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

INTRODUCTION

A prior integrative, multi-omics human genetics and functional genomics study identified maelstrom (), 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 across developmental timescales and cell-lineages in the neonatal human brain towards a mechanistic understanding how variation in expression may cause HC.

OBJECTIVE

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

METHODS

Ensembl was used to delineate the evolution and taxonomy of 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 expression patterns. We quantified expression in primary cortical brain tissue obtained during the surgical treatment of HC.

RESULTS

We performed taxonomic gene-mapping to define the evolutionary origin of to assess suitability for mechanistic characterization and across species. We find that 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 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 expression, consistent with a prior human TWAS analysis.

CONCLUSIONS

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