Integrative genomics elucidates the evolutionary, temporal, and developmental origins of a hydrocephalus risk gene

A prior integrative, multi-omics human genetics and functional genomics study identified maelstrom (MAEL), a gene involved in regulation of DNA transposon activity and genome structure, as a transcriptome-wide predictor of hydrocephalus (HC) in the brain cortex. Here we expand on this discovery and further characterize the evolutionary origin and expression of MAEL across developmental timescales and cell-lineages in the neonatal human brain towards a mechanistic understanding how variation in MAEL expression may cause HC.

To characterize the evolutionary, temporal, developmental, and lineages of MAEL expression in HC and the developing human brain.

Ensembl was used to delineate the evolution and taxonomy of MAEL across species. Analysis of single-cell RNA sequencing (scRNA-seq) of 49 brain regions across pre- and post-natal timescales from the Developing Human Brain Atlas (Allen Institute) identified temporal and spatial MAEL expression patterns. We quantified MAEL expression in primary cortical brain tissue obtained during the surgical treatment of HC.

We performed taxonomic gene-mapping to define the evolutionary origin of MAEL to assess suitability for mechanistic characterization in vitro and in vivo across species. We find that MAEL is among the top 0.01% human-specific genes and < 50% sequence homology among commonly used model organisms with highly divergent functions, necessitating mechanistic validation in human tissue. scRNA-seq of the non-disease prenatal human brain identified MAEL expression enriched in cortical excitatory neurons, which was recapitulated in primary HC brain tissue obtained during surgery. Finally, using scRNA-seq of primary HC brain tissue, we functionally validated reduced MAEL expression, consistent with a prior human TWAS analysis.

We identify the evolutionary, temporal, and developmental expression pattern of MAEL in the neonatal human brain. We also provide direct evidence for reduced MAEL expression in human HC brain tissue. These data, at least in part, implicate reduced MAEL expression underlying human HC across etiologies.