Mechanism of Action of Secreted Newt Anterior Gradient Protein

Anterior gradient (AG) proteins have a thioredoxin fold and are targeted to the secretory pathway where they may act in the ER, as well as after secretion into the extracellular space. A newt member of the family (nAG) was previously identified as interacting with the GPI-anchored salamander-specific three-finger protein called Prod1. Expression of nAG has been implicated in the nerve dependence of limb regeneration in salamanders, and nAG acted as a growth factor for cultured newt limb blastemal (progenitor) cells, but the mechanism of action was not understood. Here we show that addition of a peptide antibody to Prod1 specifically inhibit the proliferation of blastema cells, suggesting that Prod1 acts as a cell surface receptor for secreted nAG, leading to S phase entry. Mutation of the single cysteine residue in the canonical active site of nAG to alanine or serine leads to protein degradation, but addition of residues at the C terminus stabilises the secreted protein. The mutation of the cysteine residue led to no detectable activity on S phase entry in cultured newt limb blastemal cells. In addition, our phylogenetic analyses have identified a new Caudata AG protein called AG4. A comparison of the AG proteins in a cell culture assay indicates that nAG secretion is significantly higher than AGR2 or AG4, suggesting that this property may vary in different members of the family.     

Longitudinal analytical approaches to genetic data

Background

Longitudinal phenotypic data provides a rich potential resource for genetic studies which may allow for greater understanding of variants and their covariates over time. Herein, we review 3 longitudinal analytical approaches from the Genetic Analysis Workshop 19 (GAW19). These contributions investigated both genome-wide association (GWA) and whole genome sequence (WGS) data from odd numbered chromosomes on up to 4 time points for blood pressure–related phenotypes. The statistical models used included generalized estimating equations (GEEs), latent class growth modeling (LCGM), linear mixed-effect (LME), and variance components (VC). The goal of these analyses was to test statistical approaches that use repeat measurements to increase genetic signal for variant identification.

Results

Two analytical methods were applied to the GAW19: GWA using real phenotypic data, and one approach to WGS using 200 simulated replicates. The first GWA approach applied a GEE-based model to identify gene-based associations with 4 derived hypertension phenotypes. This GEE model identified 1 significant locus, GRM7, which passed multiple test corrections for 2 hypertension-derived traits. The second GWA approach employed the LME to estimate genetic associations with systolic blood pressure (SBP) change trajectories identified using LCGM. This LCGM method identified 5 SBP trajectories and association analyses identified a genome-wide significant locus, near ATOX1 (p?=?1.0E^?8). Finally, a third VC-based model using WGS and simulated SBP phenotypes that constrained the β coefficient for a genetic variant across each time point was calculated and compared to an unconstrained approach. This constrained VC approach demonstrated increased power for WGS variants of moderate effect, but when larger genetic effects were present, averaging across time points was as effective.

Conclusion

In this paper, we summarize 3 GAW19 contributions applying novel statistical methods and testing previously proposed techniques under alternative conditions for longitudinal genetic association. We conclude that these approaches when appropriately applied have the potential to: (a) increase statistical power; (b) decrease trait heterogeneity and standard error; (c) decrease computational burden in WGS; and (d) have the potential to identify genetic variants influencing subphenotypes important for understanding disease progression.

     

Assessment of platelet function in patients with stroke using multiple electrode platelet aggregometry: a prospective observational study

The Qatari law, as in many other countries, uses brain death as the main criteria for organ donation and cessation of medical support. By contrast, most of the public in Qatar do not agree with the limitation or withdrawal of medical care until the time of cardiac death. The current study aims to examine the duration of somatic survival after brain death, organ donation rate in brain-dead patients as well as review the underlying etiologies and level of support provided in the state of Qatar. This is a retrospective study of all patients diagnosed with brain death over a 10-year period conducted at the largest tertiary center in Qatar (Hamad General Hospital). Among the 53 patients who were diagnosed with brain death during the study period, the median and mean somatic survivals of brain-dead patients in the current study were 3 and 4.5 days respectively. The most common etiology was intracranial hemorrhage (45.3%) followed by ischemic stroke (17%). Ischemic stroke patients had a median survival of 11 days. Organ donation was accepted by only two families (6.6%) of the 30 brain dead patients deemed suitable for organ donation. The average somatic survival of brain-dead patients is less than one week irrespective of supportive measures provided. Organ donation rate was extremely low among brain-dead patients in Qatar. Improved public education may lead to significant improvement in resource utilization as well as organ transplant donors and should be a major target area of future health care policies.     

Redrawing the map: mtDNA provides new insight into the distribution and diversity of short‐finned pilot whales in the Pacific Ocean

Correlations between morphological and genetic data provide evidence to delineate species or evolutionarily significant units, which then become the units to conserve in management plans. Here, we examine the distribution and genetic differentiation of two morphotypes of short‐finned pilot whale (Globicephala macrorhynchus) in the Pacific Ocean. Mitochondrial control region sequences from 333 samples were combined with 152 previously published sequences to describe genetic variability globally and population structure in the Pacific. Although genetic variability is low, we found strong differentiation at both broad and local levels across the Pacific. Based on genetics, two types are distributed throughout the Pacific, one predominantly in the eastern Pacific and the other in the western and central Pacific. In the eastern Pacific Ocean, no correlation was found between distribution and sea surface temperature. The two types have broad latitudinal ranges, suggesting their distributions are likely driven by more complex factors, such as prey distribution, rather than sea surface temperature.     

Oceanographic barriers,divergence, and admixture: Phylogeography and taxonomy of two putative subspecies of short‐finned pilot whale

Genomic phylogeography plays an important role in describing evolutionary processes and their geographic, ecological, or cultural drivers. These drivers are often poorly understood in marine environments, which have fewer obvious barriers to mixing than terrestrial environments. Taxonomic uncertainty of some taxa (e.g., cetaceans), due to the difficulty in obtaining morphological data, can hamper our understanding of these processes. One such taxon, the short‐finned pilot whale, is recognized as a single global species but includes at least two distinct morphological forms described from stranding and drive hunting in Japan, the “Naisa” and “Shiho” forms. Using samples (n = 735) collected throughout their global range, we examine phylogeographic patterns of divergence by comparing mitogenomes and nuclear SNP loci. Our results suggest three types within the species: an Atlantic Ocean type, a western/central Pacific and Indian Ocean (Naisa) type, and an eastern Pacific Ocean and northern Japan (Shiho) type. mtDNA control region differentiation indicates these three types form two subspecies, separated by the East Pacific Barrier: Shiho short‐finned pilot whale, in the eastern Pacific Ocean and northern Japan, and Naisa short‐finned pilot whale, throughout the remainder of the species' distribution. Our data further indicate two diverging populations within the Naisa subspecies, in the Atlantic Ocean and western/central Pacific and Indian Oceans, separated by the Benguela Barrier off South Africa. This study reveals a process of divergence and speciation within a globally‐distributed, mobile marine predator, and indicates the importance of the East Pacific Barrier to this evolutionary process.     

Early life of fathers affects offspring fitness in a wild rodent

Intergenerational fitness effects on offspring due to the early life of the parent are well studied from the standpoint of the maternal environment, but intergenerational effects owing to the paternal early life environment are often overlooked. Nonetheless, recent laboratory studies in mammals and ecologically relevant studies in invertebrates predict that paternal effects can have a major impact on the offspring's phenotype. These nongenetic, environment‐dependent paternal effects provide a mechanism for fathers to transmit environmental information to their offspring and could allow rapid adaptation. We used the bank vole Myodes glareolus, a wild rodent species with no paternal care, to test the hypothesis that a high population density environment in the early life of fathers can affect traits associated with offspring fitness. We show that the protein content in the diet and/or social environment experienced during the father's early life (prenatal and weaning) influence the phenotype and survival of his offspring and may indicate adaptation to density‐dependent costs. Furthermore, we show that experiencing multiple environmental factors during the paternal early life can lead to a different outcome on the offspring phenotype than stimulated by experience of a single environmental factor, highlighting the need to study developmental experiences in tandem rather than independent of each other.