Kin-Aggregations Explain Chaotic Genetic Patchiness, a Commonly Observed Genetic Pattern, in a Marine Fish

The phenomenon of chaotic genetic patchiness is a pattern commonly seen in marine organisms, particularly those with demersal adults and pelagic larvae. This pattern is usually associated with sweepstakes recruitment and variable reproductive success. Here we investigate the biological underpinnings of this pattern in a species of marine goby Coryphopterus personatus. We find that populations of this species show tell-tale signs of chaotic genetic patchiness including: small, but significant, differences in genetic structure over short distances; a non-equilibrium or “chaotic” pattern of differentiation among locations in space; and within locus, within population deviations from the expectations of Hardy-Weinberg equilibrium (HWE). We show that despite having a pelagic larval stage, and a wide distribution across Caribbean coral reefs, this species forms groups of highly related individuals at small spatial scales (metres). These spatially clustered family groups cause the observed deviations from HWE and local population differentiation, a finding that is rarely demonstrated, but could be more common than previously thought

Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies

Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Abstract: Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies

Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Abstract: Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies

Microgeographic adaptation in a broadcast-spawning marine invertebrate

A thesis Submitted in Partial Fulfillment of the Requirements for the Degree of MASTER OF SCIENCE in MARINE BIOLOGY from Texas A&M University-Corpus Christi in Corpus Christi, Texas.The spatial scale over which adaptive evolution occurs may be much smaller than originally predicted, affecting our understanding of the maintenance of genetic diversity and adaptive capacity. Microgeographic adaptation, where patterns of genetic adaptation develop within Wright’s dispersal neighborhood, is strongly opposed by gene flow and has been considered to be rare. Here, we test whether selection can overcome migration and drive microgeographic adaptation at a very small spatial scale (6-7 orders of magnitude less than the dispersal neighborhood) in a dispersive, broadcast-spawning, intertidal patellogastropod (Cellana exarata, ‘opihi) using molecular techniques. Adults were collected from exposed rock surfaces and sheltered crevices separated by cm-m in three semi-isolated populations on different islands. Consistent with the hypothesis that selective pressures vary between the microhabitats, mean shell size was smaller on exposed surfaces than crevices. 16,387 restriction site associated DNA sequence loci were ascertained with PCR-free ezRAD in 20-39 ‘opihi per microhabitat on each island. Consistent with a pattern of microgeographic adaptation, 126 candidate loci (1 transcribed gene) exhibited a parallel pattern of differentiation between microhabitats on all three islands (F=0.03 – 0.11). While an assessment of reproductive state indicates that spawning was more likely to be delayed in crevices, the reproductive state and DNA data indicate that there is substantial opportunity for, and evidence of, gene flow between the microhabitats. There are two explanations for these results which are not mutually exclusive. (1) Individuals seek advantageous microhabitats given their particular genetic composition. (2) Individuals with disadvantageous composite genotypes in a microhabitat are more likely to perish. Given the extreme scenario tested here, microgeographic adaptation is likely to be much more common than originally anticipated.Life SciencesCollege of Science and Engineerin

Casein kinase 2 regulates in vivo bone formation through its interaction with bone morphogenetic protein receptor type Ia.

Approximately 7.9 million fractures occur annually in the United States with 5-10% of these resulting in delayed or impaired healing. Nearly half of the trauma cost of $56 billion per year is used for the treatment of fractures. More importantly, fracture results in a substantial reduction in the quality of life. New approaches and therapies are needed to enhance fracture healing. Only a limited number of treatments are available including bone grafting, allogeneic and autologous bone marrow transplantation, and bone morphogenetic protein (BMP). We previously identified Protein Kinase CK2 to interact with BMP receptor type Ia (BMPRIa) and as a key protein for signal activation. Peptides approximately 30 AA were developed that mimicked BMP2 action in vitro by blocking this interaction. In this paper we extended our studies to investigate if the most promising peptide could induce in vivo bone formation in mice and to elucidate this mechanism of action. The CK2 blocking peptide activated the Wnt pathway. To identify the optimal peptide concentration and peptide concentration curves for mineralization studies were performed. We designed BMPRIa mutants with a point mutation in the CK2 phosphorylation site to establish a specific effect. Mineralization was initiated with the overexpression of the BMPRIa mutants indicating CK2 is a negative regulatory protein for osteoblast differentiation. Osteoclast differentiation and activity was decreased with the CK2 blocking peptide. Further, subcutaneous calvarial bone injections of a CK2 blocking peptide increased bone area, areal bone mineral density, and bone growth. These results indicate CK2 is crucial for osteoblast differentiation and could be a target for future therapeutics of fracture healing

Altered plasma membrane dynamics of bone morphogenetic protein receptor type Ia in a low bone mass mouse model.

Bone morphogenetic proteins (BMPs) are growth factors that initiate differentiation of bone marrow stromal cells to osteoblasts and adipocytes, yet the mechanism that decides which lineage the cell will follow is unknown. BMP2 is linked to the development of osteoporosis and variants of BMP2 gene have been reported to increase the development of osteoporosis. Intracellular signaling is transduced by BMP receptors (BMPRs) of type I and type II that are serine/threonine kinase receptors. The BMP type I a receptor (BMPRIa) is linked to osteogenesis and bone mineral density (BMD). BMPRs are localized to caveolae enriched with Caveolin1 alpha/beta and Caveolin beta isoforms to facilitate signaling. BMP2 binding to caveolae was recently found to be crucial for the initiation of the Smad signaling pathway. Here we determined the role of BMP receptor localization within caveolae isoforms and aggregation of caveolae as well as BMPRIa in bone marrow stromal cells (BMSCs) on bone mineral density using the B6.C3H-6T as a model system. The B6.C3H-6T is a congenic mouse with decreased bone mineral density (BMD) with increased marrow adipocytes and decreased osteoprogenitor proliferation. C57BL/6J mice served as controls since only a segment of Chr6 from the C3H/HeJ mouse was backcrossed to a C57BL/6J background. Family of image correlation spectroscopy was used to analyze receptor cluster density and co-localization of BMPRIa and caveolae. It was previously shown that BMP2 stimulation results in an aggregation of caveolae and BMPRIa. Additionally, BMSCs isolated from the B6.C3H-6T mice showed a dispersion of caveolae domains compared to C57BL/6J. The aggregation of BMPRIa that is necessary for signaling to occur was inhibited in BMSCs isolated from B6.C3H-6T. Additionally, we analyzed the co-localization of BMPRIa with caveolin-1 isoforms. There was increased percentage of BMPRIa co-localization with caveolae compared to C57BL/6J. BMP2 stimulation had no effect on the colocalization of BMPRIa with caveolin-1. Disrupting caveolae initiated Smad signaling in the isolated BMSCs from B6.C3H-6T. These data suggest that in congenic 6T mice BMP receptors aggregation is inhibited causing an inhibition of signaling and reduced bone mass

Relatedness and sibship summary of genetic clusters within sample sites.

<p>Relatedness and sibship summary of genetic clusters within sample sites.</p

PCR Conditions and locus summary statistics.

<p>PCR Conditions and locus summary statistics.</p

Kin-Aggregations Explain Chaotic Genetic Patchiness, a Commonly Observed Genetic Pattern, in a Marine Fish - Fig 3

<p>Mean pairwise relatedness () values by geographic sample (A) and cluster (B) with standard errors. The shaded region indicates the area within the 95% confidence intervals calculated using a permutation test with 1,000 iterations. Triangles in 3B indicate proportion of full and half-sibs within the cluster with shaded symbols indicating significantly elevated transitivity when compared to randomly generated networks equivalent to those observed in the clusters.</p