Welcome HHMI-ASHG Fellow, Sarah Abdallah

Posted By: Ann Klinck, ASHG Communications and Marketing Assistant

ASHG is excited to be partnering with the Howard Hughes Medical Institute (HHMI) for the HHMI-ASHG Medical Research Fellowship. We’re happy to welcome third-year Yale medical student, Sarah Abdallah, to the position.

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Sarah Abdallah, HHMI-ASHG Medical Research Fellow (Courtesy Ms. Abdallah)

This program allows medical, dental, and veterinary students to take a year off from training and perform mentored laboratory research with support of a grant. “Our hope is that the experience will ignite students’ passion for research and encourage them to pursue careers as physician-scientists,” says David Asai, HHMI’s senior director for science education in a press release.

Sarah was interested in the fellowship because “it seemed to provide access to a community of scientists and to enriching experiences on top of my research, like attending conferences and meetings.”

Sarah’s research is focused around obsessive compulsive disorder (OCD). Specifically, it involves looking for post-zygotic variants in whole-exome sequencing data from individuals with OCD and their parents. These variants arise spontaneously and are not inherited from parents. By identifying the post-zygotic variants, it may be possible to understand the contribution of such variation to OCD development, identify risk genes, and eventually find new treatments.

“I am hoping this project will contribute to the collective understanding of the genetic basis of OCD. Many people with OCD do well, but I have seen firsthand how it can present as a very disabling, persistent disorder, and current pharmacologic treatments are not completely effective for all patients,” Sarah said.

ASHG member and Sarah’s primary mentor, Thomas Fernandez, MD, is an assistant professor in the Child Study Center and of Psychiatry at Yale. Another ASHG member and her co-mentor, James Noonan, PhD, is an associate professor of genetics at Yale.

During her fellowship, Sarah is hoping to gain more experience in computational genomics and is seeking guidance on how to combine her clinical and research interests into a career. She trusts that people like Dr. Fernandez will be able help her find the right path. She is considering a career in child psychiatry and pediatrics, but “either way, I hope to keep contributing to research on the genomics of neurodevelopmental disorders along with my clinical practice,” she said.

Launched 29 years ago, the HHMI Medical Research Fellows Program supports each Fellow through a year-long research project with a mentor of the Fellow’s choosing, and facilitates peer networking among Fellows and alumni as well as seminars with senior investigators. For more information, see the Program website.

 

Inside AJHG: A Chat with Andy McCallion, Loyal Goff, and Paul Hook

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

Each month, the editors of The American Journal of Human Genetics interview the authors of a recently published paper. This month, we check in with Andy McCallion (@FunctionalDNA), Loyal Goff (@loyalgoff), and Paul Hook (@paul_hook_HuGen) of Johns Hopkins University to discuss their paper, “Single-cell RNA-seq of mouse dopaminergic neurons informs candidate gene selection for sporadic Parkinson’s disease.”

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(L-R) Paul Hook, Andy McCallion, and Loyal Goff

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

Andy: The challenge presented by endeavoring to connect common variation identified through genome wide association studies (GWAS) to affected genes and ultimately to the mechanistic understanding of disease gives all of us a headache. Where to start?

Although powerful, GWAS are inherently biologically agnostic. Despite the wealth of loci they implicate in disease, GWAS tell us nothing of the cellular context of disease or how variants mediate their effect/s. This, and the significant distances over which regulatory sequences/variants can act, complicates efforts to systematically identify gene candidates. We wanted to ask whether, beginning with an underlying biological insight into a pathologically vulnerable cell population, we could make progress on this challenge.

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

Andy: Perhaps the most exciting thing is that this work provides a biologically informed framework that systematically prioritizes candidate genes for an entire field, Parkinson’s Disease (PD). We were able to ask what (if anything) makes the transcriptomes of neurons in the substantia nigra unique among central nervous system dopamine neurons. We reasoned that any differences may contribute to their preferential vulnerability of this population in PD. The data we generated facilitated the exploration of gene networks underpinning the identity of all assayed dopamine subpopulations and in turn revealed that networks most associated with PD are active in the nigral population.

Stepwise integration of this data allowed us to establish a rubric, filtering over 1000 potential genes in 49 PD GWAS intervals to approximately 100. The genuine excitement was driven by the fact that the data holds up! Among these candidates are many established familial/syndromic PD genes. Further, we validate the functional requirement of a gene not previously known to be mutated in PD.

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

Andy: Our work demonstrates that starting from an informed biological hypothesis of (one) cellular context in which a subset of variation might be expected to mediate their effect, can yield robust, testable hypotheses of the genes modulated in disease. We’re not naïve enough to think this story is complete; we recognize that much more work needs to be done – similarly evaluating other cell populations, conditions, etc. Many others are similarly seeking ways to reveal what cellular contexts are most pertinent to a range of disorders. We see this as a proof of principle whose observations will (hopefully) synergize with those from other groups.

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

Andy: That’s a tough one! My advice would not be technical. I frequently joke with my trainees that life is not complicated – we all have only two responsibilities. First, you need to get the best out of yourself – work hard, be curious, invest in the intellectual and technical platform you create for your science, think rigorously and creatively. Second, you need to get the best out of everyone else – be fair, honest, empathetic; share information generously, recognize what you can learn from the experiences of others.

Hold those things in tension and you will reach for your success, want to ensure the success of others, and simultaneously avoid being a jerk­. The field of genetics/genomics has become so multi-disciplinary that throughout your career, you will need to develop many relationships – networks of colleagues. Hold yourself accountable for how you work and how you build and maintain relationships.

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

Andy: Outside of the lab, Paul is an avid cook and enjoys time in the kitchen. Loyal is a talented photographer and musician but currently spends most of his time chasing after his two young children. I spend much of my free time woodworking – both at home and as the carpenter on the restoration of an active second world war Liberty Ship and living museum, working alongside my teenage son. Collectively our labs (Goff and McCallion) enjoy almost anything that involves food, drink, our families, and a great laugh.

Andy McCallion, PhD; Loyal Goff, PhD; and Paul Hook, BS, study neurogenetics at the Johns Hopkins University McKusick-Nathans Institute of Genetic Medicine. Dr. McCallion, an ASHG member since 2001, served on the Society’s Program Committee from 2012-13 and as its Chair in 2014. Dr. Goff and Mr. Hook have been ASHG members since 2015.

 

 

Advances in the Genetics of Alzheimer’s Disease at AAIC 2017

Posted By: Timothy J. Hohman, Assistant Professor of Neurology, Vanderbilt Memory & Alzheimer’s Center

I just returned from the Alzheimer’s Association International Conference (AAIC) in London. AAIC always covers an amazing breadth of the most recent advances in research and clinical care for Alzheimer’s Disease (AD), and this year placed a particular emphasis on biomarkers. More specifically, the focus was on how we can integrate the growing availability of in vivo biomarkers of AD neuropathology into diagnostic criteria for research, and into screening procedures for clinical trials.

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Timothy J. Hohman, PhD (courtesy Dr. Hohman)

The Potential of Biomarkers

Philip Scheltens, MD, PhD, from the VU University Medical Center in the Netherlands kicked off the meeting with an impassioned lecture on the present landscape of biomarkers in AD, and the future potential of biomarkers in screening, diagnosis, targeted treatments, and disease prevention. AD is characterized by two primary neuropathologies: extracellular plaques composed of the amyloid-β protein and neurofibrillary tangles composed of hyper-phosphorylated tau. Over the past ten years, there has been a growing emphasis on measuring these proteinopathies in vivo, including the development of positron emission tomography tracers for amyloid and tau, and the development of assays to measure these proteins in cerebrospinal fluid. In 2011, the National Institute on Aging and the Alzheimer’s Association convened four work groups to develop new research criteria for diagnosis that integrated biomarkers of amyloid deposition into the clinical criteria for dementia. This year’s conversations focused on taking steps towards diagnosis and screening that relied solely on biomarkers.

Dr. Schelten’s emphasis on the future of biomarkers set up a somewhat heated panel presentation laying out a new NIA-AA research framework to investigate Alzheimer’s disease. Led by Clifford Jack, MD, the proposed framework would place a greater emphasis on biomarkers of the two primary proteinopathies, while also emphasizing the measurement and characterization of neurodegeneration. The panel has provided the opportunity for the community to give feedback directly to the workgroup as they continue to refine the proposed framework. Certainly, this will be a critical issue in AD research in the coming year and has important implications for clinical trials, study design, and (eventually) clinical care.

Functional Pathways, GWAS Findings, and AD

This is a genetics blog, though, so let’s get into the genetics! The primary keynote session on the genetics of AD was given by Julie Williams, PhD, from Cardiff University. Dr. Williams provided an overview of where we currently stand in unraveling the genetic architecture of the disease, and called for an increased emphasis on uncovering functional pathways that underlie the known risk loci. Dr. Williams argued the innate immunity and inflammation are fundamental pathways in AD pathogenesis, and that the causal pathways of sporadic AD may be fundamentally distinct from familial forms that operate strictly through an amyloid pathway.

Research presented throughout the conference re-emphasized the importance of innate immunity, including new risk loci in common variant and rare variant analyses completed by the Alzheimer’s Disease Genetics Consortium that implicated innate immune pathways (e.g., LILRA5).  Additionally, many of the functional genomic approaches emphasized the importance of macrophage and monocyte expression in predicting AD, including 14 genes implicated in a genetically regulated transcriptomic analysis by Towfique Raj, PhD, from the Icahn School of Medicine.

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Data parasites and data philanthropists both have important roles to play in using big data to study Alzheimer’s. (courtesy Dr. Hohman)

Given the growing emphasis on biomarkers throughout the field of AD, it was also encouraging to see substantial growth in the size of endophenotype analyses, including a GWAS of cerebrospinal fluid biomarkers of AD by Yuetiva Deming, PhD, analyzing data from over 3,000 individuals. Simon Lovestone, PhD, gave an additional “big data” plenary lecture in which he laid out how large-scale European collaborations integrating electronic medical record data and other big data resources will change the way research is completed. He called on #DataParasites (those who perform secondary analyses on existing datasets) to make use of rich data resources to identify new treatment targets and #DataPhilanthropists (data providers) to continue to step up and provide open access to collected data. Large scale data collection, data sharing, and secondary data analysis are becoming central components of AD research.

Varied Approaches to #EndALZ

There were many other areas of focus: from advances in neuroimaging and large-scale omics, to a growing emphasis on sex differences, racial disparities, and pathways of resilience, and a growing acceptance of the heterogeneity in the neuropathological presentation of the disease. If you are interested in AD and want to learn more from a variety of perspectives, this is a fantastic conference to attend. The field of AD is necessarily interdisciplinary and this conference is a fantastic representation of that diversity. Multiple perspectives, approaches, and treatment pathways will be needed to beat this devastating disease. After another year and another great conference, I’m hopeful and inspired to keep working to #EndALZ. Join us!

Timothy J. Hohman, PhD, is an Assistant Professor of Neurology at the Vanderbilt Memory & Alzheimer’s Center. He has been part of the ASHG community since 2013.

Do You Love DNA as Much as Jim Sikela?

Posted by: Nalini Padmanabhan, MPH, ASHG Communications Manager

About ten years ago, ASHG’s education department was looking for creative ways to teach human genetics and make it more appealing to K-12 students and teachers. Longtime member James Sikela, PhD, happened to have just the thing: his original song “I Love DNA,” sung and recorded with the help of his daughter Megan, under the band name Gene and the Chromosomes. (You can listen to “I Love DNA” or read the lyrics on the ASHG website).

We rediscovered Jim’s song around DNA Day in April, and decided to catch up with him and learn how this recording came to be.

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Gene and the Chromosomes onstage. (courtesy Dr. Sikela)

Jim: For a long time, I’ve been a fan of Randy Newman, who wrote a song called “I Love L.A.” That’s where the music and vocal style for “I Love DNA” came from. I’d been into music for quite a while – writing, recording, and playing with various bands. This song took a few years to write and record, which we finally did around 2005. It wasn’t a focused project, but more a natural outgrowth of my interest in both science and music.

ASHG: Your daughter’s vocals are featured towards the end of the song. Tell us about that.

Jim: That part was recorded in 1992, when Megan was five. It was during the early days of the Human Genome Project, and I’d brought home a stack of ABI fluorograms to work on. Each one had about 400 bases of DNA sequence data on it. We were playing at night before she went to sleep, and I showed her the sequence, saying “bet you can’t read off all those letters!” She, being five, was sure she could do it, and fortunately I had a tape recorder nearby to capture that. Years later, when I put together the song, I thought it fit really well.

By the way, the funny line right after that saying “please fund my grant!” was also a real plea. Funding was tight and we had been turned down several times. But fortunately we finally did get funded, so it must have worked.

ASHG: What was it like working on the Human Genome Project in the early 1990s?

Jim: It was a fun time. My lab had the first automated DNA sequencer in Colorado, so we were doing a lot of experimentation with how to use it. My lab came up with a novel way to rapidly map genes on a detailed level, which we were asked to use to map genes for the Human Genome Project.  All of those sequences were deposited into a public database, which led, among other things, to the discovery of Presenilin 2, a gene associated with Alzheimer’s disease. I recounted those early days of the HGP, including some personal perspectives, a few years ago in Genetics.

ASHG: What are you doing now?

Jim: I’m still doing human genome work. My lab uses genomic approaches to study human disease and human evolution, and how they are related. For the last ten years or so, we’ve focused on DUF1220 protein domains, which we believe show the largest human-specific increase in copy number of any gene coding region in the genome. Humans have about 300 copies of this domain, chimpanzees have about 120, monkeys have about 30, and other mammals have only 1-8. We published our initial results describing this discovery in Science in 2006, and more recently have linked the domain to autism and schizophrenia. The studies suggest that the same gene sequences that underlie human brain evolution may also be involved in autism and schizophrenia. If true, it means that the human brain may have come at a severe price.

ASHG: Any plans for a remix of “I Love DNA”?

Jim: Besides wanting to make a technically more polished recording, I always thought it would be fun to make a video. While we never got around to it, if someone would like to take that on, I’m sure Megan and I would be happy to help.

James Sikela, PhD, is a Professor at the University of Colorado School of Medicine. He has been a member of ASHG since 1988.