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Mortality and morbidity due to infants being born preterm remains one of the greatest health burdens facing society. Many factors influence the risk for spontaneous preterm birth, both genetic and environmental. To date, generally effective interventions to prevent preterm birth have not been identified. In this paper, we discuss the impact of preterm birth and the challenges that have limited insights so far. New advances in genomics, systems biology, and population/personalized medicine show promise in overcoming previous barriers and leading to new insights and preventive treatments.

Jaundice affects almost all neonates in their first days of life and is caused by the accumulation of bilirubin. Although the core biochemistry of bilirubin metabolism is well understood, it is not clear why some neonates experience more severe jaundice and require treatment with phototherapy. Here, we present the first genome-wide association study of neonatal jaundice in nearly 30,000 parent-offspring trios from Norway (cases ≈ 2,000), with the most compelling locus located in theUGT1A*genes region. The alternate allele of a common missense variant affecting the sequence ofUGT1A4(with low affinity for bilirubin) reduces the susceptibility to jaundice five-fold (rs6755571, A allele OR = 0.2, p-value = 2.7 × 10−55, frequency = 6.4%). eQTL colocalization analyses indicate that the association may be driven by regulation ofUGT1A1(the primary bilirubin conjugation enzyme) in the intestines, but not in the liver. The analysis of the parental transmitted and non-transmitted alleles in 23,000 parent-offspring trios captures known effects of maternal-fetal ABO blood group incompatibility on neonatal jaundice. Our results reveal marked differences in the pathways involved in neonatal jaundice compared to those regulating bilirubin levels in adults, suggesting a distinct biological basis.

Preterm birth (PTB), or birth that occurs earlier than 37 weeks of gestational age, is a major contributor to infant mortality and neonatal hospitalization. Mutations in the mitochondrial genome (mtDNA) have been linked to various rare mitochondrial disorders, and may be a contributing factor in PTB given that maternal genetic factors have been strongly linked to PTB. However, to date, no study has found a conclusive connection between a particular mtDNA variant and PTB. Given the high mtDNA copy number per cell, an automated pipeline was developed for detecting mtDNA variants using low-pass whole genome sequencing (lcWGS) data. The pipeline was first validated against samples of known heteroplasmy, and then applied to 929 samples from a PTB cohort from diverse ethnic backgrounds with an average gestational age of 27.18 weeks (range: 21-30). Our new pipeline successfully identified haplogroups and a large number of mtDNA variants in this large PTB cohort, including 8 samples carrying known pathogenic variants and 47 samples carrying rare mtDNA variants. These results confirm that lcWGS can be utilized to reliably identify mtDNA variants. These mtDNA variants may make a contribution toward preterm birth in a small proportion of live births. This article is protected by copyright. All rights reserved.

In mammals, the placenta mediates maternal–fetal nutrient and waste exchange and acts in an immunomodulatory way to facilitate maternal–fetal tolerance. The placenta is highly diverse across mammalian species, yet the molecular mechanisms that distinguish the placenta of human from other mammals are not fully understood. Using an interspecies transcriptomic comparison of human, macaque, and mouse late-gestation placentae, we identified hundreds of genes with lineage-specific expression—including dozens that are placentally enriched and potentially related to pregnancy. We further annotated the enhancers for different human tissues using epigenomic data and demonstrate that the placenta and chorion are unique in that their enhancers display the least conservation. We identified numerous lineage-specific human placental enhancers and found they highly overlap with specific families of endogenous retroviruses (ERVs), including MER21A, MER41A/B, and MER39B that were previously linked to immune response and placental function. Among these ERV families, we further demonstrate that MER41A/B insertions create dozens of lineage-specific serum response factor-binding loci in human, including one adjacent to FBN2, a placenta-specific gene with increased expression in humans that produces the peptide hormone placensin to stimulate glucose secretion and trophoblast invasion. Overall, our results demonstrate the prevalence of lineage-specific placental enhancers which are frequently associated with ERV insertions and likely facilitate the lineage-specific evolution of the mammalian placenta.

Gene regulation is essential to placental function and fetal development. We report a genome-scale transcriptional regulatory network (TRN) of the human placenta built using digital genomic footprinting and transcriptomic data. We integrated 475 transcriptomes and 12 DNase hypersensitivity datasets from placental samples to globally and quantitatively map transcription factor (TF)-target gene interactions. In an independent dataset, the TRN model predicted target gene expression with an out of sample R2 value greater than 0.25 for 74% of target genes. We performed siRNA knockdowns of 4 TFs and achieved concordance between the predicted gene targets in our TRN and differences in expression of knockdowns with an accuracy of >0.7 for 3 of the 4 TFs. Our final model contained 113,158 interactions across 391 TFs and 7,712 target genes and is publicly available. We identified six TFs which were significantly enriched as regulators for genes previously associated with preterm birth.

We performed an observational cohort study to assess associations between genetic factors of dengue fever (DF) severity in children in the Dominican Republic. A total of 488 participants had serologically confirmed DF. We replicated the association between the IFIH1 gene (rs1990760) and severe DF (n = 80/488, p = 0.006) and identified novel associations needing further investigation.

Preterm birth contributes significantly to neonatal mortality and morbidity. Despite its global significance, there has only been limited progress in preventing preterm birth. Spontaneous preterm birth (sPTB) results from a wide variety of pathological processes. Although many non-genetic risk factors influence the timing of gestation and labor, compelling evidence supports the role of substantial genetic and epigenetic influences and their interactions with the environment contributing to sPTB. To investigate a common and complex disease such as sPTB, various approaches such as genome-wide association studies, whole-exome sequencing, transcriptomics, and integrative approaches combining these with other 'omics studies have been used. However, many of these studies were typically small or focused on a single ethnicity or geographic region with limited data, particularly in populations at high risk for sPTB, or lacked a robust replication. These studies found many genes involved in the inflammation and immunity-related pathways that may affect sPTB. Recent studies also suggest the role of epigenetic modifications of gene expression by the environmental signals as a potential contributor to the risk of sPTB. Future genetic studies of sPTB should continue to consider the contributions of both maternal and fetal genomes as well as their interaction with the environment.

BackgroundC-reactive protein (CRP) is an acute-phase marker of inflammation. Previous epidemiological studies have associated elevated maternal CRP levels during pregnancy with preterm birth risk and lower birth weight. However, the causal relationships behind these observed associations are not clear.Methods and FindingsWe utilized phenotype and genotype data on 10,734 mother/child pairs of European ancestry collected from six birth cohorts. We performed two-sample multivariate Mendelian Randomization (MR) using maternal non-transmitted alleles to interrogate the causal effect of maternal CRP on gestational duration and birth weight. Based on the non-transmitted alleles of 55 CRP associated single nucleotide polymorphisms (SNPs), a unit increase in log-transformed maternal CRP level was associated with a reduction of 1.58 days (95% CI: 0.23, 2.94, P = 0.022) in gestational duration and a reduction of 76.3g (95% CI: 18.2, 134.4, P = 0.010) in birth weight. The magnitude of the association between genetically increased CRP and birth weight was reduced after adjusting for gestational age. Utilizing the effect estimates of CRP-associated SNPs on birth weight from the UK Biobank genome-wide association (GWA) summary results, our results suggested one unit of genetically increased maternal CRP was associated with a decrease of 50.1g (95% CI: 24.7, 75.5, P = 9.6E-5) of birth weight (unadjusted by gestational age). We validated the results using a single genetic variant (rs2794520) near the CRP gene, which is less prone to horizontal pleiotropy bias.ConclusionsIncreased maternal CRP levels appear to causally reduce gestational duration and birth weight. The effect of maternal CRP on birth weight is partially due to its effect on gestational duration. The estimated causal effect sizes are consistent with previous epidemiological reports and this triangulation increases confidence in these results being causal.

BACKGROUND: Pain control in infants is an important clinical concern, with potential long-term adverse neurodevelopmental effects. Intravenous morphine is routinely administered for post-operative pain management; however, its dose-concentration-response relationship in neonates and infants has not been well characterized. Although the current literature provides dosing guidelines for the average infant, it fails to control for the large unexplained variability in morphine clearance and response in individual patients. Bayesian estimation can be used to control for some of this variability. The authors aimed to evaluate morphine pharmacokinetics and exposure in critically ill neonates and infants receiving standard of care morphine therapy and compare a population-based approach to the model-informed Bayesian techniques. METHODS: The pharmacokinetics and exposure of morphine and its active metabolites were evaluated in a prospective opportunistic pharmacokinetic study using 221 discarded blood samples from 57 critically ill neonates and infants in the neonatal intensive care unit. Thereafter, a population-based pharmacokinetic model was compared to a Bayesian adaptive control strategy to predict an individual’s pharmacokinetic profile and morphine exposure over time. RESULTS: Among the critically ill neonates and infants, morphine clearance showed substantial variability with a 40-fold range (i.e., 2.2 to 87.1, mean 23.7 L/h/70 kg). Compared to the observed morphine concentrations, the population-model based predictions had an R(2) of 0.13 while the model-based Bayesian predictions had an R(2) of 0.61. CONCLUSION: Model-informed Bayesian estimation is a better predictor of morphine exposure than pharmacokinetic models alone in critically ill neonates and infants. A large variability was also identified in morphine clearance. A further study is warranted to elucidate the predictive covariates and precision dosing strategies that use morphine concentration and pain scores as feedbacks.

Recent revolutionary advances at the intersection of medicine, omics, data sciences, computing, epidemiology, and related technologies inspire us to ponder their impact on health. Their potential impact is particularly germane to the biology of pregnancy and perinatal medicine, where limited improvement in health outcomes for women and children has remained a global challenge. We assembled a group of experts to establish a Pregnancy Think Tank to discuss a broad spectrum of major gestational disorders and adverse pregnancy outcomes that affect maternal-infant lifelong health and should serve as targets for leveraging the many recent advances. This report reflects avenues for future effects that hold great potential in 3 major areas: developmental genomics, including the application of methodologies designed to bridge genotypes, physiology, and diseases, addressing vexing questions in early human development; gestational physiology, from immune tolerance to growth and the timing of parturition; and personalized and population medicine, focusing on amalgamating health record data and deep phenotypes to create broad knowledge that can be integrated into healthcare systems and drive discovery to address pregnancy-related disease and promote general health. We propose a series of questions reflecting development, systems biology, diseases, clinical approaches and tools, and population health, and a call for scientific action. Clearly, transdisciplinary science must advance and accelerate to address adverse pregnancy outcomes. Disciplines not traditionally involved in the reproductive sciences, such as computer science, engineering, mathematics, and pharmacology, should be engaged at the study design phase to optimize the information gathered and to identify and further evaluate potentially actionable therapeutic targets. Information sources should include noninvasive personalized sensors and monitors, alongside instructive “liquid biopsies” for noninvasive pregnancy assessment. Future research should also address the diversity of human cohorts in terms of geography, racial and ethnic distributions, and social and health disparities. Modern technologies, for both data-gathering and data-analyzing, make this possible at a scale that was previously unachievable. Finally, the psychosocial and economic environment in which pregnancy takes place must be considered to promote the health and wellness of communities worldwide.

Currently, there is no comprehensive framework to evaluate the evolutionary forces acting on genomic regions associated with human complex traits and contextualize the relationship between evolution and molecular function. Here, we develop an approach to test for signatures of diverse evolutionary forces on trait-associated genomic regions. We apply our method to regions associated with spontaneous preterm birth (sPTB), a complex disorder of global health concern. We find that sPTB-associated regions harbor diverse evolutionary signatures including conservation, excess population differentiation, accelerated evolution, and balanced polymorphism. Furthermore, we integrate evolutionary context with molecular evidence to hypothesize how these regions contribute to sPTB risk. Finally, we observe enrichment in signatures of diverse evolutionary forces in sPTB-associated regions compared to genomic background. By quantifying multiple evolutionary forces acting on sPTB-associated regions, our approach improves understanding of both functional roles and the mosaic of evolutionary forces acting on loci. Our work provides a blueprint for investigating evolutionary pressures on complex traits., There is a need for analytical frameworks to investigate the evolution of complex genetic traits. Here, the authors develop an approach to simultaneously evaluate different evolutionary signatures on trait-associated genetic variants for complex traits and apply it to study spontaneous preterm birth.

Preterm birth (PTB) is a major cause of neonatal mortality and morbidity, often triggered by chorioamnionitis or Intra-uterine Inflammation (IUI) with or without infection. Recently, there has been a strong association of Interleukin-1 (IL-1) with PTB. We hypothesized that IL-1 receptor-associated kinase 1 (IRAK1), a key signaling mediator in the TLR/IL1 pathway, plays a critical role in PTB. In human fetal membranes (FM) collected immediately after birth from women delivering preterm, phosphorylation of IRAK1 (pIRAK1) was significantly increased in all the layers of FM with chorioamnionitis, compared to no chorioamnionitis subjects. In a preterm rhesus macaque model of IUI given intra-amniotic LPS, induction of pIRAK1 and downstream pro-inflammatory signaling mediators were seen in the FM. In a PTB C57BL/6J mouse model of IUI given intra-uterine LPS, an IRAK1 inhibitor significantly decreased preterm birth and increased live birth in WT mice in a dose-dependent manner. Furthermore, IRAK1 knockout mice were protected from LPS induced preterm birth which were seen in WT controls. Activation of IRAK1 was maintained by K63 mediated ubiquitination in preterm FM of humans with chorioamnionitis, rhesus and mouse IUI model. Mechanistically, IRAK1-induced preterm birth in the mouse model of IUI by upregulating expression of COX-2. Thus, our data from human, Rhesus and mouse demonstrates a critical role IRAK1 in IUI and inflammation associated PTB and suggest it as potential therapeutic target in IUI induced preterm birth.

Purpose Clinicians and researchers must contextualize a patient’s genetic variants against population-based references with detailed phenotyping. We sought to establish globally scalable technology, policy, and procedures for sharing biosamples and associated genomic and phenotypic data on broadly consented cohorts, across sites of care. Methods Three of the nation’s leading children’s hospitals launched the Genomic Research and Innovation Network (GRIN), with federated information technology infrastructure, harmonized biobanking protocols, and material transfer agreements. Pilot studies in epilepsy and short stature were completed to design and test the collaboration model. Results Harmonized, broadly consented institutional review board (IRB) protocols were approved and used for biobank enrollment, creating ever-expanding, compatible biobanks. An open source federated query infrastructure was established over genotype–phenotype databases at the three hospitals. Investigators securely access the GRIN platform for prep to research queries, receiving aggregate counts of patients with particular phenotypes or genotypes in each biobank. With proper approvals, de-identified data is exported to a shared analytic workspace. Investigators at all sites enthusiastically collaborated on the pilot studies, resulting in multiple publications. Investigators have also begun to successfully utilize the infrastructure for grant applications. Conclusions The GRIN collaboration establishes the technology, policy, and procedures for a scalable genomic research network.

Cis-regulatory elements coordinate the regulation of their targeted genes’ expression. However, the joint measurement of cis-regulatory elements’ activities and their interactions in spatial proximity is limited by the current sequencing approaches. We describe a method, NOMe-HiC, which simultaneously captures single nucleotide polymorphisms, DNA methylation, chromatin accessibility (GpC methyltransferase footprints), and chromosome conformation changes from the same DNA molecule, together with the transcriptome, in a single assay. NOMe-HiC shows high concordance with state-of-the-art mono-omic assays across different molecular measurements and reveals coordinated chromatin accessibility at distal genomic segments in spatial proximity and novel types of long-range allele-specific chromatin accessibility.

The genetic basis of phenotypic variation across populations has not been well explained for most traits. Several factors may cause disparities, from variation in environments to divergent population genetic structure. We hypothesized that a population-level polygenic risk score (PRS) can explain phenotypic variation among geographic populations based solely on risk allele frequencies. We applied a population-specific PRS (psPRS) to 26 populations from the 1000 Genomes to four phenotypes: lactase persistence (LP), melanoma, multiple sclerosis (MS) and height. Our models assumed additive genetic architecture among the polymorphisms in the psPRSs, as is convention. Linear psPRSs explained a significant proportion of trait variance ranging from 0.32 for height in men to 0.88 for melanoma. The best models for LP and height were linear, while those for melanoma and MS were nonlinear. As not all variants in a PRS may confer similar, or even any, risk among diverse populations, we also filtered out SNPs to assess whether variance explained was improved using psPRSs with fewer SNPs. Variance explained usually improved with fewer SNPs in the psPRS and was as high as 0.99 for height in men using only 548 of the initial 4208 SNPs. That reducing SNPs improves psPRSs performance may indicate that missing heritability is partially due to complex architecture that does not mandate additivity, undiscovered variants or spurious associations in the databases. We demonstrated that PRS-based analyses can be used across diverse populations and phenotypes for population prediction and that these comparisons can identify the universal risk variants. Supplementary Information The online version contains supplementary material available at 10.1186/s40246-021-00370-z.

Objective: To establish if low maternal selenium (Se) was associated with sPTB in women with recurrent sPTB and identify genetic link with maternal Se levels. Design: Nested case-control study. Setting: Tertiary Maternity Hospital. Population: Plasma and whole blood from pregnant women with history of early sPTB/PPROM < 34 +0 and European ancestry were obtained at 20 weeks (range 15–24 weeks). ‘Cases’ were recurrent PTB/PPROM < 34 +0 weeks and term (≥37 +0) deliveries were classified as ‘high-risk controls.’ Women with previous term births and index birth ≥ 39 weeks were ‘low-risk controls’. Methods: Maternal plasma Se measured by ICP-MS was used as a continuous phenotype in a GWAS analysis. Se was added to a logistic regression model using PTB predictor variables. Main outcome measures: Maternal Se concentration, recurrent early sPTB/PPROM. Results: 53/177 high-risk women had a recurrent sPTB/PPROM < 34 +0weeks and were 2.7 times more likely to have a Se level < 83.3 ppm at 20weeks of pregnancy compared with low-risk term controls (n = 179), (RR 2.7, 95%CI 1.5–4.8; p =.001). One SNP from a non-coding region (FOXN3 intron variant, rs55793422) reached genome-wide significance level (p = 3.73E −08). Targeted analysis of Se gene variant did not show difference between preterm and term births. (χ 2 test, OR = 0.95; 95%CI = 0.59–1.56; p = 0.82). When Se levels were added to a clinical prediction model, only an additional 5% of cases (n = 3) and 0.6% (n = 1) of controls were correctly identified. Conclusions: Low plasma Se is associated with sPTB risk but is not sufficiently predictive at individual patient level. We did not find a genetic association between maternal Se levels and Se-related genes.

The first positive genome-wide association study on gestational length and preterm delivery showed the involvement of an Se metabolism gene. In the present study, we examine the association between maternal intake of Se and Se status with gestational length and preterm delivery in 72 025 women with singleton live births from the population-based, prospective Norwegian Mother, Father and Child Cohort Study (MoBa). A self-reported, semi-quantitative FFQ answered in pregnancy week 22 was used to estimate Se intake during the first half of pregnancy. Associations were analysed with adjusted linear and Cox regressions. Se status was assessed in whole blood collected in gestational week 17 (n 2637). Median dietary Se intake was 53 (interquartile range (IQR) 44–62) µg/d, supplements provided additionally 50 (IQR 30–75) µg/d for supplement users (n 23 409). Maternal dietary Se intake was significantly associated with prolonged gestational length (β per sd = 0·25, 95 % CI, 0·07, 0·43) and decreased risk of preterm delivery (n 3618, hazard ratio per sd = 0·92, 95 % CI, 0·87, 0·98). Neither Se intake from supplements nor maternal blood Se status was associated with gestational length or preterm delivery. Hence, the present study showed that maternal dietary Se intake but not intake of Se-containing supplements, during the first half of pregnancy was significantly associated with decreased risk of preterm delivery. Further investigations, preferably in the form of a large randomised controlled trial, are needed to elucidate the impact of Se on pregnancy duration.

The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P = 3.96 × 10−14). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality., Gestational duration depends on both maternal and fetal genetic influences. Here, the authors perform a fetal genome-wide association meta-analysis and find that a locus on 2q13 is associated with pregnancy duration and further show that the lead SNP rs7594852 changes the binding properties of transcriptional repressor HIC1.

Background Exposure to particulate matter, particularly with aerodynamic diameter Methods Exposure to PM2.5 in each trimester and for each gestational week was determined using data from 57 Environmental Protection Agency network monitoring stations across the state of Ohio. We restricted the data to 224,921 singleton live births, with a gestational age of 20–42 weeks, no genetic disorders or congenital abnormalities, and who had home addresses within a 10 km radius of any PM2.5 monitoring station. We estimated odds ratios of SGA using Generalized Linear Models (GLMs) and Distributed Lag Models (DLMs), and adjustment for maternal age, race, education, parity, body mass index, insurance type, tobacco use, prenatal care initiation, birth year, season of birth, and sex of the baby. Results Mean PM2.5 levels during the entire pregnancy were 13.03 µg/m3 with a standard deviation of 1.57 µg/m3. Covariates adjusted odds ratios and 95% confidence intervals of a 10 µg/m3 increase in PM2.5 levels with a 10 km buffer radius for SGA and trimesters modeled separately were 0.94 (0.88, 1.00) for the first trimester, 0.93 (0.86, 1.00) for the second trimester, 1.07 (1.00, 1.15) for the third trimester, and 0.92 (0.81, 1.06) for the entire pregnancy. When a 5 km buffer radius was used, adjusted odds ratios and 95% confidence intervals for SGA were 0.97 (0.89, 1.05) for the first trimester, 0.96 (0.88, 1.05) for the second trimester, 1.09 (1.02, 1.17) for the third trimester, and 0.99 (0.85, 1.14) for the overall pregnancy, indicating sensitivity to buffer choice. DLMs showed gestational weeks 30–35 to be a particular window of vulnerability. Conclusion Increasing exposure to PM2.5 during the third trimester of pregnancy was associated with a small increase in risk of SGA in this population-based study. Selection of a buffer radius significantly impacted our results in the first trimester, but not in the third trimester.

The peripartum period is considered a sensitive period where adverse maternal exposures can result in long-term negative consequences for both mother and offspring, including the development of neuropsychiatric disorders. Risk factors linked to the emergence of affective dysregulation in the maternal-infant dyad have been extensively studied. Exposure to psychosocial stress during pregnancy has consistently emerged as one of the strongest predictors. Several rodent models have been created to explore this association; however, these models rely on the use of physical stressors or a limited number of psychosocial stressors presented in a repetitive fashion, which do not accurately capture the type, intensity, and frequency of stressors experienced by women. To overcome these limitations, a chronic psychosocial stress (CGS) paradigm was generated that employs various psychosocial insults of different intensity presented in an unpredictable fashion. The manuscript describes this novel CGS paradigm where pregnant female mice, from gestational day 6.5 to 17.5, are exposed to various stressors during the day and overnight. Day stressors, two per day separated by a 2 h break, range from exposure to foreign objects or predator odor to frequent changes in bedding, removal of bedding, and cage tilting. Overnight stressors include continuous light exposure, changing cage mates, or wetting bedding. We have previously shown that exposure to CGS results in the development of maternal neuroendocrine and behavioral abnormalities, including increased stress reactivity, the emergence of fragmented maternal care patterns, anhedonia, and anxiety-related behaviors, core features of women suffering from perinatal mood and anxiety disorders. This CGS model, therefore, becomes a unique tool that can be used to elucidate molecular defects underlying maternal affective dysregulation, as well as trans-placental mechanisms that impact fetal neurodevelopment and result in negative long-term behavioral consequences in the offspring.

Heat shock proteins are involved in the response to stress including activation of the immune response. Elevated circulating heat shock proteins are associated with spontaneous preterm birth (SPTB). Intracellular heat shock proteins act as multifunctional molecular chaperones that regulate activity of nuclear hormone receptors. Since SPTB has a significant genetic predisposition, our objective was to identify genetic and transcriptomic evidence of heat shock proteins and nuclear hormone receptors that may affect risk for SPTB. We investigated all 97 genes encoding members of the heat shock protein families and all 49 genes encoding nuclear hormone receptors for their potential role in SPTB susceptibility. We used multiple genetic and genomic datasets including genome-wide association studies (GWASs), whole-exome sequencing (WES), and placental transcriptomics to identify SPTB predisposing factors from the mother, infant, and placenta. There were multiple associations of heat shock protein and nuclear hormone receptor genes with SPTB. Several orthogonal datasets supported roles for SEC63, HSPA1L, SACS, RORA, and AR in susceptibility to SPTB. We propose that suppression of specific heat shock proteins promotes maintenance of pregnancy, whereas activation of specific heat shock protein mediated signaling may disturb maternal–fetal tolerance and promote labor.

The successful establishment, maintenance, and completion of pregnancy are essential for human development and survival. A series of structural and physiologic changes in the mother and fetus ensue, including implantation of the developing embryo into the endometrium; its avoidance of immunologic rejection by the maternal immune system; adaptation of the maternal uterus to sustain a pregnancy; and specific changes in maternal physiology to meet the nutritional, metabolic, and physical needs of the growing conceptus. Moreover, the duration of gestation must be optimized to ensure survival of both the mother and fetus. In this chapter, we provide an overview of these stages of pregnancy required to deliver the human newborn at term or lead to adverse pregnancy outcomes, such as preterm birth, preeclampsia, and growth restriction.

Cis-regulatory elements (CREs) play instrumental roles in the regulation of mammalian gene expression. Sets of transcriptional factors bring together multiple CREs, which can be up to megabases away, to initiate and maintain the gene expression. How to measure the activity of CREs and their coordination with the genetic variants over large genomic distances to regulate gene expression is the central question for regulatory genomics, which is still limited by the current sequencing approaches. We report a method, TAGMe-seq, which simultaneously captures the single nucleotide polymorphisms (SNPs), chromosome conformation, DNA methylation, and GpC methyltransferase footprints from a single molecule, together with transcriptome in the same assay.To demonstrate the performance of TAGMe-seq, we applied it to the IMR-90 and GM12878 cell lines, both of which have been comprehensively profiled publically. TAGMe-seq showed high concordances with the state-of-art mono-omics assays across all the molecular measurements at the same cell types. We next asked if the genomic regions linearly separated but positioned proximity in space would have coordinated footprint status. We analyzed the GCH (H=A, C, or T) methyltransferase footprint on TAGMe-seq reads separated in chromatin loop anchors. Indeed, the GCH methyltransferase footprint in TAGMe-seq read pairs mapping to separated loop anchors showed a significantly higher correlation than that in the shuffled read pairs from the same genomic regions. To further demonstrate the utility of TAGMe-seq, we utilized it to analyze the long-range (>1kb) allele-specific GpC methyltransferase footprint. We separated TAGMe-seq reads into two groups by their parent-of-origin at the heterozygous SNPs (SNP anchors). Naturally, the other ends of the read pairs were also separated into two alleles, even though they are not overlapped with the SNPs and mapped over large genomic distances (non-SNP anchors). Thus, we are able to analyze the long-range allele-specific GCH methyltransferase footprint. We identified three groups of allele-specific footprint loci based on their differences of GCH accessibility between the two alleles at both anchors, or only at SNP anchors, or only at non-SNP anchors, which showed distinct enrichment levels of TF binding. Overall, combining multiple assays in TAGMe-seq allowed us to uncover the coordinated GpC methyltransferase footprint and long-range allele-specific footprint at genomic regions that are far away in linear DNA sequences but spatially close in the nucleus, which will eventually pave the road to dissect the mechanisms of gene-regulatory aberrations in complex diseases, such as cancer. Citation Format: Hailu Fu, Haizi Zheng, Louis J. Muglia, Li Wang, Yaping Liu. Simultaneous profiling of genetic variants, 3D genome, GpC methyltransferase footprints, DNA methylation, and transcriptome in a single assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5797.

Eutherian mammals have characteristic lengths of gestation that are key for reproductive success, but relatively little is known about the processes that determine the timing of parturition, the process of birth, and how they are coordinated with fetal developmental programs. This issue remains one of biology's great unsolved mysteries and has significant clinical relevance because preterm birth is the leading cause of infant and under 5 year old child mortality worldwide. Here, we consider the evolutionary influences and potential signaling mechanisms that maintain or end pregnancy in eutherian mammals and use this knowledge to formulate general theoretical evolutionary models. These models can be tested through evolutionary species comparisons, studies of experimental manipulation of gestation period and birth timing, and human clinical studies. Understanding how gestation time and parturition are determined will shed light on this fundamental biological process and improve human health through the development of therapies to prevent preterm birth.

High maternal investment in pregnancy and the perinatal period are prominent features of eutherian reproduction. Viviparity increases offspring survival, favoring high maternal prenatal investment. Matrotrophy through the placenta reduces maternal investment at early pregnancy, allowing the mother to abort embryos of subpar quality, therefore reducing resources wastage. On the other hand, intimate maternal-fetal interplay enables the fetus to manipulate maternal physiology to acquire more resources. This parent-offspring conflict likely drives the evolution of eutherian placentation, which is facilitated by the endogenous retroviruses (ERVs), ancient retroviruses that invaded host genome millions of years ago. ERVs bring new genes and novel regulatory elements into host genome, contribute to maternal-fetal tolerance, placenta-specific cell type formation, trophoblast gene expression network rewiring, and the establishment of imprinting. However, retroviruses/ERVs can function as infectious pathogens that interfere with host immune and inflammation pathways and cause genomic instability. In addition, ERVs coopted for host function may contribute to pathogenesis during infections due to their susceptibility to mechanisms activated by the invading pathogens. ERVs have been implicated in multiple perinatal adverse outcomes, therefore, eutherians must have evolved control mechanisms to regulate their function. Here we propose the TRIM family as an important participant of host antiviral defense and a likely candidate that mediates the coevolution of ERVs and their eutherian host. TRIMs have been shown to interact with retroviruses during each step of the infectious cycle. Understanding TRIMs' role in ERV regulation in the placenta may provide insight to both the physiology and pathology of eutherian reproduction.