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 Hugo Bellen and Julia Wang

Posted by: Sara Cullinan, 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 Hugo Bellen, DVN, PhD, and his student Julia Wang, two of the co-authors of “MARRVEL: Integration of Human and Model Organism Genetic Resources to Facilitate Functional Annotation of the Human Genome.”

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Zhandong Liu, PhD (left); Julia Wang (center); and Hugo Bellen, DVM, PhD (right). (courtesy Dr. Bellen)

AJHG: How did you begin working on this project?

Hugo and Julia: As the Model Organism Screening Center for the Undiagnosed Diseases Network (UDN), we receive cases from the UDN clinical sites to assess if variants of unknown significance or variants in genes that have not yet been associated with human diseases might affect protein function. Our goal is to functionally test variants in fruit fly or zebrafish homologues. This project began because of our need to efficiently identify the best human candidate variants of those submitted by the clinical sites for a specific human disease. As each gene and variant requires a substantial amount of work, we need to be as selective as possible and mine as much information as possible before making a decision. We therefore screen public human and model organism databases to systematically extract information that may guide our project and selection. We developed MARRVEL to gather all this information and help us in the selection of the best candidates for further analysis.

AJHG: What about this paper most excites you?

Hugo and Julia: The ability to immediately obtain key information such as allele frequency in different human populations, human gene function, phenotypes, and expression and function of homologues of the human gene in all model organisms. Through MARRVEL, the accessibility of human genetics and model organism data is greatly facilitated. As of mid-June, we have about a thousand returning users spanning the USA, Europe, Asia, Australia, and beyond.

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

Hugo and Julia: We foresee that model organisms will play a progressively more important role in human genetics in the future. By providing human geneticists with an approachable gateway to model organism research, and vice versa, MARRVEL will likely increase collaboration between human geneticists and model organism researchers at a critical point. Indeed, in a few years, the vast majority of genes that cause disease will have been identified. We will then have to focus on the mechanisms by which these genes cause disease. This can best be done in model organisms like worms, flies, and zebrafish as nothing can replace whole organisms in the quest for mechanisms and development of drugs. In our lab, we have successfully used fruit flies to better understand the pathogenic mechanisms associated with Parkinson’s disease, Alzheimer’s disease, Friedreich’s ataxia, and others. We anticipate that discovering mechanisms associated with loss and gain of gene function implicated in rare diseases will tell us heaps about common disease and how to tackle some problems in patients.

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

Hugo: The model organisms, such as yeast, worms, flies, fish and mice, provide us with the necessary sophisticated tools to tackle many probing questions related to human pathobiology and drive discovery. Note that of the 106 Nobel prices in Physiology and Medicine, 94 were dependent on animal model systems. This includes every prize for the past 30 years. I anticipate that many more will follow as our model organisms allow us to develop superb tools like monoclonal Ab, RNAi, and CRISPR, as well as many elegant genetic tools to manipulate their genomes. Hence, we will continue to break the code of human life and disease. If I were a young scientist, I would again embark on a career in genetic research in yeast, worms, or flies with more emphasis on the integration of the acquired knowledge with human biology.

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

Hugo: I love fishing and especially fly fishing. In a nutshell, flies rule my work and hobby.  Unfortunately, the hobby part is restricted to less than 0.5% of my available time.

Hugo Bellen, DVM, PhD, is a Professor in the Departments of Molecular & Human Genetics and Neuroscience as well as the Program in Developmental Biology, and an Investigator of the Howard Hughes Medical Institute, at the Baylor College of Medicine.

 

Inside AJHG: A Chat with Eleazar Eskin

Posted by: Sara Cullinan, 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 checked in with Eleazar Eskin, PhD, former AJHG editorial board member and senior author of “Widespread Allelic Heterogeneity in Complex Traits”.

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Eleazar Eskin, PhD, and recent ZarLab graduate Farhad Hormozdiari, PhD. (courtesy Dr. Eskin)

AJHG: How did you begin working on this project? 

Eleazar: This project originated when we observed a surprising result in a previous study, which was also published in AJHG. In our paper, “Colocalization of GWAS and eQTL Signals Detects Target Genes,” published in the December 2016 issue, we observed that for many loci which had both an observed expression quantitative loci (eQTL) signal as well as a GWAS signal, the actual variant responsible for these signals was different in the two studies. This was very surprising and was counter to the intuition of the field. We conjectured that what was going on was that many of the eQTL loci had multiple causal variants, referred to as allelic heterogeneity, and what could explain the observation is that the variants we are observing in the eQTL studies are only some of the variants affecting expression.

AJHG: What about this paper most excites you? 

Eleazar: The method that we developed can identify alleleic heterogeneity even when we can’t pinpoint the actual causal variants. We also showed that alleleic heterogeneity is very prevalent; the primary reason we haven’t been able to detect if more frequently is that our studies are under-powered.

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

Eleazar: Our study suggests that many variants are affecting each locus. Our result informs attempts to understand the mechanism underlying GWAS loci by providing a better understanding of how variants affect expression. In addition, this study helps us understand why we have, to date, been unable to detect colocalization of many GWAS and eQTL variants.

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

Eleazar: My main advice is to write up your research quickly. So much time is spent inefficiently in the writing process. On my lab website, zarlab.cs.ucla.edu, I have a series of blog posts with writing tips to help young scientists get their research published faster.

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

Eleazar: I love to cook using traditional ethnic ingredients. I also love training for triathlons.

Eleazar Eskin, PhD, is a Professor of Computer Science and Human Genetics at UCLA. He has been a member of ASHG since 2006.