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.