PATTERNS AND MECHANISMS UNDERLYING SOMATIC MUTATIONS ACROSS LONG-LIVED BATS - AGING IS UBIQUITOUS ACROSS TH…

Assistance award details

Assistance award identifier

ASST_NON_R00AG088361_075

FAIN

R00AG088361

Recipient

THE PENNSYLVANIA STATE UNIVERSITY

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.866

Total obligated

$493,019

Period

Aug 1, 2024 – Aug 31, 2028

Fiscal year

2025

Place of performance state

PA

Source file

FY2025_All_Assistance_Full_20261006.zip

Description

PATTERNS AND MECHANISMS UNDERLYING SOMATIC MUTATIONS ACROSS LONG-LIVED BATS - AGING IS UBIQUITOUS ACROSS THE TREE OF LIFE, IMPACTING BIOLOGY AT ALL LEVELS. AMONG THE HALLMARKS OF AGING, THE ACCUMULATION OF SOMATIC MUTATIONS OVER TIME HAS BEEN IMPLICATED IN MANY LEADING CAUSES OF DEATH INCLUDING CANCER10-12, HEART DISEASE4, AND DEMENTIA5. HOWEVER, MOST RISK FACTORS GOVERNING SOMATIC MUTATION RATES AND PATTERNS WITH AGE REMAIN UNKNOWN. IT HAS RECENTLY BECOME POSSIBLE TO STUDY THE RELATIONSHIP BETWEEN SOMATIC MUTATION RATES AND LONGEVITY USING COMPARATIVE GENOMICS. CAGAN ET AL. (2022) DEMONSTRATED A NEGATIVE CORRELATION BETWEEN SOMATIC MUTATION RATES AND LONGEVITY, AND IDENTIFIED CONSERVED, LONGEVITY-ASSOCIATED MUTATIONAL SPECTRA ACROSS MAMMALS. YET, THIS STUDY LACKED THE POWER TO EXPLORE FURTHER DUE TO BOTH SPARCE TAXONOMIC SAMPLING AND LOW SAMPLE SIZES PER SPECIES. THUS, THERE IS AN OUTSTANDING GAP IN OUR KNOWLEDGE OF HOW SOMATIC MUTATIONAL SPECTRA RELATE TO CHANGES IN LONGEVITY, AND THE GENES INVOLVED IN LONGEVITY- ASSOCIATED MUTATIONAL SPECTRA. TO PROPERLY STUDY THE MECHANISMS GOVERNING MUTATION RATES AND PATTERNS, ONE MUST SAMPLE MANY INDIVIDUALS FROM A GROUP OF CLOSELY-RELATED SPECIES SPANNING A WIDE RANGE OF LIFESPANS. MY CENTRAL HYPOTHESIS IS THAT SOMATIC MUTATION SPECTRA UNIQUE TO LONG-LIVED MAMMALS ARE SIGNATURES OF ENHANCED DNA DAMAGE REPAIR RESPONSES THAT CONTRIBUTE TO THEIR EXTRAORDINARY LONGEVITY. IN ORDER TO IDENTIFY THE GENETIC MECHANISMS UNDERLYING LONGEVITY-ASSOCIATED SOMATIC MUTATIONAL SPECTRA, I HAVE GENERATED MATCHED SKIN TISSUE AND CELL LINES FROM OVER 200 INDIVIDUALS ACROSS 10 SPECIES OF A CLOSELY RELATED (14 MILLION YEARS) CLADE OF BATS SPANNING A 3-FOLD RANGE IN LIFESPANS, INCLUDING THE LONGEST-LIVED BAT SPECIES IN NORTH AMERICA. IN AIM 1, TO EXPLORE HOW SOMATIC MUTATION RATES CO-EVOLVE WITH LONGEVITY AND IDENTIFY LONGEVITY-ASSOCIATED MUTATIONAL SPECTRA IN BATS, I WILL USE THE HIGHLY SENSITIVE NANOSEQ TO SEQUENCE 60 INDIVIDUALS ACROSS A TRIO OF