Genetic Variation in Recombination as a Risk Factor for Nondisjunction Pubblico
Hollis, NaTasha (2010)
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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