POPULATION STRUCTURE OF GENETIC VARIATION IN PREGNANCY

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ABSTRACT OF RESEARCH PLAN The overall goal of Project I is to determine the extent and distribution of sequence variation in candidate genes in the maternal-placental-fetal (MPF) endocrine pathway of pregnancy and premature birth. Although the precise genetic factors that influence premature birth have not yet been identified, the importance of genetics is indicated by familial aggregation, differences in prevalence among racial/ethnic groups, and molecular genetic studies that have identified significant associations with DMA polymorphisms in candidate genes of parturition. Previous studies have shown large disparities in the prevalence of premature birth across racial/ethnic groups, likely due to both genetic and environmental factors. Project I will contrast patterns of variation in 16 candidate genes for each of three major racial/ethnic groups (African Americans, Hispanics of Mexican Origin, and non-Hispanic Whites). We will identify sequence variations (SNPs) and directly determine SNP haplotypes for each of three racial/ethnic groups by resequencing in haploid cell lines that separately contain maternal and paternal chromosomes (molecular haplotyping). The SNPs we identify in Project I will be genotyped in the 1,200 mother-child pairs by Core C for subsequent population genetic analyses. The specific aims are: Aim 1: Resequence 16 candidate genes in the maternalplacental- fetal (MPF) neuroendocrine pathway to identify and characterize the distribution of DMA sequence variations (SNPs) within and among samples of individuals representative of three local populations: African-American, Hispanic of Mexican origin, and non-Hispanic Whites. Aim 2: Model and test hypotheses about the structure of the variation in the 16 candidate genes to establish which alleles, which haplotypes, and which genotypes of which genes vary within and between which of the three racial/ethnic samples. The underlying causes of racial/ethnic disparities in the prevalence of premature birth in the United States are not well-understood. We and others have recently discovered significant racial/ethnic differences in the biology of the maternal-placental-fetal neuroendocrine system over the course of gestation. By determining the population structure of genetic variation in the three major racial/ethnic groups, this project will make an important contribution to our understanding of the extent to which the observed racial/ethnic differences in biology and clinical outcome (premature birth) reflect differences in genetic variation or differences that arise from altered expression of the same genes and variants as a consequence of racial/ethnic differences in environmental conditions/triggers.