Browsing by Author "Hallgrímsson, Benedikt"

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    Adaptability and Function of the Placental Endocrine System
    (2020-06-08) Eaton, Malcolm Ellis; Cross, James C.; Hallgrímsson, Benedikt; De Bruyn, Raylene; Pittman, Quentin J.; Slater, Donna M.; Davidge, Sandra Thomas
    The placenta acts as the arbitrator for the exchange of nutrients and gases across the feto-maternal interface, ensuring that the fetus can grow, and the mother can remain healthy to deliver and nurture her offspring. The placenta achieves this by changing its structure and function throughout gestation. Failure to undergo these changes is a major cause of obstetric syndromes, intrauterine growth restriction and pre-term birth. These complications result in deleterious long-term outcomes for both fetus and mother and understanding the complex aetiology of these complications is fundamental to impacting lifelong health. One of the less well-studied ways that the placenta adapts is by secreting hormones that regulate maternal adaptations to pregnancy. Previous work in the Cross lab established that a family of 22 Prolactin-related hormone genes, termed the placenta Prolactin-related hormones (PPRH), that are specifically expressed from the mouse placenta regulate maternal adaptations to pregnancy. The mouse provided a model to study how the placenta adapted its structure and function to changes in the maternal environmental and PPRH levels. We first established the normal course of cell growth in the placenta to understand the timing of changes in trophoblast cells number and found evidence of cell hypertrophy and endoreduplication in addition to hyperplasia. We then challenged pregnancies with a maternal diet low in protein. We found that the normal course of cellular differentiation and growth was altered, but that these changes were adapting to preserve fetal growth. Interestingly, we found that male and female fetuses used different strategies. We then created a model that was haplo-deficient in PPRH genes and, to our surprise, fetuses were overgrown while mothers failed to gain weight late-term. Interpreting the expression patterns of individual hormone genes in the context of other placental knockouts helped us identify putative roles for several hormones and demonstrated that this locus is highly adaptable. Distinguishing the targets and functions of these hormones and separating between primary and secondary effects remains a topic of interest. In examining PPRH null mutants, we found that the size of the maternal liver, spleen and gut were altered, along with the gut microbiota. These results indicate that the placenta is a highly adaptable organ that changes in normal pregnancy and has mechanisms built in to mitigate impacts of environmental changes. By studying the changes over time, we reveal insights into how placenta-specific hormones regulate maternal physiology, placental function and fetal growth outcomes. There is still a great deal to learn about the placenta but increasing our understanding of this fascinating organ will contribute to the interpretation and treatment of obstetric syndromes.
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    Building generic anatomical models using virtual model cutting and iterative registration
    (BioMed Central, 2010-02-08) Xiao, Mei; Soh, Jung; Meruvia-Pastor, Oscar; Schmidt, Eric; Hallgrímsson, Benedikt; Sensen, Christoph W.
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    Computer-Assisted Diagnosis of Genetic Syndromes Using 3D Facial Surface Scans
    (2023-03-09) Bannister, Jordan J.; Forkert, Nils D.; Hallgrímsson, Benedikt; Lebel, Catherine; Bernier, Francois Paul J.
    Due to the complexity and rarity of genetic syndromes, one of the primary difficulties in treating afflicted patients is diagnosing their condition. Gene technologies have been a key tool to improve diagnosis rates, but genetic testing remains inaccurate, inaccessible, or expensive for many people. Computer-assisted facial phenotyping is a complementary strategy that makes use of inexpensive and widely available technologies. Many genetic syndromes are known to be associated with altered facial morphology, and clinical geneticists often make use of facial phenotype to inform diagnoses. The overarching objective of this research was to develop clinically useful image processing algorithms and machine learning models to improve computer-assisted facial phenotyping and syndrome diagnosis systems based on 3D facial surface images. First, a fully automated 3D facial landmarking algorithm was developed to prepare 3D facial surface scans for analysis without manual labor. Next, analyses comparing different 2D and 3D facial representations were performed to determine an optimal facial image acquisition strategy. Machine learning models of 3D facial morphology were then developed to identify abnormal and characteristically syndromic faces. Additionally, an analysis of non-syndromic facial morphology was performed to present quantitative information about facial sex differences to facial surgeons. The main contributions of this thesis are the automated 3D scan processing methods and normalizing flow framework for 3D facial shape modelling that provide the computational methods needed to create a complete and highly interpretable 3D face-based computer aided diagnosis system. Additionally, results from the subject-matched analysis of 2D and 3D facial representations are the first to empirically suggest that using 3D facial imaging instead of 2D photography improves the performance of face-based syndrome diagnosis systems. Finally, the analysis performed for facial surgeons demonstrates that the methods developed in this thesis are applicable to medical domains other than computer-assisted diagnosis.
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    Developmental constraint through negative pleiotropy in the zygomatic arch
    (2018-01-27) Percival, Christopher J; Green, Rebecca; Roseman, Charles C; Gatti, Daniel M; Morgan, Judith L; Murray, Stephen A; Donahue, Leah R; Mayeux, Jessica M; Pollard, K. M; Hua, Kunjie; Pomp, Daniel; Marcucio, Ralph; Hallgrímsson, Benedikt
    Abstract Background Previous analysis suggested that the relative contribution of individual bones to regional skull lengths differ between inbred mouse strains. If the negative correlation of adjacent bone lengths is associated with genetic variation in a heterogeneous population, it would be an example of negative pleiotropy, which occurs when a genetic factor leads to opposite effects in two phenotypes. Confirming negative pleiotropy and determining its basis may reveal important information about the maintenance of overall skull integration and developmental constraint on skull morphology. Results We identified negative correlations between the lengths of the frontal and parietal bones in the midline cranial vault as well as the zygomatic bone and zygomatic process of the maxilla, which contribute to the zygomatic arch. Through gene association mapping of a large heterogeneous population of Diversity Outbred (DO) mice, we identified a quantitative trait locus on chromosome 17 driving the antagonistic contribution of these two zygomatic arch bones to total zygomatic arch length. Candidate genes in this region were identified and real-time PCR of the maxillary processes of DO founder strain embryos indicated differences in the RNA expression levels for two of the candidate genes, Camkmt and Six2. Conclusions A genomic region underlying negative pleiotropy of two zygomatic arch bones was identified, which provides a mechanism for antagonism in component bone lengths while constraining overall zygomatic arch length. This type of mechanism may have led to variation in the contribution of individual bones to the zygomatic arch noted across mammals. Given that similar genetic and developmental mechanisms may underlie negative correlations in other parts of the skull, these results provide an important step toward understanding the developmental basis of evolutionary variation and constraint in skull morphology.
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    Estimating Cell Count and Distribution in Labeled Histological Samples Using Incremental Cell Search
    (2011-05-24) Meruvia-Pastor, Oscar E.; Soh, Jung; Schmidt, Eric J.; Boughner, Julia C.; Xiao, Mei; Jamniczky, Heather A.; Hallgrímsson, Benedikt; Sensen, Christoph W.
    Cell proliferation is critical to the outgrowth of biological structures including the face and limbs. This cellular process has traditionally been studied via sequential histological sampling of these tissues. The length and tedium of traditional sampling is a major impediment to analyzing the large datasets required to accurately model cellular processes. Computerized cell localization and quantification is critical for high-throughput morphometric analysis of developing embryonic tissues. We have developed the Incremental Cell Search (ICS), a novel software tool that expedites the analysis of relationships between morphological outgrowth and cell proliferation in embryonic tissues. Based on an estimated average cell size and stain color, ICS rapidly indicates the approximate location and amount of cells in histological images of labeled embryonic tissue and provides estimates of cell counts in regions with saturated fluorescence and blurred cell boundaries. This capacity opens the door to high-throughput 3D and 4D quantitative analyses of developmental patterns.
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    How Patterns of Craniofacial Variation Are Driven by Genetic Variation
    (2023-04-19) Aponte, Jose David; Hallgrímsson, Benedikt; Forkert, Nils; Roseman, Charles
    Craniofacial shape is extraordinarily diverse and highly heritable in humans. We often feel an intuition from facial presentation that allows us to guess the ethnicity, sex, and even syndromic conditions of people we see every day. These aspects of facial shape likely have a strong genetic basis, although it has proven difficult to elucidate exactly which genes contribute to this variation that we intuitively understand. This dissertation aims to better understand why it can be so difficult to unravel the genetic underpinnings of facial shape variation. It starts with an interactive atlas of syndromic facial shape that allows a user to visualize the range of craniofacial phenotypes observed in over 80 congenital syndromes across ages, sexes, and severities. I then delve into how well syndromes can be classified from measurements of facial shape using machine learning. The challenges in classifying syndromes then directly led me to compare non- syndromic and syndromic facial shape to test how morphologically and genetically unique craniofacial phenotypes can be. Finally, I turned to mice to compare the craniofacial variation associated with groups of genes to the craniofacial variation produced in mouse mutants of large effect. These studies in humans and mice have shown substantial overlap in morphology between non-syndromic and syndromic facial variation, suggesting that facial variation operates in a limited scope of dimensionality. Importantly, that variation has a quantifiable genomic basis that suggests that many developmental pathways jointly contribute to the patterns of craniofacial variation that we observe.
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    Micro-computed tomography-based phenotypic approaches in embryology: procedural artifacts on assessments of embryonic craniofacial growth and development
    (BioMed Central, 2010-02-17) Schmidt, Eric J.; Parsons, Trish E.; Jamniczky, Heather A.; Gitelman, Julian; Trpkov, Cvett; Boughner, Julia C.; Logan, C Cairine.; Sensen, Christoph W.; Hallgrímsson, Benedikt
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    Microarchitecture, but Not Bone Mechanical Properties, Is Rescued with Growth Hormone Treatment in a Mouse Model of Growth Hormone Deficiency
    (Hindawi Publishing Corporation, 2012-01-02) Kristensen, Erika; Hallgrímsson, Benedikt; Morck, Douglas W.; Boyd, Steven K.
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    Microarchitecture, but Not Bone Mechanical Properties, Is Rescued with Growth Hormone Treatment in a Mouse Model of Growth Hormone Deficiency
    (2012-03-13) Kristensen, Erika; Hallgrímsson, Benedikt; Morck, Douglas W.; Boyd, Steven K.
    Growth hormone (GH) deficiency is related to an increased fracture risk although it is not clear if this is due to compromised bone quality or a small bone size. We investigated the relationship between bone macrostructure, microarchitecture and mechanical properties in a GH-deficient (GHD) mouse model undergoing GH treatment commencing at an early (prepubertal) or late (postpubertal) time point. Microcomputed tomography images of the femur and L4 vertebra were obtained to quantify macrostructure and vertebral trabecular microarchitecture, and mechanical properties were determined using finite element analyses. In the GHD animals, bone macrostructure was 25 to 43% smaller as compared to the GH-sufficient (GHS) controls (). GHD animals had 20% and 19% reductions in bone volume ratio (BV/TV) and trabecular thickness (Tb.Th), respectively. Whole bone mechanical properties of the GHD mice were lower at the femur and vertebra (67% and 45% resp.) than the GHS controls (). Both early and late GH treatment partially recovered the bone macrostructure (15 to 32 % smaller than GHS controls) and the whole bone mechanical properties (24 to 43% larger than GHD animals) although there remained a sustained 27–52% net deficit compared to normal mice (). Importantly, early treatment with GH led to a recovery of BV/TV and Tb.Th with a concomitant improvement of trabecular mechanical properties. Therefore, the results suggest that GH treatment should start early, and that measurements of microarchitecture should be considered in the management of GHD.
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    Mobility at the Center of the Viking World
    (2020-04-23) Peschel, Emily M.; Katzenberg, Mary Anne; Dawson, Peter C.; Hallgrímsson, Benedikt; Wieser, Michael E.; Schillaci, Michael A.
    This dissertation examines migration at Gotland, an important island in Viking Age Scandinavia (750-1050 CE) that is widely recognized for its role in trade. Located off the southeast coast of Sweden in the Baltic Sea, Gotland connected western European and Eastern trade routes. Despite its economic importance, there has been little investigation into the political affiliation of this island. It is argued that Gotland was both independently ruled, and that it was a part of the Svear kingdom, a Swedish polity that ruled over the Baltic Sea. One step toward addressing the political identity of Gotland is to investigate mobility on the island. Although artifacts indicate trade occurred with much of the known world, the degree of migration to the island is not known. This project examines the degree of mobility of two skeletal populations from Gotland, Fröjel and Kopparsvik. Biological distance (biodistance) from cranial and dental nonmetric traits were used to assess gene flow between Gotlandic populations and among Scandinavian populations. Strontium isotope analysis was used to determine the geological origins of individuals from the Gotlandic populations. The dental biodistance results showed that Fröjel and Kopparsvik were biologically isolated from mainland Scandinavian populations. The cranial biodistance results, however, indicated a small biodistance between Kopparsvik and the Svear kingdom, while Fröjel remained isolated from biologcial interactions with the mainland populations. While dental nonmetric traits reflected the ancestral relationships among Scandinavian populations, cranial nonmetric traits indicated more recent changes to the population structure. These interpretations of migration on the island are corroborated by the increase in non-local individuals at the Kopparsvik cemetery throughout its use, as determined by strontium isotope analysis. While there were only local individuals interred at the cemetery during the earliest phase of use, there was an increase in nonlocal individuals throughout the latter half of the Viking Age. Gotland, therefore, saw increased Swedish presence throughout the Viking Age, which suggests an effort by the Svear kingdom to take advantage of trade on the island. Fröjel, however, remained isolated from gene flow and immigration, indicating that the Svear kingdom had limited authority on Gotland.