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. However, the developmental timing, cell-type specificity, evolutionary conservation, and direct measurement of MAEL expression in human HC cortex remain unknown.

To characterize the evolutionary origin and developmental, cell-type specificity, and temporal expression patterns of MAEL in the developing human brain and to measure MAEL expression in primary human HC cortical tissue.

Ensembl was used to delineate the evolution and taxonomy of MAEL across species. Analysis of single-nucleus RNA sequencing (snRNA-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 via snRNA-seq.

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. snRNA-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 HC surgery. Finally, using snRNA-seq of primary HC brain tissue, we functionally validated reduced MAEL expression, consistent with a prior human TWAS analysis.

Our findings extend prior genetic association data by defining the developmental and cellular context of MAEL expression in the human brain and by providing direct evidence of reduced MAEL expression in the human HC cortex. While these data support a plausible role of MAEL in HC pathobiology, further mechanistic studies are needed to prove causality.