AJHG Welcomes Its New Editor: Q&A with Bruce Korf

Posted By: Staff

A warm welcome to Bruce R. Korf, MD, PhD, new Editor-in-Chief of The American Journal of Human Genetics (AJHG)! We chatted with Dr. Korf about his vision for the journal, which he also described in an editorial in this month’s AJHG.

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Bruce R. Korf, MD, PhD, Editor of AJHG

ASHG: What excites you about human genetics research today?

Bruce: Human genetics encompasses an enormous range of research activity. We are in a golden age of gene discovery, including the identification of genes that underlie rare disorders and revealing genetic contributions to common disorders. From my own perspective as a medical geneticist, it’s exciting that disorders we used to only be able to diagnose are now potentially treatable as we uncover the genetic mechanisms and underlying pathophysiology.

There is also fascinating research into human origins and history, independent of medical implications. As a reader of the Journal I did not previously focus on this type of work, but now as AJHG Editor, I am finding this work to be really interesting – these papers bring together ideas we can all relate to.

ASHG: How do you view AJHG’s role in advancing the field?

Bruce: AJHG is the place for geneticists to showcase their best research. It’s a forum to publish findings of broad interest in genetics, and has long been trusted for its scientific rigor, integrity, and careful review of manuscripts. It’s also a resource for the next generation of geneticists, to both encourage and educate early-career scientists and trainees.

As we learn more about ways to diagnose and increasingly, to treat genetic conditions, the Journal can be involved in publishing papers that demonstrate the clinical utility of these interventions – to show that they actually improve outcomes in a cost-effective way. Findings published in AJHG also help highlight the value of publicly funded research: this important work produces new knowledge that leads to better health care and outcomes.

ASHG: ASHG members receive a free subscription to AJHG and are exempt from publishing fees. What other benefits does AJHG offer members?

Bruce: When you’re reading AJHG, you’re looking at the final product of an intense team process. Our staff and editorial board share a strong sense that the papers should represent as carefully vetted a story as possible, which happens at every step from submission to review to acceptance and editing of manuscripts. AJHG and Cell Press put in a lot of effort to ensure reliability of the findings we publish.

The Journal can also serve as an educational forum, for example to help trainees understand the background of why and how a study was put together.

As AJHG is the Society’s journal, we would welcome members’ advice and suggestions on what we can do better, do more of, etc.

ASHG: Are there new areas of emphasis where you’d like to see more submissions?

Bruce: Genetics has advanced tremendously in recent years, and conditions that we could previously only identify can now be treated. I would love to see more submissions on treatment, from preclinical testing to even reporting of clinical trials.

Cancer genetics is another area of interest. Historically, many cancer papers published in AJHG have emphasized germline and Mendelian changes associated with cancer risk. I would like to see more submissions on somatic cancer genetics in addition to work on inherited predisposition to cancer.

ASHG: You’ve also expressed interest in addressing genetics questions that affect society more broadly. Tell us about that.

Bruce: Advances in genetics are bringing up ELSI-related questions, such as how to responsibly use genetic information and how to protect genetic privacy. We look to ASHG to serve as a voice of reason and thoughtful analysis, weighing in on important issues of the day through Society statements. Beyond those statements, I would like to see more Commentaries from individuals in the genetics community, which provide a venue to share personal opinions and generate thoughtful discussion.

Inside AJHG: A Chat with Barbara Evans

Posted By: Sara Cullinan, PhD, Deputy Director, 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 Barbara Evans of the University of Houston, to discuss her Commentary, “HIPAA’s individual right of access to genomic data: reconciling safety and civil rights.”

Through such Commentaries, AJHG encourages individuals in the genetics community to share their personal views on a policy issue. Distinct from journal editorials and official ASHG statements, it is our hope that these commentaries will help spur discussion within the field.

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Barbara Evans, University of Houston (Credit: S. Chandler)

AJHG: How did you become interested in this topic?

Barbara: Last summer, I was getting a lot of calls from research participants who were having trouble exercising their HIPAA right of access to their own genomic data. The HIPAA Privacy Rule is a U.S. federal privacy law. It grants people a right to obtain copies of data about themselves that is stored at HIPAA-regulated facilities. Since 2013, the Privacy Rule protects genetic data and, since 2014, its access right extends to data stored at HIPAA-regulated labs. People heard that they have a right to see their data, so naturally they wanted to see it. Many were being told “no.” Law professors play an informal role as society’s help line for questions about the laws we write about. I write about HIPAA, so I’m like the canary in the coal mine if a new HIPAA problem is emerging: my phone starts to ring. I checked around, and other HIPAA lawyers were getting those same calls from frustrated research participants. “Strange…why now?” we wondered. It seemed worth looking into—which, for a Law Prof, means you write an article. This is the article.

AJHG: What about this topic most interests/concerns you?  

Barbara: Regulatory lawyers are like primary-care docs: when someone shows up with a regulatory problem, you order a battery of diagnostic tests. The first test you run is to trace back in legal history till you find the statute (the Act of Congress) that gave rise to the regulation. Like most people, I always assumed that HIPAA’s access right must flow from the HIPAA statute. That’s true, but with a fascinating twist. As it relates to genetic information, HIPAA’s access right flows from a mandate Congress laid down in the Genetic Information Nondiscrimination Act of 2008. It’s a civil right! That fact has impacts that my commentary explores.

What concerns me most? Under the U.S. system of law, one of the worst ways things can go wrong in a democracy is if government agencies, which are supposed to protect people, take actions that deprive people of their civil rights. Your right under HIPAA to see your own genetic information is a federally protected civil right. That limits the range of actions regulators like the U.S. Food and Drug Administration and the Centers for Medicare and Medicaid Services, which regulates clinical labs, can take to block people’s access to their own genomic data. My commentary hopes to spark a dialogue about ways to address valid safety concerns about individual data access, without violating people’s civil rights.

AJHG: Tell us a bit more about the bigger picture—for scientists and the general public.

Barbara: Using people’s genomic data in research offers huge benefits to society, but it exposes people to privacy risks and other threats to their civil rights. Dating back to the dawn of the information age in the early 1970s, Congress has approved policies that let researchers use people’s data to advance public health and research. The quid pro quo is that Congress has consistently stood by the idea that if researchers have broad access to your data, then you should have broad access, too. Doesn’t that seem fair?

People who want to block individuals’ access to data need to appreciate that, over the past 50 years, Congress gave this matter a lot of thought and commissioned multiple ethical analyses. What they found is that if you want to take people’s access away, you can do so. But in return for taking people’s access away, you would then need to severely curtail researchers’ access to people’s data as an alternative way to protect people’s civil rights. So which world do you want? In World 1, researchers and people both have broad access to the people’s data. In World 2, neither group has access. Those are the two ethical options. It’s just not ethically defensible to have a World in which researchers have broad access to people’s data, but the people do not.

AJHG: What advice do you have for trainees?

Barbara: If your job doesn’t excite you and make you feel useful most of the time, get another job. Risks work out more often than we are led to believe. Take them. You hold your talents in trust, and you have a fiduciary duty to shepherd your talents to a green pasture where they can thrive.

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

Barbara: It’s generally tranquil, but last year was anything but with Hurricane Harvey, 52 inches of rain, fences down, and administering a portfolio of family interests across Texas. The saving grace is the lack of speed limits on rural Texas highways and discovering—in the fullness of middle age—the joy of really fast cars.

Barbara Evans, PhD, JD, LLM, is an Alumnae College Professor of Law and a Professor of Electrical and Computer Engineering at the University of Houston.

Inside AJHG: A Chat with Christian Schaaf

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 Christian Schaaf to discuss his paper, “Functional consequences of CHRNA7 copy number alterations in induced pluripotent stem cells and neural progenitor cells.

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Christian Schaaf, MD, PhD, Baylor College of Medicine (courtesy Dr. Schaaf)

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

Christian: My work on copy number variation of chromosome 15q13.3 started with a patient I saw as a genetics resident on the genetics consultation service at Texas Children’s Hospital. As a physician-scientist, all my work has been inspired by patients, and my ultimate goal is to provide a deeper understanding of the mechanisms of disease, which then can be translated into new therapeutic avenues for the respective disorders.

AJHG: What about this paper most excites you?

Christian: There are two aspects that are most exciting to me. First, we have been able to generate a human model of disease, and we can measure functional consequences of a genomic change in the patient-derived cell lines. This may become particularly relevant as we begin thinking about pharmacologic intervention, as it allows us to test new drugs and compounds on these patient-derived neuronal cell lines prior to subjecting actual human patients to those drugs in clinical trials.

Second, one of the most fascinating findings of our study is the fact that increased genomic copy number of the CHRNA7 gene does not necessarily lead to increased functionality of the respective protein. This may have important implications on how we think about this duplication, and how we would consider approaching it therapeutically.

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

Christian: We have always been puzzled that for several genomic loci, both deletions and duplications of the same locus predispose to neurodevelopmental disorders that look somewhat similar. One would expect that opposing genomic events cause clinical phenotypes that are also in different direction. For 15q13.3, we now provide first pieces of evidence why opposing genomic events may lead to functional changes that are actually in the same direction. This could be the case for several other genomic disorders, and is kind of a paradigm-shifting concept.

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

Christian: For all trainees in the medical field: treat every patient with the care and curiosity as if you could learn something entirely new. All of my research projects started with individual patients. They continue to be the inspiration for everything that I do.

For all trainees and young scientists (MD and PhD): have a hypothesis for every experiment, but be completely open to the outcome. Do not “expect” a certain result. Some of your most important discoveries will originate in the unexpected.

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

Christian: I have four children: 6 years, 5 years, 2 years, and 6 months old. Life is crazy at home. Coming to the laboratory feels like vacation to me.

Christian Schaaf, MD, PhD, is an Assistant Professor at Baylor College of Medicine and has been an ASHG member since 2009.

Inside AJHG: A Chat with Diego Calderon, Audrey Fu, and Jonathan Pritchard

Posted by: Sara Cullinan, PhD, Deputy 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 Diego Calderon (@diegoisworking), a Stanford University graduate student, along with senior authors Audrey Fu and Jonathan Pritchard (@jkpritch), to discuss their paper, “Inferring Relevant Cell Types for Complex Traits by Using Single-Cell Gene Expression.”

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Diego Calderon, PhD student, Stanford University (courtesy Mr. Calderon)

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

Diego: Single-cell RNA-seq is a hugely powerful tool for finding novel fine-scale cell types in complex tissues. But if we’re interested in human disease, how can we prioritize potentially trait-involved cells, out of all the newly identified cell types, for further characterization? Our idea was to focus on cell types that tend to specifically express genes near mutations associated with the trait of interest. Surprisingly, when we started thinking about this project, there hadn’t been work published attempting to connect GWAS data and such findings from single-cell assays.

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

Diego: The development of RolyPoly allowed us to find finer-scale trait-associated cell types from complex tissues; particularly, we focused on neuropsychiatric traits and single-cell data from human brains. There had been hints of immune involvement in Alzheimer’s disease, thus we were intrigued to see this association with microglia, which are the brain’s immune cells. Additionally, there has been wonderful work clustering single-cells into cell states, which we can also scan for links with complex traits. For example, we found that actively replicating cell types from early timepoints of fetal brain development were associated with schizophrenia. These findings are exciting because they can be used to inform the development of cell type or state models that more specifically capture human disease processes.

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

Diego: When we began this project, there were only a limited number of human single-cell datasets publicly available. Earlier this year, plans for the human cell atlas were announced, which will result in large publicly accessible datasets of single-cell RNA-seq measurements. Our hope is that researchers can use our tool along with other single-cell methods to further our understanding of biology and complex traits.

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

Diego: As a young scientist, you should think deeply about your chosen scientific problem. However, it’s also worth considering how best to communicate your new ideas. The ability to make complex biological or computational concepts accessible is a skill that’s worth refining and will help advance your career regardless of your chosen field. As a result, it takes time and persistence to continue to refine your writing and ideas without becoming discouraged. It took us many months to finalize our manuscript.

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

When not in the lab, Diego enjoys throwing clay coffee mugs at the ceramics studio and eating a hot meal after a long day of backpacking. Audrey appreciates listening to opera and singing karaoke. Jonathan is fond of spending time with his family, searching for the best veggie burrito at Stanford, and running through the foothills of Palo Alto.

Diego Calderon, BA, is a graduate student at Stanford and has been an ASHG member since 2014. Audrey Fu, PhD, is an assistant professor at the University of Idaho, and has been an ASHG member since 2014. Jonathan Pritchard, PhD, is a professor of biology and genetics at Stanford, and has been involved with ASHG since 2002.

Inside AJHG: A Chat with Janet Kelso

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 Janet Kelso, to discuss the paper, “The Contribution of Neanderthals to Phenotypic Variation in Modern Humans.”

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A Neanderthal scene re-created by research group members. (courtesy Dr. Kelso)

AJHG: How did you begin working on this project? 

Janet: We previously studied regions of the genome where there is evidence for Neanderthal DNA in the genomes of present day non-Africans and had inferred, based on the functions of genes nearby to these Neanderthal segments, the influence of Neanderthal DNA by looking at predicted gene functions and at changes in gene expression.

However, directly identifying associations between Neanderthal DNA and phenotypes requires access to large datasets that provide both genetic information as well as well-characterized phenotypes in very large numbers of people. Such datasets were not available until quite recently. In 2016, a study from the Capra group looked specifically at the influence of Neanderthal alleles on disease phenotypes by using medical records for over 25,000 people. They identified a number of really interesting associations between Neanderthal DNA and disease risk. We were interested in extending this idea to include non-disease phenotypes in order to determine what influence Neanderthal DNA might have on ordinary variation in people today.

Because Neanderthal alleles are rather rare in people today, we need to have a really large number of people. The UK Biobank pilot study now provides such an extensive resource, including genetic information as well as information about hundreds of common phenotypes in more than 100,000 individuals. Therefore, we were finally able to investigate the impact of Neanderthal alleles on common phenotypes in modern humans.

AJHG: What about this paper most excites you? 

Janet: A notable aspect of our study is that the growing move to collect both genotype and phenotype information in biobanks, such as the UK Biobank, now provides us with the ability to answer not only biomedical questions but also to understand the evolutionary history of modern human traits.

We were able to determine directly the effect of Neanderthal DNA on the phenotypes of people today. Our findings are consistent with previous inferences that genes involved in skin and hair biology were strongly influenced by Neanderthal DNA. However, in those previous studies it wasn’t possible to determine what aspect of skin or hair biology was affected. We were able to show that it is skin and hair color and the ease with which one tans that are affected.

It was somewhat surprising that we observe multiple different Neanderthal alleles contributing to skin and hair tones. Some Neanderthal alleles are associated lighter tones and others with darker skin tones, and some with lighter and others with dark hair colors. This may indicate that Neanderthals themselves were variable in these traits.

A number of the phenotypes to which Neanderthal DNA contributes in people today seem to be related to sunlight exposure. For example we see contributions to skin and hair pigmentation, mood, sleeping patterns, and smoking status. It is therefore tempting to speculate that Neanderthal contributions may have been important in our adaptation to a modified sunlight regime during the colonization of Eurasia.

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

Janet: Our study is notable in that it shows the enormous benefits provided by biobanks in which both genotype and extensive phenotype information are collected. The use of biobanks in in such studies is relatively new, and demonstrates that resources such as the UK Biobank provide us with the ability to answer not only biomedical questions but also to understand the evolutionary history of modern human traits.

More specifically, we have been able to determine directly the effect of Neanderthal DNA on a very broad range of non-disease phenotypes in people today.

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

The growing amount of genetic data from both archaic and modern humans provides a tremendous opportunity for creative people to tackle interesting questions in understanding the evolutionary basis of modern human traits and diseases.

Janet Kelso, PhD, is a computational biologist and Group Leader of the Minerva Research Group for Bioinformatics at the Max Planck Institute for Evolutionary Anthropology.

Inside AJHG: A Chat with Wouter de Laat

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 Wouter de Laat, PhD, to discuss his paper, “Sensitive Monogenic Noninvasive Prenatal Diagnosis by Targeted Haplotyping.”

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Carlo Vermeulen, MSc, first author of the paper (left); and Wouter de Laat, PhD (right) (courtesy Dr. de Laat)

AJHG: How did you begin working on this project? 

Wouter: The realization that our TLA technology is powerful for targeted haplotyping of any genomic locus of interest triggered us to think about clinically relevant applications. Our background in thalassemia research and our close collaborations with the University Medical Centre Utrecht soon made us excited to explore whether TLA haplotyping would enable non-invasive prenatal diagnosis for monogenic diseases.

AJHG: What about this paper most excites you? 

Wouter: Two things. To me, the fact that our knowledge acquired through basic research on the structure and function of our genome led us to develop a novel prenatal diagnostic test emphasizes once more the societal relevance to support fundamental research. I find this important to mention, coming from a country where national policy makers propagate almost exclusively the virtues of translational research. The other very rewarding aspect of this project was our interaction with Dutch, Greek, and Iranian clinicians who work daily with cystic fibrosis and thalassemia families: they made us truly appreciate the clinical impact of this work.

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

Wouter: I expect that, now that pre-conception screening programs for severe Mendelian disorders are being implemented in our health care system, non-invasive prenatal diagnosis (NIPD) methods will be very welcome alternatives to the more burdensome invasive tests for giving desired comfort during pregnancy. A genetic test based on a simple blood draw may in the future also provide risk couples opting for embryo selection with an easy means to confirm that the familial disease was not transmitted to the child. And variants of the NIPD method presented here may offer an attractive way to confirm parenthood, for example following in vitro fertilization.

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

Wouter: Always, even if you are considering pursuing a tenure track academic position, ask yourself at the end of your PhD and certainly as an early postdoc: am I, and is my CV, in the top among my peers and am I truly passionate about science? If not, realize that there is a world of careers outside of academia that may be equally inspiring and rewarding to you and that this is the moment to start exploring these opportunities.

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

Wouter: Scientists are sometimes not very different from other human beings. To recharge the batteries, I love doing sports (soccer, cycling) and love traveling with my wife and three daughters: we just returned from an amazing trip to Sri Lanka.

Wouter de Laat, PhD, is a Professor of Biomedical Genomics at the University Medical Center Utrecht, Professor at Utrecht University, and Founder of Cergentis.

Inside AJHG: A Chat with Jay Shendure, Molly Gasperini, and Greg Findlay

Posted by: Sara Cullinan, Deputy 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 former AJHG Editorial Board member Jay Shendure (@JShendure) and his students, Molly Gasperini (@MollyGasp) and Greg Findlay (@TheNobleDust), to discuss their paper, “CRISPR/Cas9-Mediated Scanning for Regulatory Elements Required for HPRT1 Expression via Thousands of Large, Programmed Genomic Deletions.

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(L-R) Greg Findlay, MD/PhD student; Jay Shendure, MD/PhD, Principal Investigator; and Molly Gasperini, Graduate Student (courtesy Dr. Shendure)

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

Authors: Despite the many ways of annotating the noncoding genome, a fundamental question will always be what the consequences are when you make direct changes to genomic sequence. Now that CRISPR allows us to do exactly that with unprecedented ease, we wanted to leverage its power to look for distal regulatory elements that affect gene expression. We reasoned such elements are likely a reason why methods such as exome sequencing fail in a minority of patients, and we were curious if we could find any such elements for a well-studied Mendelian disease gene

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

Authors: We engineered literally thousands of large genomic deletions in a single experiment. Function aside, that was just a cool thing to have succeeded in. What we learned from the assay was interesting as well, in that there wasn’t a single element in our screen outside of the exons that was essential for the gene’s function. It’s important to validate CRISPR screens like this to make sure the programmed deletions are truly what’s responsible for the effect on the cells – in this case, drug resistance. When we did this, the results came to life even more. We observed with high resolution that even deletions that go very near the transcriptional start site of HPRT1 are still tolerated by the cells.

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

Authors: We only interrogated a single locus, so any biological claims from this paper must be limited to HPRT1’s expression in this cell type. However, we hope our method will be applied more broadly to understand the role of noncoding sequence in other disease genes’ expression, too – essentially scanning vast amounts of the genome in a multilayered way for functional importance. The benefits of generating more datasets like this are twofold to the human genetics community: 1) we’ll better understand noncoding mutations’ role in affecting any one disease gene, and 2) after enough loci are interrogated, we’ll know more about how the role of noncoding sequences varies across gene categories, cell types, and disorders.

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

Authors: Where you can, design experiments where the result is going to be interesting no matter which way it turns out. In this case, we asked a question and got what was effectively a negative result. Importantly, a negative result is not at all the same as a failed experiment (i.e. a technical failure). Obviously, we would have been delighted to discover critical distal regulatory elements, but apparently there aren’t any across the region that we scanned. But that’s still really interesting! Perhaps more so because it’s not what we expected. Too often, technically sound, negative results go unreported, and that doesn’t do anyone a service.

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

Authors: Outside of the lab, Molly hangs out with her baby nephew, listens to Motown music, and helps organize the local and national Communication Science Conventions. Greg enjoys biking around the city, exploring nature, and watching sports. Jay’s life these days consists solely of chasing after his three kids, chasing after his lab, and absorbing Game of Thrones theories. A highlight for the whole Shendure lab is the annual retreat to the Cascade mountains, which provide the perfect backdrop for re-energizing, brainstorming the next wave of experiments to try, and having fun with colleagues.

Jay Shendure, MD/PhD, is a Professor of Genome Sciences and Principal Investigator at the University of Washington. A member of ASHG since 2009, he received the Society’s Curt Stern Award in 2012 and currently serves on its Awards Committee. Molly Gasperini, Graduate Student (Genome Sciences) and 2016 Epstein Trainee Award recipient, and Greg Findlay, MD/PhD Student (Genome Sciences), belong to the Shendure Lab.