Exploring regulatory genomic variation in the developing human brain to understand autism

Despite advances in elucidating the genetic basis of autism, there remains uncertainty about the specific causal genes involved in pathogenesis and how their functions are neurodevelopmentally regulated. Human brain development is known to involve spatially and temporally coordinated changes in gene expression, but the precise molecular mechanisms underlying this process have not been fully described.

The primary goal of Jonathan Mill’s project is to characterize multiple layers of gene regulation during brain development, facilitating a systematic exploration of hypotheses related to the neurodevelopmental origins of autism. The current project leverages past work from Mill’s laboratory profiling DNA and histone modifications in postmortem brain tissue from individuals with autism and other neuropsychiatric phenotypes, as well as pilot studies exploring epigenomic trajectories across human brain development^1-4. Many autism-associated variants are hypothesized to influence gene regulation rather than directly affecting protein structure. Because regulatory genomic signatures are cell- and developmental-stage-specific, it is critical that these relationships are explored in the relevant cell types and at the correct time point in development. Building on the laboratory’s past work describing molecular quantitative trait loci in the fetal brain^3,4, Mill’s team will also characterize genetic effects on gene regulation during neurodevelopment, facilitating the interpretation of genetic findings for autism.

The specific aims of this project are to:

1. Profile markers of (epi)genomic regulation in purified nuclei populations isolated from cortex tissue dissected from human fetal brain samples ranging from ~7 weeks post-conception (WPC) to birth (~40 WPC).
2. Use novel single-nucleus RNA-seq (snRNA-seq) approaches to examine patterns of gene expression in individual nuclei from human fetal cortex samples. These analyses will reveal cell-type-specific regulatory genomic heterogeneity during human brain development, enabling inference of developmental gene networks and mapping of results from genome-wide association studies (GWAS) and postmortem studies using adult brain tissue to specific cell types and developmental stages.
3. Apply novel long-read sequencing approaches to perform the first comprehensive analysis of RNA splicing during human brain development and explore the role of isoform variation in remodelling the transcriptome.
4. Examine how autism-associated genetic variation influences regulatory processes during neurodevelopment, facilitating the interpretation of recent GWAS findings using integrative colocalization approaches^5-6.

Finally, Mill’s team will generate an accessible web-based interface, creating a human developmental genomics data resource for the autism research community.

References

1. Wong C. et al. bioRxiv (2018) Preprint
2. Sun W. et al. Cell 167, 1385-1397 (2016) PubMed
3. Spiers H. et al. Genome Res. 25, 338-352 (2015) PubMed
4. Spiers H. et al. BMC Genomics 18, 738 (2017) PubMed
5. Hannon E. et al. Nat. Neurosci. 19, 48-54 (2016) PubMed
6. Hannon E. et al. Am. J. Hum. Genet. 103, 654-665 (2018) PubMed