Cytosolic DNA, Telomeres/Subtelomeres, and Epigenetics: A Longitudinal Twin Study to Assess the Role of Genetics and Environment on their Frequency and Inter-relationships

细胞质 DNA、端粒/亚端粒和表观遗传学:评估遗传和环境对其频率和相互关系的作用的纵向双胞胎研究

基本信息

项目摘要

Cystolic DNA (cyDNA), which is acquired in somatic cells, is emerging as an instigator/integrator of cellular functions associated with aging, yet the causes/consequences of cyDNA are poorly understood. Do individuals have a genetic predisposition to develop cyDNA or is its frequency most heavily influenced by environmental factors? Is cyDNA an early trigger for the acquisition of other age-related biomarker hallmarks, or does it arise in response to perturbations involving a subset of these hallmarks? To answer these primary questions, we will complete a longitudinal study (10 to 15 years timeframe) of 100 twin pairs [70 identical (MZ) and 30 fraternal (DZ) twin pairs; 200 individuals] who are discordant (35 MZ; 15 DZ) or concordant (35 MZ; 15 DZ) for cyDNA frequencies. The twin pairs will vary in age (currently 22 to at least 80 y.o) to allow us to chronicle associations between aging hallmarks and the acquisition of cyDNA. For each time point we will determine: (a) cyDNA levels, (b) chromosome specific-telomere/subtelomere lengths, (c) senescence markers, and (d) DNA methylation patterns in cells from two different tissues (blood and buccal mucosa cells [to assess potential soma-related differences]). Two measures of cyDNA will be quantified: (1) micronuclei (MN) frequency; and (2) extrachromosomal circular DNA (eccDNA) frequency. The MN frequencies will be identified for each of the 24 human chromosomes using a novel assay we developed that combines spectral karyotyping and fluorescence in situ hybridization technologies. The genetic contents of the eccDNA will be determined using our rolling circle amplification and sequencing protocol. Chromosome-specific telomere and subtelomere lengths will be determined using our Q-FISH method and our newly developed nanomapping method that exploits atomic force microscopy, CRISPR-Cas9, and our novel genome sequence algorithm to provide unprecedented resolution of telomere/subtelomere measures. We will also use “state of the art” tools we developed/optimized, to quantify telomere dysfunction; senescence (SADS, classical, and transcriptome studies), and genome-wide DNA methylation patterns. Using a method of robust variance component estimation (implemented in the FISHER quantitative genetics package), this study will provide the first measure of the extent to which individual differences in cyDNA and subtelomere lengths (which are associated with TERRA) are determined by additive genetic, common environmental, and specific environmental effects. We will also use “state of the art” statistical modeling and bioinformatic tools that we developed/optimized to analyze biomarker patterns within individuals, between co-twins, and among twin pairs to determine the stability of patterns with aging, and to identify temporal, as well as driver/mediator, relationships among cyDNA and other aging hallmarks (telomeres/subtelomeres, DNA methylation, senescence). The information gained from this study could also lead to the development of a health screening test(s) and/or identify new therapeutic targets that could transform our approach for developing treatments to alleviate symptoms of age-related health conditions.
在体细胞中获得的Cystolic DNA (cyDNA)正逐渐成为细胞分化的策动者/整合者

项目成果

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COLLEEN K JACKSON-COOK其他文献

COLLEEN K JACKSON-COOK的其他文献

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{{ truncateString('COLLEEN K JACKSON-COOK', 18)}}的其他基金

2023 International Mosaic Down Syndrome Association Community-Empowered Research and Retreat Weekend: Increasing Partnerships, Cohorts, and Diversity for Research Related to Down Syndrome
2023 年国际马赛克唐氏综合症协会社区赋权研究和静修周末:增加唐氏综合症相关研究的合作伙伴关系、群体和多样性
  • 批准号:
    10682970
  • 财政年份:
    2023
  • 资助金额:
    $ 82.05万
  • 项目类别:
A mosaic Down syndrome model system comparing isogenic trisomic/disomic cells to unmask trisomy-21 related genomic, epigenomic, and senescence changes acquired across the lifespan
镶嵌唐氏综合症模型系统比较同基因三体/二体细胞,以揭示在整个生命周期中获得的与 21 三体相关的基因组、表观基因组和衰老变化
  • 批准号:
    10656746
  • 财政年份:
    2023
  • 资助金额:
    $ 82.05万
  • 项目类别:
Epigenetic, Telomere & Chromosome Changes in Adult Twins Having Child Adversity
表观遗传、端粒
  • 批准号:
    8317612
  • 财政年份:
    2010
  • 资助金额:
    $ 82.05万
  • 项目类别:
Epigenetic, Telomere & Chromosome Changes in Adult Twins Having Child Adversity
表观遗传、端粒
  • 批准号:
    8726264
  • 财政年份:
    2010
  • 资助金额:
    $ 82.05万
  • 项目类别:
Epigenetics and Psychoneurologic Symptoms in Women with Breast Cancer
乳腺癌女性的表观遗传学和心理神经症状
  • 批准号:
    8511845
  • 财政年份:
    2010
  • 资助金额:
    $ 82.05万
  • 项目类别:
Epigenetic, Telomere & Chromosome Changes in Adult Twins Having Child Adversity
表观遗传、端粒
  • 批准号:
    7988804
  • 财政年份:
    2010
  • 资助金额:
    $ 82.05万
  • 项目类别:
Epigenetic, Telomere & Chromosome Changes in Adult Twins Having Child Adversity
表观遗传、端粒
  • 批准号:
    8136597
  • 财政年份:
    2010
  • 资助金额:
    $ 82.05万
  • 项目类别:
Epigenetics and Psychoneurologic Symptoms in Women with Breast Cancer
乳腺癌女性的表观遗传学和心理神经症状
  • 批准号:
    8711107
  • 财政年份:
    2010
  • 资助金额:
    $ 82.05万
  • 项目类别:
Epigenetics and Psychoneurologic Symptoms in Women with Breast Cancer
乳腺癌女性的表观遗传学和心理神经症状
  • 批准号:
    8305955
  • 财政年份:
    2010
  • 资助金额:
    $ 82.05万
  • 项目类别:
Epigenetics and Psychoneurologic Symptoms in Women with Breast Cancer
乳腺癌女性的表观遗传学和心理神经症状
  • 批准号:
    8073362
  • 财政年份:
    2010
  • 资助金额:
    $ 82.05万
  • 项目类别:

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