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Investigating the landscape and genetic architecture of germline mutagenesis

Award Number: R35GM133428
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: 08/07/2019
PERIOD OF PERFORMANCE END DATE: 04/30/2030

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Investigating the landscape and genetic architecture of germline mutagenesis - PROJECT SUMMARY Variation in the efficacy of DNA proofreading and repair can alter germline and somatic mutation rates and cause ripple effects on many important determinants of health, including the frequency of birth defects and the likelihood of developing cancer. It is becoming feasible to measure mutation rate variation within and between species, but we lack a solid frame of reference for its interpretation–for example, the clinical meaning of an ele- vated mutation rate in a human family or the relevance of mutation rate to the survival prognosis of an endangered species. The goal of this research program is to investigate why mutation rates vary within and between species and to what extent this variation is shaped by selection to preserve longevity or population fitness. Since selection can only act on variation that is genetically determined, it will first be crucial to disentangle the heritable compo- nent of mutation rate variation from the effects of environmental mutagens or reproductive life history. We thus propose several complementary strategies for identifying genetic variants that perturb mutation rates in germline and somatic tissues. First, we will investigate the genetic architecture of somatic mutagenesis in the BXD mice, a collection of recombinant progeny of the lab strains C57BL/6J and DBA2/J that we previously used to map quantitative trait loci affecting germline mutagenesis. We will measure the rates and spectra of somatic mutations occurring in aged BXD mouse tissues and test for associations between inherited alleles and the rate of mutation accumulation over time. We will pay special attention to any somatic mutator effects of known germline mutator alleles, including a Mutyh variant whose human homolog is linked to heritable colorectal cancer. Second, we will scan for germline mutator allele activity in human whole genome sequence biobanks. We will cluster haplotypes based on evidence that they were inherited identical-by-descent from the same common ancestor and identify clusters whose mutation spectrum is inconsistent with the genomic background, indicating the likely presence of a germline mutator allele that increases the relative rates of certain mutation types. After applying this method to the UKBiobank, which includes many biometric and biomedical phenotype measurements, we will then test whether mutator alleles tend to be associated with traits such as disease status, hormone levels and fertility. Third, we will use a similar haplotype clustering method to identify mutations in whole-population pedigrees of endangered Florida scrub jays and black rhinos and test for mutation spectrum shifts that appear consistent with the presence of mutator alleles. We will then evaluate whether these data support a longstanding theoretical pre- diction that selection against mutator alleles is inefficient in threatened populations with low effective population sizes. Finally, we will measure the age dependence of de novo mutation rates and spectra in three strains of the short-lived killifish Nothobranchius furzeri and test whether the rate of reproductive aging appears to have accelerated in the populations that have evolved the shortest lifespans. Together, these studies will illuminate how variation in DNA proofreading and repair efficacy may contribute to variation in health and longevity.


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: 2026 ( Subtotal = $465,348 )
2026	2026	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Biomedical Research and Research Training	003	7	5/4/2026	NON-COMPETING CONTINUATION	$465,348
2026	2023	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Biomedical Research and Research Training	001	5	4/23/2026	NON-COMPETING CONTINUATION	$2,532
2026	2023	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Biomedical Research and Research Training	002	5	4/23/2026	NON-COMPETING CONTINUATION	$0
2026	2023	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Biomedical Research and Research Training	000	5	4/10/2026	NON-COMPETING CONTINUATION	-$2,532
														Subtotal = $465,348

Issue Date FY: 2025 ( Subtotal = $465,348 )
2025	2025	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Biomedical Research and Research Training	002	6	4/17/2025	COMPETING CONTINUATION	$465,348
2025	2023	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Biomedical Research and Research Training	000	5	12/20/2024	NON-COMPETING CONTINUATION	$0
2025	2023	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Biomedical Research and Research Training	001	5	4/11/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $465,348

Issue Date FY: 2023 ( Subtotal = $368,279 )
2023	2023	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Biomedical Research and Research Training	000	5	7/11/2023	NON-COMPETING CONTINUATION	$368,279
														Subtotal = $368,279

Issue Date FY: 2022 ( Subtotal = $435,395 )
2022	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Biomedical Research and Research Training	001	4	7/28/2022	NON-COMPETING CONTINUATION	$403,123
2022	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Biomedical Research and Research Training	000	3	3/28/2022	SUPPLEMENT FOR EXPANSION	$32,272
														Subtotal = $435,395

Issue Date FY: 2021 ( Subtotal = $368,279 )
2021	2021	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Biomedical Research and Research Training	000	3	7/19/2021	NON-COMPETING CONTINUATION	$368,279
														Subtotal = $368,279

Issue Date FY: 2020 ( Subtotal = $368,279 )
2020	2020	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Biomedical Research and Research Training	000	2	7/16/2020	NON-COMPETING CONTINUATION	$368,279
														Subtotal = $368,279

Issue Date FY: 2019 ( Subtotal = $368,279 )
2019	2019	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Biomedical Research and Research Training	000	1	8/7/2019	NEW	$368,279
														Subtotal = $368,279

Grand Total All Awards = $2,839,207

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Investigating the landscape and genetic architecture of germline mutagenesis

Award Number: R35GM133428

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: 08/07/2019

PERIOD OF PERFORMANCE END DATE: 04/30/2030

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