New 10Be exposure ages improve Holocene ice sheet thinning history near the grounding line of Pope Glacier, Antarctica

Evidence for the timing and pace of past grounding line retreat of the Thwaites Glacier system in the Amundsen Sea embayment (ASE) of Antarctica provides constraints for models that are used to predict the future trajectory of the West Antarctic Ice Sheet (WAIS). Existing cosmogenic nuclide surface exposure ages suggest that Pope Glacier, a former tributary of Thwaites Glacier, experienced rapid thinning in the early to mid-Holocene. There are relatively few exposure ages from the lower ice-free sections of Mt. Murphy (<300 m a.s.l.; metres above sea level) that are uncomplicated by either nuclide inheritance or scatter due to localised topographic complexities; this makes the trajectory for the latter stages of deglaciation uncertain. This paper presents 12 new 10Be exposure ages from erratic cobbles collected from the western flank of Mt. Murphy, within 160 m of the modern ice surface and 1 km from the present grounding line. The ages comprise two tightly clustered populations with mean deglaciation ages of 7.1 ± 0.1 and 6.4 ± 0.1 ka (1 SE). Linear regression analysis applied to the age–elevation array of all available exposure ages from Mt. Murphy indicates that the median rate of thinning of Pope Glacier was 0.27 m yr−1 between 8.1–6.3 ka, occurring 1.5 times faster than previously thought. Furthermore, this analysis better constrains the uncertainty (95 % confidence interval) in the timing of deglaciation at the base of the Mt. Murphy vertical profile (∼ 80 m above the modern ice surface), shifting it to earlier in the Holocene (from 5.2 ± 0.7 to 6.3 ± 0.4 ka). Taken together, the results presented here suggest that early- to mid-Holocene thinning of Pope Glacier occurred over a shorter interval than previously assumed and permit a longer duration over which subsequent late Holocene re-thickening could have occurred

Achieving the "triple aim" for inborn errors of metabolism: a review of challenges to outcomes research and presentation of a new practice-based evidence framework

Across all areas of health care, decision makers are in pursuit of what Berwick and colleagues have called the “triple aim”: improving patient experiences with care, improving health outcomes, and managing health system impacts. This is challenging in a rare disease context, as exemplified by inborn errors of metabolism. There is a need for evaluative outcomes research to support effective and appropriate care for inborn errors of metabolism. We suggest that such research should consider interventions at both the level of the health system (e.g., early detection through newborn screening, programs to provide access to treatments) and the level of individual patient care (e.g., orphan drugs, medical foods). We have developed a practice- based evidence framework to guide outcomes research for inborn errors of metabolism. Focusing on outcomes across the triple aim, this framework integrates three priority themes: tailoring care in the context of clinical heterogeneity; a shift from “urgent care” to “opportunity for improvement”; and the need to evaluate the comparative effectiveness of emerging and established therapies. Guided by the framework, a new Canadian research network has been established to generate knowledge that will inform the design and delivery of health services for patients with inborn errors of metabolism and other rare diseases.This work was supported by a CIHR Emerging Team Grant (“Emerging team in rare diseases: acheiving the ‘triple aim’ for inborn errors of metabolism,” B.K. Potter, P. Chakraborty, and colleagues, 2012– 2017, grant no. TR3–119195). Current investigators and collaborators in the Canadian Inherited Metabolic Diseases Research Network are: B.K. Potter, P. Chakraborty, J. Kronick, D. Coyle, K. Wilson, M. Brownell, R. Casey, A. Chan, S. Dyack, L. Dodds, A. Feigenbaum, D. Fell, M. Geraghty, C. Greenberg, S. Grosse, A. Guttmann, A. Khan, J. Little, B. Maranda, J. MacKenzie, A. Mhanni, F. Miller, G. Mitchell, J. Mitchell, M. Nakhla, M. Potter, C. Prasad, K. Siriwardena, K.N. Speechley, S. Stocker, L. Turner, H. Vallance, and B.J. Wilson. Members of our external advisory board are D. Bidulka, T. Caulfield, J.T.R. Clarke, C. Doiron, K. El Emam, J. Evans, A. Kemper, W. McCormack, and A. Stephenson Julian. J. Little is supported by a Canada Research Chair in Human Genome Epidemiology. K. Wilson is supported by a Canada Research Chair in Public Health Policy

Data gaps and opportunities for comparative and conservation biology

Biodiversity loss is a major challenge. Over the past century, the average rate of vertebrate extinction has been about 100-fold higher than the estimated background rate and population declines continue to increase globally. Birth and death rates determine the pace of population increase or decline, thus driving the expansion or extinction of a species. Design of species conservation policies hence depends on demographic data (e.g., for extinction risk assessments or estimation of harvesting quotas). However, an overview of the accessible data, even for better known taxa, is lacking. Here, we present the Demographic Species Knowledge Index, which classifies the available information for 32,144 (97%) of extant described mammals, birds, reptiles, and amphibians. We show that only 1.3% of the tetrapod species have comprehensive information on birth and death rates. We found no demographic measures, not even crude ones such as maximum life span or typical litter/clutch size, for 65% of threatened tetrapods. More field studies are needed; however, some progress can be made by digitalizing existing knowledge, by imputing data from related species with similar life histories, and by using information from captive populations. We show that data from zoos and aquariums in the Species360 network can significantly improve knowledge for an almost eightfold gain. Assessing the landscape of limited demographic knowledge is essential to prioritize ways to fill data gaps. Such information is urgently needed to implement management strategies to conserve at-risk taxa and to discover new unifying concepts and evolutionary relationships across thousands of tetrapod species

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Does inbreeding distort sex-ratios?

Inbreeding is reputed to distort sex-ratios by reducing the proportion of the homogametic sex. However, many data sets do not show such an effect, and there is a known selective publication bias. To resolve the issue, we (a) developed detailed theoretical expectations for the effects of inbreeding on sex-ratios for autosomal and sex-linked loci with sex-limited effects or with equal effects in the two sexes, (b) evaluated the effects of inbreeding on sex-ratios in a new sample of 25 vertebrate taxa, and (c) evaluated the effects of inbreeding on sex-ratios for 69 replicate populations of "Drosophila melanogaster". Theoretical analyses indicated that directional distortions of sex-ratios under inbreeding due to sex-linked loci with sex-limited expression are expected to be small and uncommon and that there will be no distortions in marsupials. Further, sex linked alleles expressed equally in both sexes may also distort sex-ratios following inbreeding. Autosomal sex-limited alleles should not result in directional sex-ratio distortions in large populations or across many replicates, but may lead to distortions of random direction in some small populations. There were no significant directional distortions of sex-ratio due to inbreeding in either the vertebrates or the "Drosophila" populations. However, there were significant random distortions of sex-ratios in both data sets, presumably from autosomal sex-limited alleles that had drifted in individual populations. Thus, directional distortions in sex-ratio are not a consistent signal of inbreeding depression.15 page(s

Reversible ice sheet thinning in the Amundsen Sea Embayment during the Late Holocene [in review]

Cosmogenic-nuclide concentrations in subglacial bedrock cores show that the West Antarctic Ice Sheet (WAIS) at a site between Thwaites and Pope Glaciers was at least 35 m thinner than present in the past several thousand years, and subsequently thickened. This is important because of concern that present thinning and grounding line retreat at these and nearby glaciers in the Amundsen Sea Embayment may be irreversible, potentially leading to decimeter- to meter-scale sea level rise within decades to centuries. A past episode of ice sheet thinning, which took place in a similar although not identical climate, was not irreversible. We propose that the past thinning-thickening cycle was due to a glacioisostatic rebound feedback, similar to that invoked as a possible stabilizing mechanism for current grounding line retreat, in which isostatic uplift caused by early Holocene thinning led to relative sea level fall favoring grounding line advance

Offshore-onshore record of Last Glacial Maximum−to−present grounding line retreat at Pine Island Glacier, Antarctica

Pine Island Glacier, West Antarctica, is the largest Antarctic contributor to global sea-level rise and is vulnerable to rapid retreat, yet our knowledge of its deglacial history since the Last Glacial Maximum is based largely on marine sediments that record a retreat history ending in the early Holocene. Using a suite of 10Be exposure ages from onshore glacial deposits directly adjacent to Pine Island Glacier, we show that this major glacier thinned rapidly in the early to mid-Holocene. Our results indicate that Pine Island Glacier was at least 690 m thicker than present prior to ca. 8 ka. We infer that the rapid thinning detected at the site furthest downstream records the arrival and stabilization of the retreating grounding line at that site by 8−6 ka. By combining our exposure ages and the marine record, we extend knowledge of Pine Island Glacier retreat both spatially and temporally: to 50 km from the modern grounding line and to the mid-Holocene, providing a data set that is important for future numerical ice-sheet model validation

New 10Be ages improve Holocene ice sheet thinning history near the grounding line of Pope Glacier, Antarctica

Evidence for the timing and pace of past grounding line retreat of the Thwaites Glacier system in the Amundsen Sea embayment (ASE) of Antarctica provides constraints for models that are used to predict the future trajectory of the West Antarctic Ice Sheet (WAIS). Existing cosmogenic nuclide surface exposure ages suggest that Pope Glacier, a former tributary of Thwaites Glacier, experienced rapid thinning in the early to mid-Holocene. There are relatively few exposure ages from the lower ice-free sections of Mount Murphy (< 300 m asl) that are uncomplicated by either nuclide inheritance or scattering due to localised topographic complexities; this makes the trajectory for the latter stages of deglaciation uncertain. This paper presents 12 new 10Be exposure ages from erratic cobbles collected from the western flank of Mt Murphy, within 160 m of the modern ice surface and 1 km from the present grounding line. The ages comprise two tightly clustered populations with mean deglaciation ages of 7.1 ± 0.1 ka and 6.4 ± 0.1 ka (1SE). Linear regression analysis applied to the age-elevation array of all available exposure ages from Mt Murphy indicates that the median rate of thinning of Pope Glacier was 0.27 m yr-1 between 8.1–6.3 ka, occurring 1.5 times faster than previously thought. Furthermore, this analysis better constrains the uncertainty (95 % confidence interval) in the timing of deglaciation at the base of the Mt Murphy vertical profile (~80 m above the modern ice surface), shifting it to earlier in the Holocene (from 5.2 ± 0.7 ka to 6.3 ± 0.4 ka). Taken together, the results presented here suggest that early–mid Holocene thinning of Pope Glacier occurred over a shorter interval than previously assumed and permit a longer duration over which subsequent late Holocene rethickening could have occurred