BioProject

Most human diseases and traits are complex polygenic traits, and multiple genetic and environmental interactions result in a given phenotype. During the last few years, we and others have taken the first steps to uncover some of the nuclear genomic and epigenomic mechanisms linked to both rare and common diseases and quantitative traits. Despite our collective initial optimism that genome-wide association studies (GWAS) would serve as the “Holy Grail” of genomic research, current results point to a relatively small contribution of nuclear genetic variants to the common perinatal disorders, such as preterm birth (PTB). Based on several lines of emerging evidence, it has been postulated that this may be due to a previously underestimated role for mitochondrial genomic variation in regulating expression of complex traits and modulating disease pathogenesis. Mitochondrial DNA (mtDNA) mutations have been implicated in regulating inflammatory responses. Interestingly, little is known about the role that mitochondrial genomic variation has on establishing risk for preterm birth. This is somewhat surprising based upon three converging fundamental properties of the mitochondrial genome and early human development. First, it is well-established that the mitochondrial organelles and genome are dynamic structures whose quantity and quality alter in response to cellular oxidative and metabolic demands. In placental mammals, the majority of common pregnancy disorders are associated with altered metabolism (gestational diabetes, fetal growth disorders) and oxidative stress (preeclampsia, intrauterine growth restriction, preterm delivery, and pregnancy loss). Second, human mtDNA is a 16 kb double stranded, circular molecule that displays an independent replication mechanism, has a high mutation rate, and is solely transmitted maternally. Moreover, most cells contain thousands of mitochondria, each with their own mutable genome. Hence, both mutant and wild-type mitochondrial genomes can co-exist in cells of the organism (heteroplasmy). Third, multiple exposures (e.g., cigarette smoke, oxidative stress, hypercholesterolemia) have been associated with significantly increased mtDNA damage and mitochondrial dysfunction. Tobacco exposure, hypertensive disorders, and maternal obesity are independent predictors of preterm birth. For several centuries we have understood that the microbiota of the genital tract can be altered in pregnancy, and that such alterations can be pathogenic with respect to maternal and perinatal mortality. With respect to PTB, common vaginal disorders such as bacterial vaginosis (BV) and pathogens such as Trichomonas vaginalis (TV) have been long-standing in their supposed association with preterm birth. However, meta-analyses and randomized, double-blinded, placebo control trials have actually demonstrated that treatment of such “infections” or microbial dysbioses may actually increase the rate of preterm birth. It has therefore been hypothesized that it is a combination of ascending microbes with an aberrant host inflammatory response which actually leads to PTB. Traditional microbiology has focused on the study of individual species as isolated units. However many, if not most, have never been successfully isolated as viable specimens for analysis, presumably because their growth is dependent upon a specific microenvironment that has not been, or cannot be, reproduced in the laboratory. Among those species that have been isolated, analyses of genetic makeup, gene expression patterns, and metabolic physiologies have rarely extended to inter-species interactions or microbe-host interactions. Advances in DNA sequencing technologies have created a new field of research, called metagenomics, allowing comprehensive examination of microbial communities of multiple different organisms, including non-cultivable organisms. Instead of examining the genome of an individual bacterial strain that has been grown in a laboratory, the metagenomic approach allows analysis of genetic material derived from complete microbial communities harvested from natural environments. We propose to employ a novel and innovative approach to investigate predisposition to risk for preterm birth by interrogating the interaction of maternal-fetal mitochondrial genomic variants in rendering genomic susceptibility to infection in association with preterm birth. We will provide an unparalleled level of multidisciplinary investigation with a metagenomics approach for the unbiased characterization of the microbiota, alongside whole mitochondrial genome sequencing for the detection of mtDNA variants and clinical parameters associated with PTB. With our transformative approach, we will test the hypothesis that mtDNA variation mediates susceptibility to both the phylogeny of the vaginal microbiome and aberrant inflammatory responses, resulting in preterm birth. Taken together, this study will provide unprecedented information about the complexity of the microbiome in its interactions with host mitochondrial variations and their association with PTB. Less...