{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T13:51:33Z","timestamp":1768571493250,"version":"3.49.0"},"posted":{"date-parts":[[2025,9,2]]},"group-title":"Genetic and Genomic Medicine","reference-count":53,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T00:00:00Z","timestamp":1756771200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,9,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Introduction<\/jats:title>\n                  <jats:p>\n                    A prior integrative, multi-omics human genetics and functional genomics study identified maelstrom (\n                    <jats:italic>MAEL<\/jats:italic>\n                    ), 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\n                    <jats:italic>MAEL<\/jats:italic>\n                    across developmental timescales and cell-lineages in the neonatal human brain towards a mechanistic understanding how variation in\n                    <jats:italic>MAEL<\/jats:italic>\n                    expression may cause HC.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>\n                    To characterize the evolutionary, temporal, developmental, and lineages of\n                    <jats:italic>MAEL<\/jats:italic>\n                    expression in HC and the developing human brain.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Ensembl was used to delineate the evolution and taxonomy of\n                    <jats:italic>MAEL<\/jats:italic>\n                    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\n                    <jats:italic>MAEL<\/jats:italic>\n                    expression patterns. We quantified\n                    <jats:italic>MAEL<\/jats:italic>\n                    expression in primary cortical brain tissue obtained during the surgical treatment of HC.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    We performed taxonomic gene-mapping to define the evolutionary origin of\n                    <jats:italic>MAEL<\/jats:italic>\n                    to assess suitability for mechanistic characterization\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    across species. We find that\n                    <jats:italic>MAEL<\/jats:italic>\n                    is among the top 0.01% human-specific genes and &lt; 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\n                    <jats:italic>MAEL<\/jats:italic>\n                    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\n                    <jats:italic>MAEL<\/jats:italic>\n                    expression, consistent with a prior human TWAS analysis.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>\n                    We identify the evolutionary, temporal, and developmental expression pattern of\n                    <jats:italic>MAEL<\/jats:italic>\n                    in the neonatal human brain. We also provide direct evidence for reduced\n                    <jats:italic>MAEL<\/jats:italic>\n                    expression in human HC brain tissue. These data, at least in part, implicate reduced\n                    <jats:italic>MAEL<\/jats:italic>\n                    expression underlying human HC across etiologies.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.09.01.25334358","type":"posted-content","created":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T01:20:16Z","timestamp":1756862416000},"source":"Crossref","is-referenced-by-count":1,"title":["Integrative genomics elucidates the evolutionary, temporal, and developmental origins of a hydrocephalus risk gene"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3182-2966","authenticated-orcid":false,"given":"Andrew T.","family":"Hale","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuwei","family":"Song","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caroline","family":"Davies","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shanrun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Regan","family":"Gaskin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anastasia","family":"Arynchyna-Smith","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brandon G.","family":"Rocque","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zechen","family":"Chong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025090510500717000_2025.09.01.25334358v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(15)60694-8"},{"key":"2025090510500717000_2025.09.01.25334358v1.2","doi-asserted-by":"publisher","DOI":"10.1159\/000484173"},{"key":"2025090510500717000_2025.09.01.25334358v1.3","doi-asserted-by":"crossref","unstructured":"Hale AT , Zhou B , Rajan A , et al. 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