advantage of the opportunities to hear great music every chance we get.

Nancy Cox, PhD, is Director, Vanderbilt Genetics Institute; Professor of Medicine, Division of Genetic Medicine; Director, Division of Genetic Medicine; and Mary Phillips Edmonds Gray Professor of Genetics at Vanderbilt University. She was the  ASHG President in 2017

Inside AJHG: A Chat with Elizabeth Wright

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 Elizabeth Wright to discuss her paper ‘Practical and ethical considerations of using the results of personalized DNA ancestry tests with middle-school-aged learners’.

Elizabeth Wright, PhD
Elizabeth Wright (photo courtesy Dr. Wright)

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

Elizabeth: I could give you a long answer about being a former middle school science teacher and what drove me to get a PhD in Science Education, but simply put, I am committed to finding ways for each and every student to see themselves connected to science and each other, and supporting teachers in that work.

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

Elizabeth: I am equally thrilled and cautious about having adolescents use their own personal DNA to explore who they are genetically, genealogically/socioculturally, and intentionally. We are not all of one thing and none of another. We can use what we know about pieces of ourselves to imagine something new and amazing. We can reveal these pieces of ourselves to our families and friends and see how we are connected to each other and the grander tree of life.

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

Elizabeth: In the previous question I mentioned a bit about what thrills me. I am cautious because the privacy issues surrounding over-the-counter, direct-to-consumer DNA testing are monumental, and ever-shifting. It is both exciting and nerve-wrecking to ask, and watch, young scholars to embark on this intellectual journey. The engagement and electricity in the classroom when young scientists encounter themselves in new and unique ways keeps me going.

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

Elizabeth: I think the most important thing I would say is: you belong here. You belong in science. Your voice, your experiences, your viewpoint are all incredibly important. If you feel left out or unwelcome, create your own community and persevere because you are going to change things.

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

Elizabeth: I’m a Red Sox season ticket holder and I love the game of baseball. I’ve been to baseball games in 27 different MLB parks, and 3 AAA baseball parks. Also, I love Orangetheory Fitness! Base-Push-All Out, that’s good advice.

Elizabeth Wright, PhD, is a postdoctoral fellow in the Jablonski laboratory at Pennsylvania State University.