Sunday, June 29, 2025 6/29/2025

Detection and genotyping complex human genetic variation using single-molecule sequencing

Award Number: R01HG011649
ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Detection and genotyping complex human genetic variation using single-molecule sequencing - Project summary Although single-molecule sequencing (SMS) technologies have advanced in recent years to enable routine sequencing and assembly of human genomes, new software is required to utilize the potential of SMS in human genetics. The long term goal is to help improve our understanding of complex variation in human diversity and its role in disease. To achieve this, we will develop methods to (1) detect variation in SMS reads, (2) assemble duplicated sequences missing from SMS de novo assemblies, and (3) genotype complex variation in large HTS datasets using lightweight data structures. While several years of algorithm development for SMS data have resulted in an software ecosystem to detect variation in SMS genomes, the rationale for the need to continue development is that sensitivity and specificity are not yet sufficient for disease studies, important classes of variation are not resolved by current assembly approaches, and the knowledge gained from sequencing SMS genomes must be used to improve what can be discovered in large disease studies that rely heavily on short read data such as those conducted under TOPMed. The algorithmic innovations we will provide for SMS data are an alignment algorithm that explicitly optimizes over rearranged sequences, an assembly approach that exploits minor differences between duplication copies to resolve genome function. Software will be supported through Bioconda installation and distributed test cases. Once a variant is discovered by SMS, it may be more easily genotyped in short read data. We will develop methods to generate databases of SMS variation that may be queried with short read data. To aid in development of assembly algorithms for duplicated sequences, we will generate a public resource of SMS data for individuals with known copy number polymorphisms. The significance of this work is to enable SMS genomes to be used in disease studies, both by uncovering previously hidden variation, and by increasing the amount of variation found in large short-read datasets.


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 = $404,250 )
2025	2025	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Human Genome Research	000	5	4/30/2025	NON-COMPETING CONTINUATION	$404,250
														Subtotal = $404,250

Issue Date FY: 2024 ( Subtotal = $404,250 )
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90089	LOS ANGELES	USA	Human Genome Research	000	4	6/28/2024	NON-COMPETING CONTINUATION	$404,250
														Subtotal = $404,250

Issue Date FY: 2023 ( Subtotal = $412,500 )
2023	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Human Genome Research	000	3	4/28/2023	NON-COMPETING CONTINUATION	$412,500
														Subtotal = $412,500

Issue Date FY: 2022 ( Subtotal = $412,500 )
2022	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Human Genome Research	000	2	6/29/2022	NON-COMPETING CONTINUATION	$412,500
														Subtotal = $412,500

Issue Date FY: 2021 ( Subtotal = $412,500 )
2021	2021	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Human Genome Research	000	1	7/7/2021	NEW	$412,500
														Subtotal = $412,500

Grand Total All Awards = $2,046,000

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Detection and genotyping complex human genetic variation using single-molecule sequencing

Award Number: R01HG011649

ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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