Doctor of Philosophy

dissertationSpontaneous preterm birth (SPTB) is defined as birth before 37 completed weeks gestation that is not secondary to iatrogenic intervention. SPTB is both a pressing personal and public health issue that is not well understood. Previous studies have shown genetics as an important factor to SPTB. Here I present my PhD work on genetic analyses of SPTB. I dissected the problem with: (1) candidate gene, (2) quantitative genetics, and (3) genome-wide approaches. In Chapter 1, I explore why published candidate gene studies are inconsistent with each other. Allele frequency difference across populations provides one reason. I conducted a meta-analysis on the single nucleotide polymorphism (SNP) rs1800795, located in the promoter region of interleukin-6. With population stratification, I unmasked the signal showing that the CC genotype is protective against PTB in women of European descent. This also highlights how positive genetic signals can become obscured when the population structure is not controlled for. In Chapter 2, I use quantitative genetic approaches to decompose the etiologies of SPTB with massive data from the Utah Population Database. A generation effect, which confounds the heritability estimate, was discovered. I then utilized a sibling analysis and partitioned components contributing to the phenotypic variance of SPTB: iv heritability (13.33%), dominance genetic (11.12%), maternal effect (15.23%), and individual environment (60.33%). These findings shed light on the architecture of SPTB pathogenesis and quantify the maternal and fetal contribution to SPTB. In Chapter 3, I perform an unbiased genome-wide association study for SPTB on 22 autosomal chromosomes. The data, which contain cases and controls collected by the Danish National Birth Cohort, were acquired from the National Center for Biotechnology Information Genotypes and Phenotypes Database. No SNP reached genome-wide significance. Although negative, the result provides proof of principle regarding the relatively low heritability of SPTB. Finally, I address insights learned from these analyses that may help guide future SPTB research and may be applicable to other human genetic studies. With these lessons, progress can be made in understanding the genetics of SPTB

Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations

International audienceCongenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most frequent birth defects and represent the most common cause of chronic kidney disease in the first three decades of life. Despite the discovery of dozens of monogenic causes of CA-KUT, most pathogenic pathways remain elusive. We performed whole-exome sequencing (WES) in 551 individuals with CAKUT and identified a heterozygous de novo stop-gain variant in ZMYM2 in two different families with CAKUT. Through collaboration, we identified in total 14 different heterozygous loss-of-function mutations in ZMYM2 in 15 unrelated families. Most mutations occurred de novo, indicating possible interference with reproductive function. Human disease features are replicated in X. tropicalis larvae with morpho-lino knockdowns, in which expression of truncated ZMYM2 proteins, based on individual mutations, failed to rescue renal and cranio-facial defects. Moreover, heterozygous Zmym2-deficient mice recapitulated features of CAKUT with high penetrance. The ZMYM2 protein is a component of a transcriptional corepressor complex recently linked to the silencing of developmentally regulated endoge-nous retrovirus elements. Using protein-protein interaction assays, we show that ZMYM2 interacts with additional epigenetic silencing complexes, as well as confirming that it binds to FOXP1, a transcription factor that has also been linked to CAKUT. In summary, our findings establish that loss-of-function mutations of ZMYM2, and potentially that of other proteins in its interactome, as causes of human CAKUT, offering new routes for studying the pathogenesis of the disorder

First M87 Event Horizon Telescope Results. II. Array and Instrumentation

The Event Horizon Telescope (EHT) is a very long baseline interferometry (VLBI) array that comprises millimeter- and submillimeter-wavelength telescopes separated by distances comparable to the diameter of the Earth. At a nominal operating wavelength of similar to 1.3 mm, EHT angular resolution (lambda/D) is similar to 25 mu as, which is sufficient to resolve nearby supermassive black hole candidates on spatial and temporal scales that correspond to their event horizons. With this capability, the EHT scientific goals are to probe general relativistic effects in the strong-field regime and to study accretion and relativistic jet formation near the black hole boundary. In this Letter we describe the system design of the EHT, detail the technology and instrumentation that enable observations, and provide measures of its performance. Meeting the EHT science objectives has required several key developments that have facilitated the robust extension of the VLBI technique to EHT observing wavelengths and the production of instrumentation that can be deployed on a heterogeneous array of existing telescopes and facilities. To meet sensitivity requirements, high-bandwidth digital systems were developed that process data at rates of 64. gigabit s(-1), exceeding those of currently operating cm-wavelength VLBI arrays by more than an order of magnitude. Associated improvements include the development of phasing systems at array facilities, new receiver installation at several sites, and the deployment of hydrogen maser frequency standards to ensure coherent data capture across the array. These efforts led to the coordination and execution of the first Global EHT observations in 2017 April, and to event-horizon-scale imaging of the supermassive black hole candidate in M87

Event Horizon Telescope imaging of the archetypal blazar 3C 279 at an extreme 20 microarcsecond resolution

3C 279 is an archetypal blazar with a prominent radio jet that show broadband flux density variability across the entire electromagnetic spectrum. We use an ultra-high angular resolution technique - global Very Long Baseline Interferometry (VLBI) at 1.3 mm (230 GHz) - to resolve the innermost jet of 3C 279 in order to study its fine-scale morphology close to the jet base where highly variable gamma -ray emission is thought to originate, according to various models. The source was observed during four days in April 2017 with the Event Horizon Telescope at 230 GHz, including the phased Atacama Large Millimeter/submillimeter Array (ALMA), at an angular resolution of similar to 20 mu as (at a redshift of z=0.536 this corresponds to similar to 0.13 pc similar to 1700 Schwarzschild radii with a black hole mass M-BH=8x10(8) M-circle dot). Imaging and model-fitting techniques were applied to the data to parameterize the fine-scale source structure and its variation. We find a multicomponent inner jet morphology with the northernmost component elongated perpendicular to the direction of the jet, as imaged at longer wavelengths. The elongated nuclear structure is consistent on all four observing days and across different imaging methods and model-fitting techniques, and therefore appears robust. Owing to its compactness and brightness, we associate the northern nuclear structure as the VLBI "core". This morphology can be interpreted as either a broad resolved jet base or a spatially bent jet. We also find significant day-to-day variations in the closure phases, which appear most pronounced on the triangles with the longest baselines. Our analysis shows that this variation is related to a systematic change of the source structure. Two inner jet components move non-radially at apparent speeds of similar to 15 c and similar to 20 c (similar to 1.3 and similar to 1.7 mu as day(-1), respectively), which more strongly supports the scenario of traveling shocks or instabilities in a bent, possibly rotating jet. The observed apparent speeds are also coincident with the 3C 279 large-scale jet kinematics observed at longer (cm) wavelengths, suggesting no significant jet acceleration between the 1.3 mm core and the outer jet. The intrinsic brightness temperature of the jet components are less than or similar to 10(10) K, a magnitude or more lower than typical values seen at >= 7 mm wavelengths. The low brightness temperature and morphological complexity suggest that the core region of 3C 279 becomes optically thin at short (mm) wavelengths

3C 279 Event Horizon Telescope imaging

VizieR online Data Catalogue associated with article published in journal Astronomy & Astrophysics with title 'Event Horizon Telescope imaging of the archetypal blazar 3C 279 at an extreme 20 microarcsecond resolution.' (bibcode: 2020A&A...640A..69K