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Discovery of structural RNAs involved in human health and disease

Award Number: R01GM144423
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Discovery of structural RNAs involved in human health and disease - Many fundamental cellular functions depend on a variety of RNA structures conserved through evolution, and other functional RNA structures are expected to be discovered. A signature of a conserved RNA structure is found in alignments where paired positions display correlated substitutions (covariation) that preserve the base pair. This evolutionary signal can be used both to predict RNA structure and to identify new conserved RNAs. Recent publications and preliminary results have made three important advances: A statistical covariation test that identiﬁes signiﬁcant covariation over background covariation due to phylogeny. This test, implemented in a method called R-scape (RNA Structural Covariation Above Phylogenetic Expectation), provides information and control over the rate of false positive predictions. A power of covariation calculation, recently published, that identiﬁes “negative” pairs with power (variation) but insigniﬁcant covariation, unlikely to form RNA base pairs. A new cascading folding algorithm, named CaCoFold (Cascade covariation/variation Constrained Folding) also recently published, that combines all positive and negative evolutionary information into complex structures including all types of pseudoknots and triplets. In human, the efﬁcacy of these advances has been tested by ac- curately predicting the structures of the human non-coding RNAs MALAT1 and telomerase RNA, and by inferring that the non-coding RNAs HOTAIR and XIST do not have a conserved structure. These three advances give us a competitive advantage to perform unbiased genome-wide screens for con- served structural RNAs in vertebrates with accurate 3D structure prediction. Previous vertebrate screens for structural RNAs have been hindered by thousand of false positive predictions. In contrast, our new covariation statistical test allows for controlling the rate of false positives. R-scape has already been used to ﬁnd struc- tural RNAs in bacteria and viruses. Our recent eukaryotic pilot screen in fungi has identiﬁed 17 novel structural RNAs. We hypothesize that many structural RNAs with implications for human health and disease are still to be discovered, and that we now have the tools to ﬁnd and characterize these RNAs. This proposal has three speciﬁc aims that will advance the study of structural RNA biology, and the discov- ery of novel biological mechanisms involving RNA structures. The ﬁrst aim proposes systematic genome-wide searches to ﬁnd novel conserved vertebrate RNA structures in human. The second aim proposes to combine revolutionary 3D structure prediction methods in machine learning with the signals used by CaCoFold into a state of the art RNA folding method for the accurate prediction of 3D RNA structures. The third aim introduces a method to identify RNA structures in ultra conserved vertebrate UTRs where there is no covariation signal, and our current method lacks power. We expect our work will unveil primate-speciﬁc novel regulatory mecha- nisms. Novel human RNA structures found to have causal variants associated with disease will be prioritized for experimental veriﬁcation.


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: 2025 ( Subtotal = $348,575 )
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	000	4	8/14/2025	NON-COMPETING CONTINUATION	$348,575
														Subtotal = $348,575

Issue Date FY: 2024 ( Subtotal = $348,575 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	000	3	8/7/2024	NON-COMPETING CONTINUATION	$348,575
														Subtotal = $348,575

Issue Date FY: 2023 ( Subtotal = $348,575 )
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	000	2	8/10/2023	NON-COMPETING CONTINUATION	$348,575
														Subtotal = $348,575

Issue Date FY: 2022 ( Subtotal = $366,514 )
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	000	1	9/14/2022	NEW	$366,514
														Subtotal = $366,514

Grand Total All Awards = $1,412,239

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Discovery of structural RNAs involved in human health and disease

Award Number: R01GM144423

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/15/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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