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Telomere length: implications on the risk for chromosome 21 nondisjunction in oocytes

Albizua, Igor (2013)
Dissertation (65 pages)
Committee Chair / Thesis Adviser: Sherman, Stephanie
Committee Members: Zwick, Michael ; Rudd, Katie ; Kelly, William G ; Conneely, Karen N
Research Fields: Biology, Genetics
Keywords: Down Syndrome; Telomere length
Program: Laney Graduate School, Biological and Biomedical Sciences (Population Biology, Ecology & Evolution)
Permanent url: http://pid.emory.edu/ark:/25593/d7642

Abstract

Trisomy 21, the chromosomal abnormality responsible for Down syndrome (DS), is a complex condition with many characteristic symptoms as well as an increased risk for numerous congenital anomalies. Previous studies estimated that 93% of DS cases result from a chromosomal error during the generation of the oocyte, with maternal age being the best known risk factor of chromosome 21 nondisjunction. An altered recombination profile, as defined by the number of recombinant events and their location along chromosome 21, has been recognized from detailed analysis of nondisjunction events.Telomeres are specific repetitive DNA sequences formed by 6 nucleotides (TTAGGG), and its complementary sequence (AATCCC), found at the end of chromosomes. The loss of these sequencing and the concomitant shortening of chromosomes are considered a genetic marker for aging. In our study, we first test the hypothesis that mothers of children with DS have shorter telomeres than mothers of euploid children. In effect, our hypothesis suggests that mothers of children with DS will appear "biologically older" as compare to the mothers of euploid children. We developed and applied a quantitative PCR assay to measure the genome-wide relative telomere length in order to test this hypothesis. We also test the relationship between relative telomere length and absence of recombination, a known risk factor for chromosome 21 nondisjunction during the first meiotic division of the oocyte. Our data support telomere length as a biomarker of age and hence nondisjunction. We also found a relationship between maternal shortened telomeres and lower levels of recombination in the nondisjoined chromosome. This result suggests that telomere length may also be a biomarker for abnormal telomere functioning during the formation of the oocyte.

Table of Contents

Chapter 1: Introduction -- Down Syndrome -- Epidemiology of DS -- Female meiosis and human oogenesis -- Telomeres -- Background -- Function and Stricture -- Telomere shortening -- Summary -- Chapter 2: Methods development to determine telomere length -- Sample description -- Determination of type of nondisjunction error -- Determination of recombination profile -- Determination of telomere length -- Chapter 3: Telomere length as a biomarker for maternal and nondisjunction -- Telomere length and chromosome 21 nondisjunction -- Telomere length and recombination along the nondisjoined chromosome -- Statistical analysis -- Sensitivity analysis -- Chapter 4: Conclusions and future studies -- Study limitations -- Conclusions and future studies -- References -- Figures and Tables -- Figure 1. Regression line for the T PCR showing the efficiency of the reaction (E=100.5%) and the R^2 of the regression line (R^2= 1.000) -- Figure 2. Regression line for the S PCR showing the efficiency of the reaction (E=102.3%) and the R^2 of the regression line (R^2= 0.996) -- Figure 3. Regression line showing the distribution of T/S ratio as function of maternal age among control mothers -- Figure 4. Regression line showing the distribution of T/S ratio as function of maternal age among MI error mothers -- Figure 5. Regression line showing the distribution of T/S ratio as function of maternal age among MII error mothers -- Figure 6. Regression line showing the distribution of T/S ratio as function of maternal age among control, MI error and MII error mothers -- Figure 7. Regression lines showing the distribution of T/S ratio as function of age among MI error mothers in the presence or absence of recombination -- Table 1. Sample size for controls, MI errors and MII errors divided by age group -- Table 2. Mathematical models predicting T/S ratio for controls, all maternally-derived nondisjunction (NDJ) cases, those informative for stage and recombination traits (Selected) and MI and MII separately as a function of age -- Table 3. T/S ratio mean and Standard deviation (SD) for controls, MI errors and MII errors divided by age group -- Table 4. Sample size for the analysis performed on the influence of recombination on telomere length

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