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Summary of germline mutation rates in young adults

Summary of “Germline mutation rates in young adults predict longevity and reproductive lifespan”

Link to Paper

Glossary

  1. AAMR = Age-Adjusted Mutation Rates
  2. ALG = Age of Last Birth
  3. Progeroid = Resembling premature aging
  4. DNM = De Novo Mutations
  5. WGS = Whole Genome Sequencing

Abstract

  1. 30 years: Women’s fertility start declining

  2. Higher AAMR associated with:

    • lower number of live birth
    • lower ALB
  3. Adolescence: baseline of adults germline mutation accumulation rates
  4. Menarche: delayed mutation accumulation
  5. Germline mutation rates: potential systemic and reproductive aging measurement

Introduction

  1. Aging due to Somatic mutation theory:

    • Mutations compound as time passes

    • Manifestation:

      • cell: apoptosis, cellular senescence, tumorigenesis
      • tissue: disfunction, chronic disease, death

    • Monogenic progeroid syndromes:

      • Werner (WS)
      • Hutchinson-Gilford progeria
      • Bloom (BS)
      • Rothmund-Thomson (RTS)
      • Cockayne (CS)
      • Xeroderma pigmentosum (XP)
      • Trichothiodystrophy (TTD)
      • Restrictive Dermopathy (RD)

    • Measurement of somatic mutations in blood nuclear DNA:

      • More mutations: greater mortality

    • Women:

      • Germline mutations build-up lowers reproductive lifespan
      • Systemic aging relates to fecundity

      • Older ALB women at older than 40 years live unquestionably longer than women with younger ALB

        • their brothers and sisters live longer too
      • Older natural menopause ages: longer lifespans

    • Compounding of mutations:

      • At how many years old does mutations build-up starts determining longetivity ?

      • Does end of puberty coincide with either/both somatic & germline mutation build-up ?

        • Evolutionary biology: lower natural selection drive to stay healthy after reproductive stage is achieved
        • Higher IGF-1 levels in blood
        • Lower FOXO transcription factors
        • Worsening of DNA repair systems during adult life

        • Insufficiency of GH/IGF-1 during growth:

          1. slower than normal decline of DNA repair in adults, increase lifespan accordingly
          2. late start of puberty:
          3. lifespan increases in both male/female
          4. less all-cause mortality in female
          5. lower cancer risk in both male/female

      • Mutation compound rates:

        • significantly less in germline (to that in soma)
        • DNA Damage & Repair systems:
        • common across many tissue types
        • ordering by germline mutation compound rates means ordering by somatic mutation compound rates.

    • In this experiment, WGS data is used to:

      • DNM Mutation Counts attributed to each parent are quantified
      • DNM Mutations Counts are calculated to yield parental-age-adjusted germline autosomal mutation rates to check:
      • lifespan in both male/female
      • duration of childbearing
      • Check hypothesis if puberty kickstarts mutation rates compounding after prepubertal period with flat mutations rates.

Results

Survival Analysis

  1. Older parental age: more germline mutations

  2. Regression of germline autosomal mutation rates vs ageofparents: 2.1. yielding Age-Adjusted Mutation Rates (AAMR)

    2.2.

    germlinemutationrates = #germlineautosomalmutations / #diploidautosomalcallablebasepairs

    2.3. Cox proportional hazard regression models:

    • 1 std-dev higher AAMR -> increased all-cause mortality

    • Men:

      • Top Quartile AAMR:
      • 2x mortality of Bottom Quartile AAMR
      • No association with CVD mortality

    • Women:

      • AAMR associated with non-CVD mortality
      • no association with all-cause or CVD mortality

  3. Germline mutation counts:

    • Men: more unrepaired DNA damage (outside DNA replication)

  4. Median Survival Advantage:

    1. mortality between top vs bottom quartile (<25% vs >75%)
    2. all-cause, both sexes = 4.7 years
    3. male all-cause = 6 years
    4. female non-CVD = 8 years
    5. these results reflects effects of smoking / physical activity

    6. hypothesis:

      • persons with higher germline AAMRs has somatic mutations at higher rates, giving them ageing-related lethal diseases

  5. Cancer incidence

    1. Association with germline AAMR has not been established

  6. Fertility of women

    • Hypothesis: germline mutation compounding increases:
    • oocyte atresia
    • lower fertilization rates
    • higher miscarriage rates
    • earlier menopause
    • Tertiles are used (instead of quartiles)

    • higher AAMR:

      • fewer live births
      • lower ALB

  7. When are the germline mutation accumulation rates of adulthood established ?

    1. Aging rate might vary 3-fold in young adults
    2. Fetal tissue mutation rates: multiple times higher than adult tissue
    3. Rapid cell growth & proliferation needed in early development
    4. Mutations plateu in childhood / prepubescent years
    5. Then kick back up due to puberty.

Discussion

  1. Lower sex- and parental-age-adjusted germline mutation rates: lower all-cause mortality for both male/female.

    • Aging is due to somatic mutation is likely correct as seen from high association of germline mutation rates in early adults with all-cause mortality decades after.
  2. No significant association of higher cancer risk with higher AAMRs, due to small number of subjects.

  3. New analyses of published cross-sectional (Generation I) and longitudinal (Generation II) to calculate the age onset of mutation compound rates.

    1. Later puberty
    2. longer lifespans
    3. lower cancer risks
    4. later menopause

Methods

  1. 46 3-generation Utah CEPH families recruited for first extensive human genetic linkage map

    • gen-III: 4 - 16 siblings
    • gen-II: 2 parents
    • gen-I: 2 - 4 grandparents

  2. Study:

    1. Cross-sectional germline AAMRs in 2x61 gen-I
    2. Lifespan
    3. Cause-specific mortality
    4. Cancer incidence
    5. Women’s reproductive spans
    6. Women’s menarche age
    7. Timing & germline autosomal mutations accumulation rates using WGS
    8. 40 gen-II parents, 350 gen-III offsprings
    9. in blood DNA de-novo mutations
    10. blood collected 1980s and 2000s
    11. large sibship sizes:
    12. Grandparents information helps with assigning alleles to either maternal/paternal chromosomes (phasing)
    13. Selection criteria:
    14. big sibships = above average fertility
    15. alive grandparents = above average lifespans
    16. are applied for all samples
    17. 122 gen-I inviduals are European descent (DNA sequence polymorphisms)
  3. Age-adjusted germline mutation rates
  4. Germline mutations rises as parents get older
  5. Males has more mutations and faster mutation rates
  6. Mutation counts spans more than two-folds for age-matched same-sex subjects

  7. Germline mutation rates =* num mutations / num diploid autosomal callable base pairs

    • Age-adjusted mutation rates = Generalize linear model to regres germline somatic mutation rates on parental age

4.Outcomes

  • Fertility measurement

    • number of live birth (parity)
    • age of last birth (ALB)

    • ALB < 30y healthy female

      • Variations among participants taken as 0
      • Likely from individual choice and/or pathological condition
      • endometriosis
      • polycystic ovary syndrome
      • Menarche onset data from Utah Genetic Reference Project (UGRP) ? DNA sequence polymorphisms

? blood DNA de-novo mutations

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