First person – Emily Warren

Emily Warren

How would you explain the main findings of your paper to non-scientific family and friends?

Copy number variant (CNV) disorders occur when a segment of DNA is deleted or duplicated, so that there are only one (in a deletion) or three (in a duplication) total copies of the genes within that segment, instead of two. 17q12 deletion syndrome is a rare CNV disorder, with an estimated incidence ranging from 1:50,000 to 1:4000 births, where 15 genes are deleted. Typical symptoms of 17q12 deletion syndrome are renal dysfunction, developmental delay and intellectual disability. Many other rare genetic disorders, including other CNV disorders, have animal models that have facilitated the study of the mechanisms underlying the disorder, which is an important step toward developing therapies. In our study, we have established a new mouse model of 17q12 deletion syndrome on two different mouse genetic backgrounds – an inbred background (C57BL/6N), and an outbred background (CD-1), which has more heterogeneity. Deletion animals on the inbred background have severe phenotypes, including disruption of head formation early in development. Further studies of the deletion on this background or other inbred backgrounds may help improve our understanding of how the interval genes shape head development. In contrast, deletion animals on the heterogeneous outbred background have phenotypes that more closely mirror the human disorder, including impaired kidney development and glucose homeostasis, craniofacial malformations and alterations in the size of regions of the brain. Further studies on this or other outbred backgrounds may aid the exploration of factors contributing to variable penetrance and expressivity of the deletion. Moreover, establishing an animal model of 17q12 deletion syndrome will greatly accelerate study and understanding of the disorder.

What are the potential implications of these results for your field of research?

This mouse model of 17q12 deletion syndrome showing a wide-ranging set of features of the human disorder will provide other researchers with an opportunity to explore many different aspects of the disease. It establishes a system in which 17q12 deletion syndrome can be studied at an organismal level, which will complement the clinical work that has previously been performed on this disorder. Many CNV disorders have been associated with intellectual disability and autism spectrum disorder (ASD). It has previously been unclear if this association also applied to 17q12 deletion syndrome, though recent studies have shown that 17q12 deletion syndrome has a high hazard ratio for ASD. Our mouse model provides evidence that the genes within the 17q12 interval play an important role in head development, supporting the need for further research into the neurodevelopmental components of this disorder. This will improve our understanding of not only 17q12 deletion syndrome, but also more common disorders like ASD that involve similar pathways.

What are the main advantages and drawbacks of the experimental system you have used as it relates to the disease you are investigating?

This study establishes a completely novel experimental system for the study of 17q12 deletion syndrome. Developing a mouse model of this disorder has demonstrated that hemizygosity of the genes within the interval produces disease-relevant phenotypes in other organisms. This will facilitate further studies of the genes within the interval and how they individually contribute to those phenotypes, as well as the study of oligogenic interactions between the genes of the interval. However, we observed significant strain-mediated differences in penetrance and expressivity of the deletion-associated phenotypes, i.e. the 17q12 deletion phenotypes were significantly more severe on the inbred C57BL/6N background than on the outbred CD-1 background. While the outbred nature of the CD-1 background may contribute to the variable expressivity of the phenotypes we observed in CD-1 17q12 deletion mice, it is unclear which genes specific to the C57BL/6N or CD-1 backgrounds interact with those in the 17q12 deletion. Identifying these genes and others that may shape the penetrance and expressivity of the 17q12 deletion will be an important challenge for future research on this disorder.

What has surprised you the most while conducting your research?

Overall, I was surprised at the degree to which the CD-1 17q12 deletion mouse recapitulated features of the human disorder. This was my first time using an outbred mouse strain for experiments, so I was pleasantly surprised that despite the increased variability inherent to the background, we still observed consistent phenotypes among the deletion mutants. I think that outbred mouse strains and other animal models with a more diverse genetic background may play an important role in the translatability of findings in genetic disorders, particularly CNVs, which already involve oligogenic interactions.

What do you think is the most significant challenge impacting your research at this time and how will this be addressed over the next 10 years?

One of the biggest challenges facing future research into 17q12 deletion syndrome will be determining methods to interrogate the oligogenic interactions of the genes within the interval. Though our current study demonstrates that the deletion interval is haploinsufficient during early embryonic development, determining which genes are necessary and/or sufficient for these effects, in which combinations, at which developmental time points and in which cell types, will be challenging. Previous animal studies examining some of the individual genes within the interval have suggested that hemizygosity of any single 17q12 gene is unlikely to cause all of the phenotypes observed in the human disorder or our mouse model. Multiomic studies or combinatorial CRISPR screens in different model organisms may be required to fully elucidate the differential contributions of each gene to the phenotypes observed in the disorder. However, as techniques such as single-cell RNA sequencing (RNA-seq), chromatin immunoprecipitation followed by sequencing (ChIPseq) or assay for transposase-accessible chromatin using sequencing (ATACseq) become more accessible, and the ability to generate multiple mutants becomes more feasible, this determination will eventually become possible.

What changes do you think could improve the professional lives of scientists?

I believe that several changes will be necessary continue to make academic research accessible and feasible for trainees of all backgrounds. In particular, stipends will need to be raised in line with cost-of-living increases and inflation, and benefits (including health insurance, savings plans, and childcare or housing subsidies) should be improved for trainees. While many institutions have taken steps toward improving these conditions, it will be important to continue to minimize the opportunity cost inherent in PhD and postdoctoral training. In the USA, it also would be beneficial to standardize benefits between trainees who are directly employed by universities or other institutions and those who have funding from fellowships. Further, improving financial education would be beneficial for all trainees, but particularly for international students and postdocs who may need to navigate a new system.

What's next for you?

Unfortunately, I have recently been diagnosed with stage IVC colon cancer. I would like to thank my mentors at NHGRI, my oncology care team at Georgetown University Hospital, and my friends and family for their support. The incidence of colon cancer cases in young adults is increasing, and I would encourage anyone with symptoms to talk to their doctors.

While I am undergoing treatment, I have been improving my proficiency in different bioinformatic data analysis methods. I am grateful for the opportunities I have had at NIH to continue participating in my lab's research under these circumstances.