Dissertation
Cerebellar gene expression and structure in 16p11.2 duplication: a developmental perspective
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Summer 2025
DOI: 10.25820/etd.008156
Abstract
Copy number variants (CNVs) in chromosome 16p11.2 are linked to neurodevelopmental and psychiatric disorders, including autism spectrum disorder and schizophrenia. Neurodevelopmental disorders (NDDs) broadly encompass conditions that arise from altered brain development and include deficits in cognition, communication, motor coordination, and behavior. Increasing evidence suggests that rare but highly penetrant CNVs defined as deletions or duplications of large genomic regions are among the most powerful genetic risk factors for NDDs. These structural variations can simultaneously disrupt the dosage of multiple genes involved in synapse formation, neuronal migration, transcriptional regulation, and neuroplasticity. While prior research has described 16p11.2 CNVs affecting cortical and subcortical areas, the cerebellum remains poorly explored. This thesis investigates the impact of the 16p11.2 duplication on cerebellar structure and gene expression during two essential periods of development: pre-pubertal stage (1 month of age) and adulthood (3 months of age).We have performed cerebellar histology and bulk RNA sequencing in both ages in a mouse model of the 16p11.2 duplication. The cerebellar morphology in 1-month-old mice was grossly normal, and there was no evident difference in the thickness of granule and molecular layer, nor Purkinje cell density. Transcriptome analysis revealed that there is a disturbance in embryonic development pathways, synaptic signaling, and transcription regulation genes. At 3 months, the duplication induced structural alterations with thickening of the granule and molecular layers in select cerebellar lobules indicating progressive anatomical alterations over developmental time. Transcriptome analysis showed altered gene expression with enrichment in pathways involved in synaptic plasticity and ion transport, particularly in pathways involving potassium regulation. Notably, comparison of our differentially expressed genes across timepoints and with previously published datasets revealed a persistent subset of dysregulated genes outside the CNV region. Together, these findings define the 16p11.2 duplication as causing cerebellar abnormalities that are both progressive and age-dependent beginning at the molecular level and manifesting subsequently as structural effects. Our findings highlight the cerebellum as an important site affected by the CNV and point to new directions for understanding these effects developmentally.
Details
- Title: Subtitle
- Cerebellar gene expression and structure in 16p11.2 duplication: a developmental perspective
- Creators
- Krislen D. Tison
- Contributors
- Aislinn J Williams (Advisor)Adam Dupuy (Committee Member)Andrew Frank (Committee Member)Marco Hefti (Committee Member)Jacob Michaelson (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Genetics
- Date degree season
- Summer 2025
- DOI
- 10.25820/etd.008156
- Publisher
- University of Iowa
- Number of pages
- xv, 154 pages
- Copyright
- Copyright 2025 Krislen D. Tison
- Language
- English
- Date submitted
- 07/29/2025
- Description illustrations
- illustrations (some color)
- Description bibliographic
- Includes bibliographical references (pages 120-143).
- Public Abstract (ETD)
DNA mutations are involved in mental disorders such autism and schizophrenia. One particular DNA mutation is the 16p11.2 duplication, where a piece of the chromosome is duplicated in error. This can cause major problems with controlling how genes are expressed and how the brain develops. This study used a mouse model with a 16p11.2 duplication mutation to examine how the genetic mutation affects the genes and structure of the cerebellum at different ages. At one month of age, before mice hit puberty (also called juvenile mice), genes linked to mouse brain communication and development were already disrupted. By three months of age, when mice are considered young adults, these gene changes were accompanied by structural changes in the cerebellum. These results suggest that the duplication disrupts mouse brain development in stages and highlight the cerebellum s role in the origins of neurodevelopmental conditions.
- Academic Unit
- Interdisciplinary Graduate Program in Genetics
- Record Identifier
- 9984948427302771
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