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Global analysis of uORF evolution and function

Award Number: R01GM121895
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: 02/01/2017
PERIOD OF PERFORMANCE END DATE: 01/31/2023

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Global analysis of uORF evolution and function - While variation in gene expression clearly affects the phenotypes of organisms, there is a fundamental gap in understanding the role of post-transcriptional processes. Because post-transcriptional processes are critical for the regulation of protein production, addressing this knowledge gap will facilitate better models of the relationship between genotype and phenotype. upstream Open Reading Frames (uORFs) are regulatory elements found in most human genes, and some disease-linked mutations appear to alter the presence of uORFs. Recently, hundreds of uORFs initiating with non-AUG start codons have been identified in many organisms. Despite the vast number of these elements, the functions and evolution of AUG and non-AUG uORFs remain elusive. The long-term goal of this project is to determine the functions and impact of genetic variation in post-transcriptional cis-regulatory elements. The objective of this proposal is to determine how new uORFs evolve and regulate translation. Our central hypothesis is that AUG and non-AUG uORFs have different regulatory roles, leading to different evolutionary trajectories. This hypothesis is based on our preliminary data, as we have identified hundreds of AUG and non-AUG uORFs with different genomic properties in Saccharomyces yeasts. We will test our central hypothesis by pursuing the following specific aims: 1) Investigate the evolution of AUG and non-AUG uORFs; 2) Determine the functions of AUG and non- AUG uORFs; and 3) Identify the roles of RNA binding proteins in uORF-mediated regulation. In the first aim, we will identify active uORFs in diverse strains and species of yeasts grown under four conditions to test the hypothesis that AUG and non-AUG uORFs have different evolutionary tempo and mode. The second aim will determine the gene-regulatory functions of hundreds of uORFs using FACS-uORF, a novel dual-fluorescence reporter system we developed. We will use these data to generate predictive models of uORF function. Aim 3 will identify genome-wide roles of RNA Binding Proteins in regulating uORFs, and integrate this knowledge in our predictive models. This approach is innovative, in that it combines exquisite systems biology tools with an excellent model genus to investigate the evolution of post-transcriptional gene regulation. The proposed research is significant because it is expected to fundamentally advance the fields of genomics, evolutionary, and systems biology by deciphering the evolutionary and functional properties of uORFs. Because translation mechanisms are highly conserved, the knowledge generated by the proposed work is expected to improve models of the relationship between non-coding genetic variation and phenotype in other eukaryotes, including humans.


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 = $0 )
2024	2021	CARNEGIE MELLON UNIVERSITY	5000 FORBES AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Biomedical Research and Research Training	000	5	11/30/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $325,608 )
2021	2021	CARNEGIE MELLON UNIVERSITY	5000 FORBES AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Biomedical Research and Research Training	000	5	1/20/2021	NON-COMPETING CONTINUATION	$293,047
2021	2021	CARNEGIE MELLON UNIVERSITY	5000 FORBES AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Biomedical Research and Research Training	001	5	2/15/2021	NON-COMPETING CONTINUATION	$32,561
														Subtotal = $325,608

Issue Date FY: 2020 ( Subtotal = $325,891 )
2020	2020	CARNEGIE MELLON UNIVERSITY	5000 FORBES AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Biomedical Research and Research Training	000	4	1/31/2020	NON-COMPETING CONTINUATION	$293,301
2020	2020	CARNEGIE MELLON UNIVERSITY	5000 FORBES AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Biomedical Research and Research Training	001	4	3/19/2020	NON-COMPETING CONTINUATION	$32,590
														Subtotal = $325,891

Issue Date FY: 2019 ( Subtotal = $326,175 )
2019	2019	CARNEGIE MELLON UNIVERSITY	5000 FORBES AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Biomedical Research and Research Training	000	3	1/9/2019	NON-COMPETING CONTINUATION	$326,175
														Subtotal = $326,175

Issue Date FY: 2018 ( Subtotal = $326,459 )
2018	2018	CARNEGIE MELLON UNIVERSITY	5000 FORBES AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Biomedical Research and Research Training	000	2	1/16/2018	NON-COMPETING CONTINUATION	$293,813
2018	2018	CARNEGIE MELLON UNIVERSITY	5000 FORBES AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Biomedical Research and Research Training	001	2	5/18/2018	NON-COMPETING CONTINUATION	$32,646
														Subtotal = $326,459

Issue Date FY: 2017 ( Subtotal = $326,742 )
2017	2017	CARNEGIE MELLON UNIVERSITY	5000 FORBES AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Biomedical Research and Research Training	000	1	1/23/2017	NEW	$326,742
														Subtotal = $326,742

Grand Total All Awards = $1,630,875

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Global analysis of uORF evolution and function

Award Number: R01GM121895

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: 02/01/2017

PERIOD OF PERFORMANCE END DATE: 01/31/2023

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