Human chromosome nondisjunction leads to a high frequency of aneuploidy. Nondisjunction is a leading cause of miscarriage, birth defects and mental retardation. Although nondisjunction is clinically important, little is known about the mechanisms and risk factors contributing to it. For years, trisomy 21, also known as Down Syndrome (DS), has been used as a model to study human nondisjunction. It has been shown that altered patterns of recombination and maternal age are risk factors for nondisjunction. The goal of the work presented in this proposal is to look at recombination patterns in the rest of the genome to determine if the altered patterns observed on chromosome 21 are due to cis-acting or trans-acting factors. Specifically, we will examine inter-individual variation in genome-wide recombination between DS probands and their siblings. We will look at two basic characteristics: (1) the number of genome-wide recombinant events and (2) location of recombinant events throughout the genome. The results of this research will offer insight into the cause(s) of altered recombination which is risk factor for human nondisjunction. Furthermore, the results will enhance our ability to tease apart the susceptibility for nondisjunction in humans into its individual influential factors. Once risk factors are identified, targeted treatment can be considered to assure proper chromosome segregation during meiosis. To accomplish the specific aims of the proposal, we will perform genome-wide SNP genotyping on probands and their families to determine their recombination profiles. The rates of recombination will be compared for three groups: probands, their siblings, and individuals from an unrelated control population. Through comparison of the three groups, we will be able to determine if the rates of recombination are the same or different between siblings. If they are different, then the effect in recombination may be specific to each individual. However, if they are the same, it may be due to a maternal effect shared by all offspring of a woman. The research proposed in the training plan is important because it will provide an understanding of the causes of nondisjunction. Nondisjunction is the leading cause of pregnancy loss, mental retardation and birth defects. As many women are waiting until later in age to have children, the risk for nondisjunction drastically increases;thus, this research will help to tease apart risk factors for human nondisjunction. Candidate: The candidate is a second year Ph.D. graduate student at Emory University. She received a B.S. in Biology from Xavier University in Louisiana in 2005. As an undergraduate, her grades were mainly As with a few Bs. Her grades as a graduate student have been seven As and four Bs. She was an academic scholarship recipient at Xavier University throughout her entire undergraduate years. She was a summer Post-Baccalaureate Research Education Program (PREP) student at the University of Alabama-Birmingham where her research examined the effect of ozone exposure on mitochondrial DNA damage and TNFa response in c57 mice. She has presented the results of her summer research at Annual Biomedical Research Conference for Minority Students (ABRCMS) and American Society for Microbiology (ASM) meetings. She was a McNair scholar from 2003 to 2005. Her goal is to become a genetic epidemiologist conducting research on diseases that are highly prevalent in African-Americans. This interdisciplinary field looks at both genetic and environmental factors and the interactions between them leading to various human diseases and traits. Sponsor and training environment: Dr. Stephanie Sherman is a full professor at the School of Medicine at Emory University. She received her baccalaureate degree from North Carolina State University and her Ph.D. from Indiana University. After a postdoctoral appointment at Edinburgh University, she was appointed an Assistant Professor at the University of Hawaii. She came to Emory University as an assistant professor in 1988. She has publications in several leading journals. She currently has 3 R01 grants, a P30 and a K12 grant. She has previously supervised 2 postdoctoral scholars and 9 graduate students. During the training period, the sponsor will interact with scientists from 10 departments in the college of medicine. She will be an excellent mentor for the applicant. The candidate will be expected to participate in standard activities for Ph.D. students such as journal clubs and weekly meetings. Necessary courses needed are available and Emory University has a world-renowned group of faculty in this field. According to the sponsor, the research environment at Emory University is one of the most interdisciplinary for a genetic epidemiologist. The laboratory is fully equipped with the necessary instrumentation to carry out the project and well established. The candidate will take courses in advanced statistics for analysis of her data. Research Project: Research in the sponsor's laboratory has focused on recombination patterns along the non-disjoined chromosome. In this application, the candidate proposes to examine genome-wide recombination among oocytes with non-disjoined chromosome 21. She will test the following hypothesis: """"""""altered recombination observed along the non-disjoined chromosome in oocytes with Ml and """"""""MIl"""""""" errors are dictated by trans-acting factors and, as such, influence the risk for non-disjunction"""""""". The project focuses on two basic characteristics: the number of genome-wide recombinant events and the location of recombinant events throughout the genome. The results of this research will offer insight into the cause(s) of altered recombination which is risk factor for human nondisjunction. Strengths of the application: The research project addresses a question that is significant for the health of minorities. With non-disjunction serving as the leading cause of pregnancy loss and, among infants, the leading genetic cause of mental retardation and birth defects, this project is important. The laboratory has built an unprecedented infrastructure to obtain population-based case and control data on infants with DS and their parents. The research plan is well written and attention has been paid to potential risks and confidentiality issues. The preliminary data collected suggest a high likelihood of success of the project. That there will be follow up studies on participating families is a good idea. The candidate has taken two courses in bioethics which are essential for this field. The environment and training program available to the candidate are excellent. Detailed information is provided about how mentors are selected and the expectations for them to continue in that role. It appears the department has put a lot of resources into providing mentors for graduate students. The letters of recommendation from the candidate's former and current institutions are strong and she has the necessary preparation and to excel in this program. Weaknesses of the application: Sections of the research proposal appear to have been written by the sponsor. The application lacks a detailed timeline. Overall Recommendation: The candidate has excellent grades as well as very good preparation and background as an undergraduate and graduate student. The reference letters are strong. She has the necessary package to excel as a pre-doctoral fellow.
