Assessment of cis and trans-acting factors for involvement in the altered recombination patterns associated with Trisomy 21 Público
Middlebrooks, Candace Denise (2013)
Abstract
Altered recombination count and placement along chromosome 21 have been identified as risk factors for nondisjunction (NDJ) which causes Trisomy 21. Hence, we performed two studies to determine: 1. whether cis-acting factors (genomic features) differ between Trisomy 21 probands and controls at sites of recombination 2. whether trans-acting factors that regulate genome-wide recombination number are dysregulated in Trisomy 21 probands.
In our study of trans-acting factors, we sought to determine if genome-wide recombination patterns in MI error probands differed from that of normal individuals. Studies have found that there is significant correlation between the number of observed recombinants on a specific chromosome and the number of recombinants in the rest of the genome and this is called the "gamete effect". We stratified by meiotic outcome group (MI error, MI error siblings, and controls) and used linear regression models to test for the "gamete effect" in each group. We found strong evidence for a gamete effect among the autosomes of the normal meiotic outcome group as well as the MI siblings, but not in the MI error group. These data indicate two things: there is a disruption in the "gamete effect" across the autosomes of the MI error group and this disruption is oocyte-specific (it does not extend to their siblings).
In our second study, we sought to determine if cis-acting factors (GC content, CpG fraction, Poly (A)/Poly (T) fraction and gene density) or the number of hotspots in a genomic region are significant predictors of the proportion of recombination in bins across disjoined versus nondisjoined chromosomes 21. We used univariate linear regression to determine the relationship between the proportion of recombination in bins across 21q and the quantity of each of our variables of interest. Results from our analysis of normal meiotic events and MI errors showed, as expected, that recombination placement was correlated with hotspots on 21q. In contrast, among MII errors, correlation was not significant between the proportion of recombination and number of hotspots per bin.
Table of Contents
Table of Contents
Abstract
Title Page
Acknowledgements
Table of contents
List of Figures and Tables
Chapters
1 Introduction.……………………………………………………………...1
1.1 History …………………………………………………………………………………………1
1.2 Meiosis and gamete formation ……………………………………………………3
a. Key components of meiosis
b. Male versus female meiosis
1.3 Nondisjunction …………………………………………………………………………...8
a. Nondisjunction and human reproduction
b. Nondisjunction Etiology: Determining a
molecular mechanism
1.4 Homologous Recombination and nondisjunction ………………….….12
a. Homologous Recombination pathway
b. Recombination: An incomplete puzzle
c. Genome-Wide Recombination (GWR): Features in
meiotically normal individuals
d. Factors associated with variation in recombination
e. Altered recombination patterns associated
with Trisomy 21
1.5 Trisomy 21: A model for Nondisjunction ………………………………..22
1.6 Research Overview …………………………………………………………………..24
2 Evidence for dysregulation of recombination count……….28
in oocytes with nondisjoined chromosomes 21
2.1 Abstract …………………………………………………………………………………….29
2.2 Introduction ……………………………………………………………………………...30
2.3 Subjects and Methods ……………………………………………………………...33
2.4 Results …………………………………………………………………………………….…41
2.5 Discussion ……………………………………………………………………………….…47
3 Differential hotspot usage is observed among ………….….62
recombinant events on nondisjoined chromosomes 21.
3.1 Abstract …………………………………………………………………………………….63
3.2 Introduction ………………………………………………………………………………64
3.3 Results ………………………………………………………………………………………66
3.4 Discussion …………………………………………………………………………………70
3.5 Materials and Methods ………………………………………………………….…74
4 Discussion …………………………………………………………….....................89
4.1 Applicability of Trisomy 21 research to other trisomies .……..…89
4.2 Scope of research ……………………………………………………………….…...89
4.3 Contribution to nondisjunction research: Variation in …………… 90
trans-acting factors contribute to nondisjunction
4.4 Contribution to nondisjunction research: MII errors may .….….92
be caused by factors that influence hotspot usage
4.5 Clinical applicability …………………………………………………………………..94
Works Cited
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