Role of the STRA6 gene family in vertebrate development

Matthew-Wood syndrome is a rare human birth defect condition defined by the phenotypic constellation of clinical anophthalmia, diaphragmatic hernia, pulmonary hypoplasia and cardiac defects. Matthew-Wood syndrome has a high mortality rate, with most patients dying due to respiratory insufficiency as a consequence of pulmonary hypoplasia, within the first year of life. Mutations within STRA6 are causative for Matthew-Wood syndrome. STRA6 acts as a retinol transporter for retinol bound to its physiological carrier RBP4 allowing regulated entry of retinol into the cell. A mammalian model for Matthew-Wood syndrome was not found within the literature; however a morpholino knockdown of stra6 in the zebrafish did show phenotypic features consistent with those observed in human patients. The desire to create a mammalian model of Matthew-Wood syndrome drove the work contained within this thesis. Stra6-/- mice do not represent a model for Matthew-Wood syndrome with homozygous animals being viable, found in the expected ratio and demonstrating none of the developmental abnormalities observed in human patients. Retinal defects, cataracts and persistent hyperplastic primary vitereous affect the microphthalmic eye of Stra6-/- offspring of Stra6-/- mothers fed a retinoid-free diet from plug to birth indicating that Stra6 is required for normal eye development under low-retinoid stress. The disparity in phenotype between human Matthew-Wood patients and Stra6-/- mice may be the result of functional redundancy in the mouse between Stra6 and its paralogue, Stra6.2. Stra6.2 is well conserved through evolution and is found in diverse species, including the basal eumetazoan Trichoplax. STRA6.2 has become split across its resident chromosome with an associated break in gene synteny, in humans and great apes, causing most of the gene to no longer be transcribed. However a small portion of the gene, representing the final transmembrane domain and the C-terminal intracellular tail of the protein, remains expressed in human. stra6.2 is required for normal development in the zebrafish with stra6.2 morphants being phenotypically distinguishable from control injected embryos from the 10-somite stage by a larger head-tail distance indicating an axial extension defect. stra6.2 morphants also display microphthalmia, jaw malformation, shortened and curved body axis and retinal lamination defects. stra6.2 was found to be required to prevent an excess of retinoic acid resulting in an upregulation of retinoic acid-dependent gene expression through an increase in RA synthesis by Raldh enzymes in morphants. Stra6.2-/- mice are viable and fertile and phenotypically normal, even under retinoid-stress, supporting the notion of functional redundancy. In compound knockouts, normal development and postnatal survival can be maintained by a single copy of Stra6 in Stra6+/-;Stra6.2-/- animals. Stra6.2 is less able to support normal development and survival with ~50% of Stra6-/-;Stra6.2+/- animals dying before weaning or showing reduced growth although the remaining animals are indistinguishable from their littermates. Stra6 and Stra6.2 are functionally redundant for development under normal dietary conditions in the mouse and a single copy of either is able to support development in at least 50% of animals. Stra6-/-;Stra6.2-/- mice were therefore hypothesised to be the logical mouse model of Matthew-Wood syndrome, however these mice die early in gestation between E7.5-E9.5. The early embryonic lethality in Stra6-/-;Stra6.2-/- mouse embryos compared to postnatal survival in human Matthew-Wood patients, to which they are the comparable genetic model, could be attributed to the shortened STRA6.2 remaining within the human genome. The equivalent portion of Stra6 has validated signalling motifs, which may still be active in STRA6.2, allowing development to proceed in human ‘STRA6-/-’ embryos

Sustainable floods: Exploring stakeholder perceptions of sedimentation strategies for the sinking Mekong delta

The Mekong delta in Vietnam, home to over 17 million people, is rapidly losing elevation due to groundwater-extraction-induced subsidence, natural compaction and global sea-level rise. These combined processes result in salinity intrusion, erosion and land loss. The delta has been extensively poldered for agri- and aquaculture, largely cutting off the land from the dwindling supplies of fluvial sediment which would otherwise accumulate on the delta during seasonal floods and increase land elevation. Considering the current state of the Mekong delta and sediment delivery from upstream, the future sustainability of the delta cannot rely on natural delta-building processes and instead must be planned and managed to prevent major degradation of the system. Sedimentation strategies are methods of ensuring that the limited sediment available is retained to increase elevation where it is desirable for the population and sustainability of the delta. Considering the potential disruption to land uses and livelihoods caused by sedimentation strategies, it is vital to discuss the possibilities for sedimentation strategies with stakeholders to ensure that people, particularly vulnerable groups, are not disadvantaged, and ensure that delta management is sustainable from all perspectives. In this research we engage with stakeholders to start an explorative dialogue on the potential of sedimentation strategies in the Mekong delta considering physical, socio-institutional, governance and legal aspects. We resent an analysis of interviews and workshop discussions with farmers, officials, and regional experts in the provinces of Soc Trang (coastal, the most downstream part of the delta) and An Giang (inland, the most upstream part of the delta) to gain insights into local perspectives in different areas of the delta, with different physical environments, land use histories and constraints. Preliminary findings suggest that the perceived role of sediment varies across different stakeholders e.g. farmers focus more on the role of sediment for their agricultural activities while experts also express their concerns on the elevation of the delta. Interestingly, while sediment is perceived to be important in the upstream area, it is considered an inconvenience in the downstream part of the delta due to, among other factors, different types of livelihoods. It is therefore recommended that the sedimentation strategies need to be designed based on the typical livelihoods of locals and communication strategies need to be enhanced to raise the awareness of local actors on the role of sediment

Imputation of Orofacial Clefting Data Identifies Novel Risk Loci and Sheds Light on the Genetic Background of Cleft Lip ± Cleft Palate and Cleft Palate Only.

Abstract Nonsyndromic cleft lip with or without cleft palate (nsCL/P) is among the most common human birth defects with multifactorial etiology. Here, we present results from a genome-wide imputation study of nsCL/P in which, after adding replication cohort data, four novel risk loci for nsCL/P are identified (at chromosomal regions 2p21, 14q22, 15q24 and 19p13). On a systematic level, we show that the association signalswithin this high-density datasetare enriched in functionally-relevant genomic regions that are active in both human neural crest cells (hNCC) and mouse embryonic craniofacial tissue. This enrichment is also detectable in hNCC regions primed for later activity. Using GCTA analyses, we suggest that 30% of the estimated variance in risk for nsCL/P in the European population can be attributed to common variants, with 25.5% contributed to by the 24 risk loci known to date. For each of these, we identify credible SNPs using a Bayesian refinementapproach, with two loci harbouring only one probable causal variant. Finally, we demonstrate that there is no polygenic component of nsCL/P detectable that is shared with nonsyndromic cleft palate only (nsCPO). Our data suggest that, while common variants are strongly contributing to risk for nsCL/P, they do not seem to be involved in nsCPO which might be more often caused by rare deleterious variants. Our study generates novel insights into both nsCL/P and nsCPO etiology and provides a systematic framework for research into craniofacial development and malformation

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Sustainable floods: Exploring stakeholder perceptions of sedimentation strategies for the sinking Mekong delta

The Mekong delta in Vietnam, home to over 17 million people, is rapidly losing elevation due to groundwater-extraction-induced subsidence, natural compaction and global sea-level rise. These combined processes result in salinity intrusion, erosion and land loss. The delta has been extensively poldered for agri- and aquaculture, largely cutting off the land from the dwindling supplies of fluvial sediment which would otherwise accumulate on the delta during seasonal floods and increase land elevation. Considering the current state of the Mekong delta and sediment delivery from upstream, the future sustainability of the delta cannot rely on natural delta-building processes and instead must be planned and managed to prevent major degradation of the system. Sedimentation strategies are methods of ensuring that the limited sediment available is retained to increase elevation where it is desirable for the population and sustainability of the delta. Considering the potential disruption to land uses and livelihoods caused by sedimentation strategies, it is vital to discuss the possibilities for sedimentation strategies with stakeholders to ensure that people, particularly vulnerable groups, are not disadvantaged, and ensure that delta management is sustainable from all perspectives. In this research we engage with stakeholders to start an explorative dialogue on the potential of sedimentation strategies in the Mekong delta considering physical, socio-institutional, governance and legal aspects. We resent an analysis of interviews and workshop discussions with farmers, officials, and regional experts in the provinces of Soc Trang (coastal, the most downstream part of the delta) and An Giang (inland, the most upstream part of the delta) to gain insights into local perspectives in different areas of the delta, with different physical environments, land use histories and constraints. Preliminary findings suggest that the perceived role of sediment varies across different stakeholders e.g. farmers focus more on the role of sediment for their agricultural activities while experts also express their concerns on the elevation of the delta. Interestingly, while sediment is perceived to be important in the upstream area, it is considered an inconvenience in the downstream part of the delta due to, among other factors, different types of livelihoods. It is therefore recommended that the sedimentation strategies need to be designed based on the typical livelihoods of locals and communication strategies need to be enhanced to raise the awareness of local actors on the role of sediment

Variation in the uric acid transporter gene (SLC2A9) and memory performance

Understanding human cognitive ageing is important to improve the health of an increasing elderly population. Serum uric acid levels have been linked to many ageing illnesses and are also linked to cognitive functioning, though the direction of the association is equivocal. SLC2A9, a urate transporter, influences uric acid levels. This study first tested four SLC2A9 SNPs, previously associated with uric acid levels, in ~1000 Scots: the Lothian Birth Cohort 1936 (LBC1936). These participants were tested on general cognitive ability at ages 11 and 70. At age 70, they took a battery of diverse cognitive tests. Two replication cohorts were investigated. First, the LBC1921, who were tested on general cognitive ability at age 11. At ages 79 (n = 520), 83 (n = 281) and age 87 (n = 177), they completed cognitive ability test batteries. Second, the Edinburgh Type 2 Diabetes Study (ET2DS) were tested for cognitive abilities aged between 60 and 75 years (n = 1066). All analyses were adjusted for age, gender, body mass index and either childhood cognitive ability test score (LBC) or vocabulary-a measure of prior cognitive ability in ET2DS. Significant associations were detected with SLC2A9 and a general memory factor in LBC1936 and other individual cognitive ability tests (lowest P = 0.0002). The association with logical memory replicated in LBC1921 at all ages (all P 0.1). If the positive associations withstand, then this study could suggest that higher uric acid levels may be associated with increased performance on memory-related tasks

p63 exerts spatio-temporal control of palatal epithelial cell fate to prevent cleft palate

Contains fulltext : 174706.pdf (publisher's version ) (Open Access