Alternative splicing events as peripheral biomarkers for motor learning deficit caused by adverse prenatal environments

Dipankar J. Dutta, Junko Sasaki, Ankush Bansal, Keiji Sugai, Satoshi Yamashita, Guojiao Li, Christopher Lazarski, Li Wang, Toru Sasaki, Chiho Yamashita, Heather Carryl, Ryo Suzuki, Masato Odawara, Yuka Imamura Kawasawa, Pasko Rakic, Masaaki Toriia, Hashimoto Toriia Kazue

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Abstract

Severity of neurobehavioral deficits in children born from adverse pregnancies, such as maternal alcohol consumption and diabetes, does not always correlate with the adversity’s duration and intensity. Therefore, biological signatures for accurate prediction of the severity of neurobehavioral deficits, and robust tools for reliable identification of such biomarkers, have an urgent clinical need. Here, we demonstrate that significant changes in the alternative splicing (AS) pattern of offspring lymphocyte RNA can function as accurate peripheral biomarkers for motor learning deficits in mouse models of prenatal alcohol exposure (PAE) and offspring of mother with diabetes (OMD). An aptly trained deep-learning model identified 29 AS events common to PAE and OMD as superior predictors of motor learning deficits than AS events specific to PAE or OMD. Shapley-value analysis, a game-theory algorithm, deciphered the trained deep-learning model’s learnt associations between its input, AS events, and output, motor learning performance. Shapley values of the deep-learning model’s input identified the relative contribution of the 29 common AS events to the motor learning deficit. Gene ontology and predictive structure–function analyses, using Alphafold2 algorithm, supported existing evidence on the critical roles of these molecules in early brain development and function. The direction of most AS events was opposite in PAE and OMD, potentially from differential expression of RNA binding proteins in PAE and OMD. Altogether, this study posits that AS of lymphocyte RNA is a rich resource, and deep-learning is an effective tool, for discovery of peripheral biomarkers of neurobehavioral deficits in children of diverse adverse pregnancies.

Original languageEnglish (US)
Article numbere2304074120
JournalProceedings of the National Academy of Sciences of the United States of America
Volume120
Issue number50
DOIs
StatePublished - 2023

All Science Journal Classification (ASJC) codes

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