Canine Genomics and Genetics: Running with the Pack

The domestication of the dog from its wolf ancestors is perhaps the most complex genetic experiment in history, and certainly the most extensive. Beginning with the wolf, man has created dog breeds that are hunters or herders, big or small, lean or squat, and independent or loyal. Most breeds were established in the 1800s by dog fanciers, using a small number of founders that featured traits of particular interest. Popular sire effects, population bottlenecks, and strict breeding programs designed to expand populations with desirable traits led to the development of what are now closed breeding populations, with limited phenotypic and genetic heterogeneity, but which are ideal for genetic dissection of complex traits. In this review, we first discuss the advances in mapping and sequencing that accelerated the field in recent years. We then highlight findings of interest related to disease gene mapping and population structure. Finally, we summarize novel results on the genetics of morphologic variation

Constraining the rate of oceanic deoxygenation leading up to a Cretaceous Oceanic Anoxic Event (OAE-2: ~94 Ma)

© The Author(s), 2017. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Science Advances 3 (2017): e1701020, doi:10.1126/sciadv.1701020.The rates of marine deoxygenation leading to Cretaceous Oceanic Anoxic Events are poorly recognized and constrained. If increases in primary productivity are the primary driver of these episodes, progressive oxygen loss from global waters should predate enhanced carbon burial in underlying sediments—the diagnostic Oceanic Anoxic Event relic. Thallium isotope analysis of organic-rich black shales from Demerara Rise across Oceanic Anoxic Event 2 reveals evidence of expanded sediment-water interface deoxygenation ~43 ± 11 thousand years before the globally recognized carbon cycle perturbation. This evidence for rapid oxygen loss leading to an extreme ancient climatic event has timely implications for the modern ocean, which is already experiencing large-scale deoxygenation.We would like to acknowledge support from the NSF grant OCE 1434785 (to J.D.O. and S.G.N.), the NASA Exobiology grant NNX16AJ60G (to J.D.O. and S.G.N.), a WHOI Summer Student Fellowship (to C.M.O.), and an Agouron Postdoctoral Fellowship (to J.D.O.). This material is based on work supported by the NSF Graduate Research Fellowship Program under grant no. 026257-001

Thallium-isotopic compositions of euxinic sediments as a proxy for global manganese-oxide burial

© The Author(s), 2017. This is the author's version of the work. It is posted here under a nonexclusive, irrevocable, paid-up, worldwide license granted to WHOI. It is made available for personal use, not for redistribution. The definitive version was published in Geochimica et Cosmochimica Acta 213 (2017): 291-307, doi:10.1016/j.gca.2017.06.041.Thallium (Tl) isotopes are a new and potentially powerful paleoredox proxy that may track bottom water oxygen conditions based on the global burial flux of manganese oxides. Thallium has a residence time of ~20 thousand years, which is longer than the ocean mixing time, and it has been inferred that modern oxic seawater is conservative with respect to both concentration and isotopes. Marine sources of Tl have nearly identical isotopic values. Therefore, the Tl sinks, adsorption onto manganese oxides and low temperature oceanic crust alteration (the dominant seawater output), are the primary controls of the seawater isotopic composition. For relatively short-term, ~million years, redox events it is reasonable to assume that the dominant mechanism that alters the Tl isotopic composition of seawater is associated with manganese oxide burial because large variability in low temperature ocean crust alteration is controlled by long-term, multi-million years, average ocean crust production rates. This study presents new Tl isotope data for an open ocean transect in the South Atlantic, and depth transects for two euxinic basins (anoxic and free sulfide in the water column), the Cariaco Basin and Black Sea. The Tl isotopic signature of open ocean seawater in the South Atlantic was found to be homogeneous with ε205Tl = -6.0 ± 0.3 (± 2 SD, n = 41) while oxic waters from Cariaco and the Black Sea are -5.6 and -2.2, respectively. Combined with existing data from the Pacific and Arctic Oceans, our Atlantic data establish the conservatism of Tl isotopes in the global ocean. In contrast, partially- and predominantly-restricted basins reveal Tl isotope differences that vary between open-ocean (-6) and continental material (-2) ε205Tl, scaling with the degree of restriction. Regardless of the differences between basins, Tl is quantitatively removed from their euxinic waters below the chemocline. The burial of Tl in euxinic sediments is estimated to be an order of magnitude less than each of the modern ocean outputs and imparts no isotopic fractionation. Thallium removal into pyrite appears to be associated with a small negative fractionation between -1 and -3 ε205Tl, which renders Tl-depleted waters below the chemocline enriched in isotopically-heavy Tl. Due to the quantitative removal of Tl from euxinic seawater, Tl isotope analyses of the authigenic fraction of underlying euxinic sediments from both the Black Sea and Cariaco Basin capture the Tl isotope value of the oxic portion of their respective water column with no net isotope fractionation. Since the Tl isotope composition of seawater is largely dictated by the relative fraction of Mn-oxide burial versus oceanic crust alteration, we contend that the Tl isotope composition of authigenic Tl in black shales, deposited under euxinic conditions but well-connected to the open ocean, can be utilized to reconstruct the Tl isotope composition of seawater, and thus to reconstruct the global history of Mn-oxide burial.JDO and SGN would like to thank NSF and NASA for funding; JDO and TJH gratefully acknowledges support from the Agouron Institute Postdoctoral Fellowship Program

Sigma1 Targeting to Suppress Aberrant Androgen Receptor Signaling in Prostate Cancer.

Suppression of androgen receptor (AR) activity in prostate cancer by androgen depletion or direct AR antagonist treatment, although initially effective, leads to incurable castration-resistant prostate cancer (CRPC) via compensatory mechanisms including resurgence of AR and AR splice variant (ARV) signaling. Emerging evidence suggests that Sigma1 (also known as sigma-1 receptor) is a unique chaperone or scaffolding protein that contributes to cellular protein homeostasis. We reported previously that some Sigma1-selective small molecules can be used to pharmacologically modulate protein homeostasis pathways. We hypothesized that these Sigma1-mediated responses could be exploited to suppress AR protein levels and activity. Here we demonstrate that treatment with a small-molecule Sigma1 inhibitor prevented 5α- dihydrotestosterone-mediated nuclear translocation of AR and induced proteasomal degradation of AR and ARV, suppressing the transcriptional activity and protein levels of both full-length and splice-variant AR. Consistent with these data, RNAi knockdown of Sigma1 resulted in decreased AR levels and transcriptional activity. Furthermore, Sigma1 physically associated with ARV7 and A

Shale heavy metal isotope records of low environmental O2 between two Archean Oxidation Events

© The Author(s), 2022. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Ostrander, C. M., Kendall, B., Gordon, G. W., Nielsen, S. G., Zheng, W., & Anbar, A. D. Shale heavy metal isotope records of low environmental O2 between two Archean Oxidation Events. Frontiers in Earth Science, 10, (2022): 833609, https://doi.org/10.3389/feart.2022.833609.Evidence of molecular oxygen (O2) accumulation at Earth’s surface during the Archean (4.0–2.5 billion years ago, or Ga) seems to increase in its abundance and compelling nature toward the end of the eon, during the runup to the Great Oxidation Event. Yet, many details of this late-Archean O2 story remain under-constrained, such as the extent, tempo, and location of O2 accumulation. Here, we present a detailed Fe, Tl, and U isotope study of shales from a continuous sedimentary sequence deposited between ∼2.6 and ∼2.5 Ga and recovered from the Pilbara Craton of Western Australia (the Wittenoom and Mt. Sylvia formations preserved in drill core ABDP9). We find a progressive decrease in bulk-shale Fe isotope compositions moving up core (as low as δ56Fe = –0.78 ± 0.08‰; 2SD) accompanied by invariant authigenic Tl isotope compositions (average ε205TlA = –2.0 ± 0.6; 2SD) and bulk-shale U isotope compositions (average δ238U = –0.30 ± 0.05‰; 2SD) that are both not appreciably different from crustal rocks or bulk silicate Earth. While there are multiple possible interpretations of the decreasing δ56Fe values, many, to include the most compelling, invoke strictly anaerobic processes. The invariant and near-crustal ε205TlA and δ238U values point even more strongly to this interpretation, requiring reducing to only mildly oxidizing conditions over ten-million-year timescales in the late-Archean. For the atmosphere, our results permit either homogenous and low O2 partial pressures (between 10−6.3 and 10−6 present atmospheric level) or heterogeneous and spatially restricted O2 accumulation nearest the sites of O2 production. For the ocean, our results permit minimal penetration of O2 in marine sediments over large areas of the seafloor, at most sufficient for the burial of Fe oxide minerals but insufficient for the burial of Mn oxide minerals. The persistently low background O2 levels implied by our dataset between ∼2.6 and ∼2.5 Ga contrast with the timeframes immediately before and after, where strong evidence is presented for transient Archean Oxidation Events. Viewed in this broader context, our data support the emerging narrative that Earth’s initial oxygenation was a dynamic process that unfolded in fits-and-starts over many hundreds-of-millions of years.This work was supported financially by the NSF Frontiers in Earth System Dynamics program award NSF EAR-1338810 (AA), a Woods Hole Oceanographic Institution Postdoctoral Scholarship (CO), a NSERC Discovery Grant (RGPIN-435930) and the Canada Research Chair program (BK), and a NASA Exobiology award 80NSSC20K0615 (SN)

An integrated 4249 marker FISH/RH map of the canine genome

BACKGROUND: The 156 breeds of dog recognized by the American Kennel Club offer a unique opportunity to map genes important in genetic variation. Each breed features a defining constellation of morphological and behavioral traits, often generated by deliberate crossing of closely related individuals, leading to a high rate of genetic disease in many breeds. Understanding the genetic basis of both phenotypic variation and disease susceptibility in the dog provides new ways in which to dissect the genetics of human health and biology. RESULTS: To facilitate both genetic mapping and cloning efforts, we have constructed an integrated canine genome map that is both dense and accurate. The resulting resource encompasses 4249 markers, and was constructed using the RHDF5000-2 whole genome radiation hybrid panel. The radiation hybrid (RH) map features a density of one marker every 900 Kb and contains 1760 bacterial artificial chromosome clones (BACs) localized to 1423 unique positions, 851 of which have also been mapped by fluorescence in situ hybridization (FISH). The two data sets show excellent concordance. Excluding the Y chromosome, the map features an RH/FISH mapped BAC every 3.5 Mb and an RH mapped BAC-end, on average, every 2 Mb. For 2233 markers, the orthologous human genes have been established, allowing the identification of 79 conserved segments (CS) between the dog and human genomes, dramatically extending the length of most previously described CS. CONCLUSIONS: These results provide a necessary resource for the canine genome mapping community to undertake positional cloning experiments and provide new insights into the comparative canine-human genome maps

Pulsed 86Sr-labeling and NanoSIMS imaging to study coral biomineralization at ultra-structural length scales

A method to label marine biocarbonates is developed based on a concentration enrichment of a minor stable isotope of a trace element that is a natural component of seawater, resulting in the formation of biocarbonate with corresponding isotopic enrichments. This biocarbonate is subsequently imaged with a NanoSIMS ion microprobe to visualize the locations of the isotopic marker on sub-micrometric length scales, permitting resolution of all ultra-structural details. In this study, a scleractinian coral, Pocillopora damicornis, was labeled 3 times with 86Sr-enhanced seawater for a period of 48h with 5days under normal seawater conditions separating each labeling event. Two non-specific cellular stress biomarkers, glutathione-S-transferase activity and porphyrin concentration plus carbonic anhydrase, an enzymatic marker involved in the physiology of carbonate biomineralization, as well as unchanged levels of zooxanthellae photosynthesis efficiency indicate that coral physiological processes are not affected by the 86Sr-enhancement. NanoSIMS images of the 86Sr/44Ca ratio in skeleton formed during the experiment allow for a determination of the average extension rate of the two major ultra-structural components of the coral skeleton: Rapid Accretion Deposits are found to form on average about 4.5 times faster than Thickening Deposits. The method opens up new horizons in the study of biocarbonate formation because it holds the potential to observe growth of calcareous structures such as skeletons, shells, tests, spines formed by a wide range of organisms under essentially unperturbed physiological condition

Dog10K: an international sequencing effort to advance studies of canine domestication, phenotypes and health

Dogs are the most phenotypically diverse mammalian species, and they possess more known heritable disorders than any other non-human mammal. Efforts to catalog and characterize genetic variation across well-chosen populations of canines are necessary to advance our understanding of their evolutionary history and genetic architecture. To date, no organized effort has been undertaken to sequence the world's canid populations. The Dog10K Consortium (http://www.dog10kgenomes.org) is an international collaboration of researchers from across the globe who will generate 20× whole genomes from 10 000 canids in 5 years. This effort will capture the genetic diversity that underlies the phenotypic and geographical variability of modern canids worldwide. Breeds, village dogs, niche populations and extended pedigrees are currently being sequenced, and de novo assemblies of multiple canids are being constructed. This unprecedented dataset will address the genetic underpinnings of domestication, breed formation, aging, behavior and morphological variation. More generally, this effort will advance our understanding of human and canine health