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Analysis of Poison Exon Inclusion in Genes Associated with Neurodevelopmental Disorders and Autism Spectrum Disorder

Award Number: F31MH126628
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 06/01/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2023

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Analysis of Poison Exon Inclusion in Genes Associated with Neurodevelopmental Disorders and Autism Spectrum Disorder - Project Summary/Abstract Over one in one hundred infants born are affected by neurodevelopmental disorders (NDDs), which can cause a host of debilitating symptoms including early-onset seizures, developmental delay, and intellectual disability. Application of whole exome/genome sequencing to examine NDD has revealed many disease-causing variations, but in a substantial proportion of cases the genetic cause remains undetermined. The analysis of deep-intronic non-coding variants has provided diagnosis when coding variation cannot be implicated in disease. For example, intronic variants in the “20N” poison exon of SCN1A results in loss of function, causing Dravet Syndrome, an NDD causing prolonged seizures in the first year of life. Poison exons are a mechanism of gene regulation whereby a premature termination codon caused by inclusion of the poison exon induces nonsense- mediated decay of the mRNA transcript. Preliminary analysis has shown that poison exon inclusion (PEI) in SCN1A and SCN8A decreases during embryonic brain development, inversely proportional to total RNA expression. The brain is a hotbed of alternative splicing during early neuronal development therefore it is plausible, if not probable that novel poison exons remain uncharacterized. The overall hypothesis of this proposal is that PEI is a mechanism to differentiallyregulate gene expression during earlyneuronal development, and intronic variants affecting PEI in genes of developmental importance contribute to disease phenotype. In Aim 1, the sodium and calcium voltage-gated channel alpha subunit families will be assessed to detect and characterize novel poison exons. Known and novel PEI will then be determined in the developing brain using publicly available RNA-seq experiments. In Aim 2 this analysis will be scaled up over 100-fold to detect and assess PEI in over 3000 genes associated with NDD and Autism Spectrum Disorder (ASD) in the developing brain and the driving forces of PEI evolution will be assessed. Comparative analysis of poison exons will be conducted using k-means hierarchical clustering and unsupervised random forest machine learning methodologies to determine prime biological factors driving PEI utilization. In Aim 3, intronic variants will be analyzed in probands of NDD and ASD in regions of known and hypothetical PEI and the affect these variants have on disease phenotype will be computationally assessed. These experiments will reveal new insights into alternative splicing in the developing brain and provide potential genetic explanation of currently unknown NDD disease phenotype. The research will be conducted at the HudsonAlpha Institute for Biotechnology, which allows developing scientists to hone skills in a dynamic, hands-on environment with supplemental training courses as necessary. Besides the research outlined in the proposal, training will include courses in conduct of responsible research, advanced biostatistics, machine learning, bioinformatics, and wet lab techniques next to personal development to improve oral and written communication and presentation skills as well as time management.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = -$1,994 )
2024	2022	HUDSONALPHA INSTITUTE FOR BIOTECHNOLOGY	601 GENOME WAY	HUNTSVILLE	AL	35806	MADISON	USA	Mental Health Research Grants	000	2	3/22/2024	NON-COMPETING CONTINUATION	-$1,994
														Subtotal = -$1,994

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	HUDSONALPHA INSTITUTE FOR BIOTECHNOLOGY	601 GENOME WAY	HUNTSVILLE	AL	35806	MADISON	USA	Mental Health Research Grants	000	2	5/30/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $43,508 )
2022	2022	HUDSONALPHA INSTITUTE FOR BIOTECHNOLOGY	601 GENOME WAY	HUNTSVILLE	AL	35806	MADISON	USA	Mental Health Research Grants	000	2	5/25/2022	NON-COMPETING CONTINUATION	$43,508
														Subtotal = $43,508

Issue Date FY: 2021 ( Subtotal = $42,792 )
2021	2021	HUDSON-ALPHA INSTITUTE FOR BIOTECHNOLOGY	601 GENOME WAY	HUNTSVILLE	AL	35806	MADISON	USA	Mental Health Research Grants	001	1	5/14/2021	NEW	$0
2021	2021	HUDSON-ALPHA INSTITUTE FOR BIOTECHNOLOGY	601 GENOME WAY	HUNTSVILLE	AL	35806	MADISON	USA	Mental Health Research Grants	000	1	5/14/2021	NEW	$42,792
														Subtotal = $42,792

Grand Total All Awards = $84,306

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Analysis of Poison Exon Inclusion in Genes Associated with Neurodevelopmental Disorders and Autism Spectrum Disorder

Award Number: F31MH126628

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 06/01/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2023

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