Genetic Variation in Recombination as a Risk Factor for Nondisjunction Öffentlichkeit

Abstract

Nondisjunction is the failure of chromosome to properly segregate during
meiosis. Nondisjunction of chromosome 21, leading to trisomy 21, is the most common
aneuploidy to survive to term. The focus of this thesis research was to better understand
altered patterns of recombination in maternally-derived meiotic chromosome 21 errors.
Information on parental origin and stage of nondisjunction, recombinant profiles
along the nondisjoined chromosome, variants within genes associated with
recombination, and folate supplementation and pathway polymorphisms allowed us to (1)
examine the role of genetic variation in recombination and in oocytes with a nondisjoined
chromosome 21 and (2) examine the role of folate as a risk factor for nondisjunction of
chromosome 21 and how it may interact with recombination.
Variation in recombination rates exists within and among individuals; however,
little is known regarding what factors may influence this variation. To determine the role
of variation in genomic regions and recombination rates, SNPs in three genomic regions
were genotyped in mothers of infants with trisomy 21. We found preliminary evidence
for an association of variants in two of the candidate genes/regions, RNF212 and the
17q21.31 inverted region, and the recombination phenotype in maternal MII
nondisjunction errors. No associations were found among maternal MI errors.
Folate deficiency results in aberrant DNA methylation, chromosome breakage,
defective chromosome recombination and aneuploidy. The possible role of folate
metabolism on the risk of having a child with trisomy 21 remains unanswered. To gain
insight, we examined the role of folate supplementation around the time when meiosis is
resumed stratified by the type of meiotic error. Our results revealed use of folate
supplementation appears to protect against MII errors in the aging oocyte, but not against
MI errors. If confirmed, examination of the recombination profile as a covariate in these
models may add insight into the role of folate in proper chromosome segregation. To
determine the association between risk of trisomy 21 and folate pathway polymorphisms,
we narrowed our phenotype to chromosome 21 nondisjunction errors that occurred in the
oocyte and examined genetic variants in mothers. We did not find an association
between the polymorphisms and chromosome 21 nondisjunction.

Table of Contents

TABLE OF CONTENTS

Abstract
Acknowledgements
List of Figures and Tables
Introduction

Chapter
1 Introduction

2 Preconception folic acid supplementation and risk for chromosome 21
nondisjunction: a report from the National Down Syndrome Project
3 Genetic variation in genes in the folate pathway as a risk factor for
nondisjunction
4 Genetic analysis of variation in chromosome 21 recombination rates

5 Genome-wide recombination as a risk factor for nondisjunction
6 Discussion
Appendix
Works Cited

LIST OF FIGURES AND TABLES
Chapter 1

Figure 1.1 Oogenesis
Figure 1.2 Types of Chromosome Nondisjunction Errors
Figure 1.2 Identification of parental origin and stage of recombinant event
Figure 1.3 Advanced Maternal Age and Down Syndrome
Figure 1.4 Specific Recombination Patterns are Associated with Nondisjoined
Chromosome 21
Figure 1.5 Folate Pathway
Chapter 2
Table 2.1 Characteristics of Mothers of Infants with Full Down Syndrome (cases)
and Those with Infants with No Major Birth Defects (controls)
Table 2.2 Association of Lack of Folic Acid Supplementation with the Birth of an
Infant with Down Syndrome Stratified by a MI and MII Meiotic Error and
by Maternal Age Group Using Logistic Regression
Chapter 3
Figure 3.1 Folate Pathway
Figure 3.2 Identification of parental origin and stage of recombinant event
Table 3.1 Characteristics of Mothers of Infants ith Down Syndrome Due to a
Meiotic Error, MI or MII
Table 3.2 Association of Folate Metabolic Pathway Genes with the Birth of an
Infant with Down Syndrome Due to Maternal Meiotic Error Using Gene-
Level Association
Chapter 4
Figure 4.1 Identification of parental origin and stage of recombinant event
Table 4.1 Minor Allele and Genotype Frequencies of SNPs Analyzed in the Control
and CEPH Populations

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Genetics and Molecular Biology
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Biology, Genetics
Stichwort	trisomy 21 folate and nondisjunction recombination and nondisjunction nondisjunction
Committee Chair / Thesis Advisor	Sherman, Stephanie, Emory University
Committee Members	Vertino, Paula M, Emory University Zwick, Michael, Emory University Epstein, Michael, Emory University Cutler, David J, Emory University

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