Announcing: AJHG “Perspectives” Series on Issues Confronting Human Genetics and Influencing Research

Posted By: David L. Nelson, ASHG President 

As part of our ongoing commitment to address how genetic findings are used in society and to foster discussion within the field and the public, I am pleased to announce that ASHG is launching a new “Perspectives” series of short statements this month, which will be published periodically in The American Journal of Human Genetics.

The first topic targets disturbing and scientifically flawed attempts to link genetics with racial supremacy. The statement denounces such attempts, stating that there can be no genetics-based support for claiming one group to be superior to another.

Read the statement on AJHG’s website.

We decided to address this important issue in the series’ first statement, recognizing that there has been a resurgence of bogus claims that racial supremacy has scientific roots. The statement explains that humans cannot be divided into biologically-distinct subcategories, given the considerable genetic overlap among members of different populations, and asserts clearly that genetics exposes the concept of ‘racial purity’ as scientifically meaningless.

This statement reflects a continuation of ASHG’s objection, over decades, to the misuse or twisting of human genetics findings for political or social ends, including past ASHG statements on genetics, ancestry, and intellectual ability and the consequences of eugenics; and more recently, my piece in the September member newsletter on the Society’s origins and early discussion of its purpose and role.

AJHG Perspectives: A Channel for Timely Discussion

Statements in the new series will address a variety of important topics in human genetics and its interface with society, reinforcing the Society’s and Journal’s role as a leading source of emerging human genetics science. They will offer timely, concise viewpoints on topics in research, health, and society that have been prioritized by the Board; will address how scientific research informs those issues; and may assert Society policy positions or note important related field activities.

Statements will also refer readers to a range of lengthier academic or other relevant work. They do not strive to cover the breadth and depth of each issue but rather to draw on, complement, and highlight the need for continuing research and member engagement.

AJHG has long been a leading home for discussion and debate about emerging science across human genetics. We are enthusiastic about this new feature, which will help ensure that scientific facts, findings, and open discussion inform larger societal dialogue,” said Bruce Korf, MD, PhD, Editor-in-Chief of AJHG.

Read an editorial announcing the new Perspectives series.

Fostering Discussion Within and Outside the Scientific Community

As research in human genetics continues to advance, it is opening new pathways of understanding and treatments that are saving lives. At the same time, ASHG has long been committed to addressing how these findings may be used in society, and we hope this new series will spark individual scientists to be increasingly vocal in discussing what the science does, might, and doesn’t say about a wide range of important issues, even—perhaps especially—when there is disagreement.

Individual members of our Society are knowledgeable, thoughtful, outspoken, and diverse in their views – these are the traits that push our field forward and help us collaboratively and thoughtfully address complex issues. Members, I encourage you to speak out, in your own voices, to represent your individual views as genetics experts on this and other important topics.

Given ASHG’s broad community of researchers, clinicians, ethicists, and other professionals, we anticipate perspectives on many topics may spark a diversity of dialogue, with strongly held perspectives on the science. We look forward to continuing that discussion through the pages of AJHG and hope to spark ongoing, constructive dialogue in the laboratory, classroom, clinic, and across the broad range of colleagues interested in human genetics.

David L. Nelson, PhD, is President of ASHG. He is a Cullen Foundation Professor of Molecular and Human Genetics at the Baylor College of Medicine, Associate Director of the BCM Intellectual and Developmental Disabilities Research Center, and Director of the BCM Integrative Molecular and Biomedical Sciences Graduate Program. 

Inside AJHG: A Chat with Sek Kathiresan

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 2018 Curt Stern Award winner Sek Kathiresan (@skathire on Twitter) to discuss his paper ‘Genetic Association of Albuminuria with Cardiometabolic Disease and Blood Pressure’.

Bulfinch Studio; Sekar Kathiresan portrait
Sek Kathiresan, Massachusetts General Hospital/Broad Institute/Harvard Medical School (courtesy Dr. Kathiresan)

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

Sek: In observational studies, many biomarkers including the concentration of protein spilling into urine (albuminuria) are correlated with health outcomes. We wondered if the association of albuminuria with adverse health outcomes reflected a causal relationship or mere correlation. Knowing this is important to determine if decreasing urinary albumin excretion should per se be a target for therapeutic intervention.

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

Sek: In addressing the question above, we identified a bi-directional relationship – genetic predisposition to albuminuria leads to higher blood pressure and genetic predisposition to higher blood pressure leads to more albuminuria. We suspect this reflects a feed-forward loop.

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

Sek: Mendelian randomization is a useful genetics approach for causal inference. The availability of biomarkers, clinical outcomes, and genetic data in a single large study – UK Biobank – is facilitating systematic Mendelian randomization analyses for a range of biomarkers.

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

Sek: Pick an important problem to study – one that not only you care about but also the rest of the world. Figure out the skills and resources you need to address the problem. Then, go out and get the training and resources to attack the problem. Stay focused on the problem and ask yourself, each day, if you are working on the most impactful thing you could be doing.

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

Sek: Life outside the lab is consumed by three children – ages 15, 13, 10. Raising them to be happy, loving, and engaged with the world is a joy.

Sekar Kathiresan, MD, is the Director of the Center for Genomic Medicine at Massachusetts General Hospital (MGH), Ofer and Shelly Nemirovsky MGH Research Scholar, Director of the Cardiovascular Disease Initiative at the Broad institute, and a Professor of Medicine at Harvard Medical School. He has been a member of ASHG since 2004.

Inside AJHG: A Chat with David Kingsley

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 David Kingsley to discuss his paper ‘Characterization of a Human-Specific Tandem Repeat Associated with Bipolar Disorder and Schizophrenia’.

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Kingsley lab group at Stanford, with co-lead authors Janet Song (standing at left of center), and Craig Lowe (seated at far right). (courtesy Dr. Kingsley)

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

David: We’ve been working on the genomic basis of evolutionary change for many years. We previously found that the deletion of key regulatory sequences can underlie classic evolutionary traits in both stickleback fish and humans. [Co-authors] Craig Lowe and Janet Song decided to look for the reciprocal type of molecular changes: insertion or gain of new regulatory sequences that might contribute to human-specific traits.

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

David: We found a particularly dramatic human insertion in an important calcium channel gene. Where most primates have a single, 30 base pair, non-coding sequence, humans have expanded the 30-mer into a huge tandem array that can be up to 30,000 base pairs long. We found that the expanded human sequence shows enhancer activity in neural cells, suggesting it contributes to increased expression of this calcium channel gene in humans compared to other primates.

We were particularly interested to see that the tandem array is located right between SNP markers that been repeatedly associated with risk of schizophrenia and bipolar disorder in many human genome-wide association studies. We found that different subtypes of the tandem arrays are associated with risk or protective genotypes at the locus, and that the risk-associated arrays have less enhancer activity than other subtypes. We think that this novel structural feature may thus contribute not only to evolutionary differences between humans and other primates, but also to common risk of psychiatric disease within human populations.

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

David: These large tandem arrays don’t appear in the reference human genome, likely because they are unstable when propagated in conventional bacterial vectors, and are impossible to assemble correctly from short sequence reads alone. Conventional SNP genotyping arrays don’t score the repeats, and exome sequencing studies miss the region entirely because the arrays are located in a large intron of a calcium channel gene.

The human-specific arrays are thus a great example of a previously hidden genome feature, that may nonetheless provide a causal basis for functional changes in the gene. The broader lesson is that the human reference genome is still a work in progress, and that lots of important biology may be embedded in the parts of our genomes that are difficult to assemble and still poorly understood.

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

David: Treasure your exceptions, and try to keep an open mind when studying any research problem. The surprises and the things that don’t initially make sense are interesting puzzles that often lead to new discoveries. But you have to embrace results that don’t fit your preconceptions, and then be willing to consider a whole range of new possibilities.

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

David: I love to explore the sky with telescopes at night and have made trips all over the world to enjoy dark skies in both the Northern and Southern hemisphere. Early astronomers slowly groped their way to a better understanding of the larger universe by cataloging individual stars, planets, and nebula with relatively simple equipment. Particular objects can look like stunning “eye-candy” or faint and subtle “mind-candy” in the eyepiece. And as you look at more and more objects, you can gradually build up a larger picture of our place in the solar system, the Milky Way galaxy, and the overall universe.

That actually has lots of parallels to biology. In genetics, we often start with an interest in particular traits or genes. But detailed studies of particular genes can grow into larger studies of chromosomes, whole genomes, variation between individuals, and the molecular basis of evolutionary differences between species. Our glimpses of the whole shebang are still very incomplete. But spend enough fun time looking at stars and genomes, and you end up with a much richer view of humans and where we came from.

David Kingsley, PhD, is an HHMI Investigator and Professor of Developmental Biology at Stanford University. He has been a member of ASHG since 2018.

Inside AJHG: A Chat with Levi Teitz and David Page

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

Each month, the editors of The American Journal of Human Genetics interview the author(s) of a recently published paper. This month, we check in with Levi Teitz and David Page to discuss their paper “Selection Has Countered High Mutability to Preserve the Ancestral Copy Number of Y Chromosome Amplicons in Diverse Human Lineages.”

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Levi Teitz, PhD, and David Page, MD (photo courtesy Dr. Page)

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

Levi: Our lab has a long history of studying the Y chromosome, but the ampliconic regions were always a bit of a mystery because of how difficult they are to study, due to their complex architecture and high sequence identity between copies. With the advent of high-throughput sequencing technologies and large, publicly available datasets, it seemed like a good time to revisit questions about amplicon variation and evolution with those new tools at our disposal.

David: The Y chromosome has been an enigma to geneticists for the last century, largely because it doesn’t play by the usual rules of being transmitted from both mother and father, and recombining with a homolog along its length, in meiosis. Despite being a sex chromosome, the Y chromosome is transmitted clonally – asexually – from father to son to son; it stands apart from all other nuclear chromosomes in this respect. This has led to all manner of unfounded insults regarding the Y chromosome’s character, medical relevance, and future prospects. My colleagues and I have spent decades defending the honor of the chromosome in the face of these insults.

AJHG: What about this paper most excites you? 

Levi: The new evolutionary questions it raises. The amplicons are extraordinarily divergent between species – so much so that it’s essentially impossible to reconstruct the steps that evolution took to get from the ancestral mammalian or primate amplicons to modern-day Y chromosomes. When we began this project, we expected that we could observe these evolutionary steps by looking within only humans. Instead, we found that the amplicon variation within human populations is an evolutionary dead end, and that the ancestral amplicon structure has been preserved for hundreds of thousands of years! This is a bit of a paradox: why is amplicon structure maintained in humans but so divergent between species? This is a hard problem, but solving it should provide incredible insight into amplicon evolution and function.

David: Learning something unanticipated about a subject you love is exciting. Massive palindromes and amplicons carrying spermatogenesis genes were known to dot the genomic landscape of the human Y chromosome, and they are frequently subject to deletion or rearrangement through non-allelic homologous recombination. The excitement for me here arises from both a computational advance and a biological insight. First, graduate student Levi Teitz, with guidance from Helen Skaletsky, mastered the computational challenge of robustly and accurately discerning the copy numbers of many different Y amplicons from whole-genome shotgun sequence data. Second, Levi applied these computational tools to the 1000 Genomes males, thereby characterizing Y amplicon copy number variation (CNV) around the globe. While the existence of such Y-amplicon CNV was unsurprising, the predominance of consistent patterns of Y-amplicon copy numbers around the globe (actually, across Y chromosome haplotypes) surprised me, and indicated that natural selection had optimized and consistently favored specific copy numbers for a host of Y amplicons. Natural selection, whose ability to maintain genes on the clonally transmitted Y had often been impugned, has evidently been effective at policing Y-amplicon copy numbers. Natural selection is alive and well on the human Y chromosome, even the parts where we might least expect it!

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

Levi: Beyond improving our understanding of the Y chromosome, our work highlights the fact that the genome can change in unexpected ways. Much genomic research today focuses exclusively on the parts of the genome that are easiest to study: single-copy coding sequence. This paper demonstrates that not only does the rest of the genome have profound evolutionary and phenotypic effects, it also varies in ways that are exquisitely dependent on its repetitive structure. In fact, it would be impossible to understand the phenotypic and evolutionary stories without first understanding the underlying complex structure of these genomic regions. There are still parts of the human genome where complex structures are unresolved; who knows what we will discover when those parts are properly sequenced?

David: Genetically inclined students of human biology, medicine, and evolution tend to focus their efforts on the parts of the genome that are most readily analyzed – the civilized, single-copy parts that approach most closely our Mendelian expectations. But there is so much to be learned in the relatively understudied and untamed parts of the genome where palindromes, amplicons, and segmental duplications bend the rules, demanding special attention to technical and analytic matters but offering rich rewards to the curious and persistent.

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

Levi: I’m a trainee and a young scientist myself, so I don’t have much career experience to draw upon, but my advice would be to never forget the human factor when choosing what to work on and who to work with. If you are surrounded by good people and you enjoy working with them, your science will be better for it.

David: Work with people whom you like, respect, and admire, on questions that you personally find to be compelling. Nothing is more satisfying than finding value and meaning where others think not to look.

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

Levi: I’m an amateur baker and have recently started accumulating kitchen gadgets, including a doughnut filling injector, a rotating cake stand, and a frying pan just for blintzes.

David: I love to explore the outdoors, and especially mountains and lakes, with family and friends, in all seasons. I would point out that some of our oldest and most acclaimed National Parks – Yellowstone and Yosemite – begin with the letter Y.

A longtime member of ASHG, David Page, MD, is Director of the Whitehead Institute, Professor of Biology at the Massachusetts Institute of Technology and Howard Hughes Medical Institute Investigator.

Inside AJHG: A Chat with Amy O’Connell

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 Amy O’Connell, first author of ‘Neonatal-Onset Chronic Diarrhea Caused by Homozygous Nonsense WNT2B Mutations.’

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Amy O’Connell (front row, left) and her lab. (courtesy Dr. O’Connell)

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

Amy: My work in Dr. Agrawal’s genetics lab focuses on confirming the functional consequences of novel mutations identified by whole exome sequencing. We identified individuals from two families who harbor homozygous nonsense WNT2B mutations and display similar severe congenital diarrhea phenotypes, suggesting this is an important gene for gut physiology. It seemed important to try and get to the bottom of it, especially since what we observed differed from what mouse studies concluded, where knocking out Wnt2b revealed no gut phenotype.

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

Amy: I am an immunologist by training, so I am excited about the potential connections between inflammatory triggers and Wnt2b. Our paper begins to explore this relationship by showing that TLR4 expression is altered in the absence of Wnt2b, but I think there is more to this story and I’m continuing to work on it.

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

Amy: To me, this project underscores the importance of personalized medicine and genomics approaches. Wnts are a very important family of molecules, and WNT2B is highly expressed in the intestine, but until now it has been somewhat neglected, viewed as being non-essential, and thought to be fully redundant with other Wnt pathway molecules. That patients with loss of Wnt2b are so severely affected clearly suggests otherwise. Taking what we’ve learned from three patients will have implications for our entire understanding of the regulation of intestinal stem cells, a good reminder that translational science works in both directions.

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

Amy: First of all, be wary of free advice. It’s not usually about the advisee. Given that, one of the best lessons I’ve learned is that it is okay to change your plans if you find that what excites you in science is not what you started off trying to do or become.

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

Amy: I have a 2-year old and two miniature schnauzers, so I get to do a lot of playing when I’m not at work. Yesterday I got to be a ballerina, ride to the “pizza store” on a “horse”, and build a doggy castle. It’s terrific exercise for the imagination!

Amy O’Connell, MD, PhD is a Neonatologist at Boston Children’s Hospital, and an instructor at Harvard Medical School. She has been an ASHG member since 2018. You can find her on Twitter at @PostCallScience.

Inside AJHG: A Chat with Garry Cutting

Posted By: Sara Cullinan, PhD, Deputy Editor, AJHG

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Garry R. Cutting, MD (courtesy Dr. Cutting)

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 Garry Cutting, to discuss ‘Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity.’

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

Garry: This project is part of an ongoing effort to interpret the molecular consequences of all variants in the CFTR gene. The variants selected for this study are associated with a wide-range of disease severity, allowing us to determine the utility of functional assays for variants that associate with moderate to mild forms of disease.

AJHG: What about this paper project most excites you?

Garry: We were surprised to find that a number of the putative disease-causing missense variants had minimal effect on protein function and that predictive algorithms have difficulty interpreting these “minimal effect” variants. Conversely, it was reassuring to find that incorporation of functional data improves annotation using expert and ACMG/AMP criteria.

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

Garry: Missense variants are challenging to interpret and many are labeled as variants of unknown significance. Our study indicates that classifying missense variants, especially those associated with intermediate severity of disease, will require functional testing in the appropriate context. Our work also shows that current predictive algorithms should be used with caution as they tend to overcall missense variants as deleterious.

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

Garry: The explosion of DNA variant information provides a wonderful opportunity to investigate their effect upon RNA transcription, RNA splicing, protein stability, and protein function. Individuals who become facile with these techniques will be highly valued as we move from DNA sequencing to variant annotation and elucidation of disease mechanism.

AJHG: Tell us something about your life outside the lab.

Garry: I really enjoy working with my hands to repair something broken or build something new. Unlike the long time frames that we experience in science, fixing something can produce results in a much shorter time frame. Sometimes things go wrong, but you always seem to learn something new when you undertake projects that are out of your established area of expertise. Consequently, I fully agree that circuit breakers and water supply values should be turned off before undertaking home projects.

Garry Cutting, MD, is an Aetna/U.S. Healthcare Professor of Medical Genetics at John Hopkins. He has been a member of ASHG since 1997. 

Inside AJHG: A Chat with Neil Hanchard

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 Neil Hanchard, a member of the ASHG Board of Directors and senior author of ‘Whole-Exome Sequencing Reveals Uncaptured Variation and Distinct Ancestry in the Southern African Population of Botswana.’

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Collaborative African Genomics Network (CAfGEN) group at a recent H3Africa meeting. (courtesy Dr. Hanchard)

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

Neil: Serendipity. The nidus for the project was the Human Heredity and Health in Africa (H3Africa project), sponsored by the NIH and the Wellcome Trust. Some of our institutional partners in Africa approached us about participating in order to gain insights to the genetics underpinning disease progression in childhood HIV, which, unlike its adult counterpart, hasn’t been extensively studied at the genomic level. They needed someone who knew something about genomic studies and Africa, and I happened to be standing nearby (almost literally). As we started looking for genetic variants influencing the phenotype, it became plainly obvious that without a genomic context, particularly for the individuals from Botswana, we would be going in circles.

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

Neil: Two things. First, the degree of uncaptured variation and the unique demographic features in our populations is exciting – if we can exploit them properly, there’s a real prospect of identifying new genes and variants that are relevant to HIV progression in children – that could be a game-changer; second, all the analyses were done by trainees from Botswana and Uganda. They have since taken that genomics experience and expertise back to their home institutions, which bodes well for the future of genomic research in Africa.

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

Neil: I hope it will make researchers and clinicians think more broadly about the genetic diversity across the continent. There’s a tendency in the field to think of ‘Africa’ as represented by the predominantly West African groups in publicly available datasets, but that’s only the proverbial tip of the iceberg. I hope this will give people a better understanding of the depth of diversity and genomic complexity that has to be considered in genetic studies of persons of African heritage.

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

Neil: I still think of myself as a ‘young scientist’, so I’d have to fall back on the words of my mentor as I was starting my lab – when I asked him what advice he had for me, he said, very unceremoniously, “don’t give up”. At the time, I recall thinking how incredibly underwhelming a response that was, but over time I’ve grown to see it as a genuine pearl of wisdom for a junior faculty (or trainee) enduring what can sometimes seem like a very long time in the academic wilderness.

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

Neil: Is there life outside the lab? (jk!) Mostly, I spend my away-from-the-lab time with my family. Accompanying my wife to the various activities my sons are involved in – be it church choir, baseball, or chess – is really enjoyable. Otherwise, I like sports, so I try to make time to play or watch any of swimming, tennis, baseball, football…and on the few occasions when I get to go on vacation, I’m perfectly happy in Jamaica (where I’m from), reading a book beside the beach and listening to the waves crash.

Neil Hanchard, MD, PhD, FACMG, serves as Early-Career Member of the ASHG Board of Directors. He is an Assistant Professor and Clinical Geneticist at Baylor College of Medicine and Texas Children’s Hospital, and has been a member of ASHG since 2010.