Ancient and recent origins of shared polymorphisms in yeast.

Shared genetic polymorphisms between populations and species can be ascribed to ancestral variation or to more recent gene flow. Here, we mapped shared polymorphisms in Saccharomyces cerevisiae and its sister species Saccharomyces paradoxus, which diverged 4-6 million years ago. We used a dense map of single-nucleotide diagnostic markers (mean distance 15.6 base pairs) in 1,673 sequenced S. cerevisiae isolates to catalogue 3,852 sequence blocks (≥5 consecutive markers) introgressed from S. paradoxus, with most being recent and clade-specific. The highly diverged wild Chinese S. cerevisiae lineages were depleted of introgressed blocks but retained an excess of individual ancestral polymorphisms derived from incomplete lineage sorting, perhaps due to less dramatic population bottlenecks. In the non-Chinese S. cerevisiae lineages, we inferred major hybridization events and detected cases of overlapping introgressed blocks across distinct clades due to either shared histories or convergent evolution. We experimentally engineered, in otherwise isogenic backgrounds, the introgressed PAD1-FDC1 gene pair that independently arose in two S. cerevisiae clades and revealed that it increases resistance against diverse antifungal drugs. Overall, our study retraces the histories of divergence and secondary contacts across S. cerevisiae and S. paradoxus populations and unveils a functional outcome.

The history of Coast Salish "woolly dogs" revealed by ancient genomics and Indigenous Knowledge.

Ancestral Coast Salish societies in the Pacific Northwest kept long-haired "woolly dogs" that were bred and cared for over millennia. However, the dog wool-weaving tradition declined during the 19th century, and the population was lost. In this study, we analyzed genomic and isotopic data from a preserved woolly dog pelt from "Mutton," collected in 1859. Mutton is the only known example of an Indigenous North American dog with dominant precolonial ancestry postdating the onset of settler colonialism. We identified candidate genetic variants potentially linked with their distinct woolly phenotype. We integrated these data with interviews from Coast Salish Elders, Knowledge Keepers, and weavers about shared traditional knowledge and memories surrounding woolly dogs, their importance within Coast Salish societies, and how colonial policies led directly to their disappearance.

Four-Year Outcome of XEN 45 Gel Stent Implantation in a Swedish Population.

Purpose: To report the long-time success rate of XEN 45 gel stent implantation in a Scandinavian population. Patients and Methods: This was a retrospective single-center analysis of all patients undergoing XEN 45 stent surgery between December 2015 and May 2017. The main outcome was success rate according to several definitions of success. Subgroup analysis was performed. Secondary outcomes were change in intraocular pressure (IOP) and number of IOP-lowering agents. Need for secondary glaucoma surgery, needling rate and complications were recorded. Results: A total of 103 eyes could be evaluated after four years. Mean age was 70.6 years. Primary open-angle glaucoma (POAG) accounted for 46.6% and exfoliative glaucoma (PEXG) for 39.8%. Mean IOP dropped from 24.0 to 15.9 mmHg (p<0.001) and IOP-lowering agents from 3.5 to 1.5 (p<0.001). The success rate with individual target pressures after four years was 43.7%. Secondary glaucoma surgery was performed in 45 (43.7%) of cases. Combined cases (n=12) were not statistically different to stand-alone procedures (p=0.28). No difference between PEXG and POAG could be detected (p=0.44). During the learning curve, stent misplacement was common and resulted in worse outcome for less experienced surgeons. Conclusion: The overall success rate of XEN 45 gel stent surgery in the present cohort is relatively low in a long-time follow-up under the given circumstances if all initial patients are included to follow-up. The influence of the surgeon's learning curve is obvious, and improvement in success can be expected when used by experienced and high-volume surgeons. No significant differences were found in PEXG compared to POAG or in XEN surgery combined with cataract surgery compared to stand-alone.

Yersinia pestis genomes reveal plague in Britain 4000 years ago.

Extinct lineages of Yersinia pestis, the causative agent of the plague, have been identified in several individuals from Eurasia between 5000 and 2500 years before present (BP). One of these, termed the 'LNBA lineage' (Late Neolithic and Bronze Age), has been suggested to have spread into Europe with human groups expanding from the Eurasian steppe. Here, we show that the LNBA plague was spread to Europe's northwestern periphery by sequencing three Yersinia pestis genomes from Britain, all dating to ~4000 cal BP. Two individuals were from an unusual mass burial context in Charterhouse Warren, Somerset, and one individual was from a single burial under a ring cairn monument in Levens, Cumbria. To our knowledge, this represents the earliest evidence of LNBA plague in Britain documented to date. All three British Yersinia pestis genomes belong to a sublineage previously observed in Bronze Age individuals from Central Europe that had lost the putative virulence factor yapC. This sublineage is later found in Eastern Asia ~3200 cal BP. While the severity of the disease is currently unclear, the wide geographic distribution within a few centuries suggests substantial transmissibility.

Current clinical practice in corneal crosslinking for treatment of progressive keratoconus in four Nordic countries.

PURPOSE: To evaluate clinical practice in the diagnosis and treatment of progressive keratoconus with corneal crosslinking (CXL) in four Nordic countries. METHODS: A questionnaire was sent to all centres at which keratoconus patients are evaluated and CXL is performed in Sweden, Denmark, Norway and Iceland. Nineteen of 20 centres participated. RESULTS: CXL is performed approximately 1300 times per year in these four Nordic countries with a population of around 21.7 million (2019). In most cases, progression is evaluated using the Pentacam HR, and the maximum keratometry reading (Kmax ) is considered the most important parameter. The most frequently used treatment protocol in Scandinavia is the 9 mW/cm2 epi-off protocol, using hydroxylpropyl methylcellulose riboflavin (HPMC-riboflavin). The participants deemed the following areas to be in most need of improvement: adaptation of the CXL protocol to individual patients (5/19), the development of effective epi-on treatment protocols (4/19), optimal performance of CXL in thin corneas (4/19), improvement of the definition of progression (2/19), and diagnosis of the need for re-treatment (2/19). CONCLUSIONS: We concluded that the diagnosis of progressive keratoconus and the diagnostic equipment used are similar. Treatment strategies are also similar but are suitably different to provide an interesting basis for the comparison of treatment outcomes. The high degree of participation in this survey indicates the possibility of future scientific collaboration on CXL focusing on the areas deemed to need improvement. It would also be of interest to evaluate the possibility of creating a Nordic CXL Registry. The high number of CXL treatments performed ensures sufficient statistical power to solve many questions. Such a registry could be an important contribution to evidence-based care and would allow for longitudinal evaluation.

Grey wolf genomic history reveals a dual ancestry of dogs.

The grey wolf (Canis lupus) was the first species to give rise to a domestic population, and they remained widespread throughout the last Ice Age when many other large mammal species went extinct. Little is known, however, about the history and possible extinction of past wolf populations or when and where the wolf progenitors of the present-day dog lineage (Canis familiaris) lived1-8. Here we analysed 72 ancient wolf genomes spanning the last 100,000 years from Europe, Siberia and North America. We found that wolf populations were highly connected throughout the Late Pleistocene, with levels of differentiation an order of magnitude lower than they are today. This population connectivity allowed us to detect natural selection across the time series, including rapid fixation of mutations in the gene IFT88 40,000-30,000 years ago. We show that dogs are overall more closely related to ancient wolves from eastern Eurasia than to those from western Eurasia, suggesting a domestication process in the east. However, we also found that dogs in the Near East and Africa derive up to half of their ancestry from a distinct population related to modern southwest Eurasian wolves, reflecting either an independent domestication process or admixture from local wolves. None of the analysed ancient wolf genomes is a direct match for either of these dog ancestries, meaning that the exact progenitor populations remain to be located.

Incidental cardiac findings on somatostatin receptor PET/CT: What do they indicate and are they of clinical relevance?

We present the case of a 47-year-old man with a history of recurrent episodes of frontal headache, fever, and chest discomfort as well as longstanding, difficult to treat arterial hypertension. Clinical work-up revealed the unexpected finding of an underlying pheochromocytoma as well as recent "silent" myocardial infarction. Our case highlights the importance of paying attention to incidental cardiac findings on somatostatin receptor positron emission tomography/computed tomography, as routinely performed in patients with clinically suspected neuroendocrine tumors. These incidental cardiac findings cannot only indicate a primary or secondary (metastatic) neuroendocrine tumor, but also areas of myocardial inflammation, as somatostatin receptors cannot only be found on the majority of neuroendocrine tumors, but also among other tissues on the surface of activated macrophages and lymphocytes. The detection of myocardial inflammation is of clinical importance and its underlying etiology should be evaluated to prompt eventual necessary treatment, as it is a potential driving force for cardiac remodeling and poor prognosis.

An inter-day assessment of the ABC parameters in the evaluation of progressive keratoconus.

The progression of keratoconus is commonly determined by comparing the results of corneal tomographic measurements on different occasions. However, investigations on the repeatability of measurements are commonly performed within the same day, thus not taking the inter-day variation into account. The effect of keratoconus disease severity on the measurement error is also seldom considered. In this post hoc investigation, the parameters A, B and C in the Belin ABCD Progression Display were evaluated in relation to disease severity in intra-day and inter-day measurements. Four consecutive measurements were performed on 61 patients with keratoconus on the same day (intra-day). In another cohort, four consecutive measurements were obtained and then repeated 3 days later in 25 patients with keratoconus and 25 healthy controls (inter-day). The results suggest that the diagnosis of disease progression would benefit from inter-day measurements, and the stratification of the parameters A and C according to disease severity. It is also recommended that tomographic systems such as the Pentacam HR be modified to allow the comparison of both single measurements and the mean of replicate measurements of the parameters used in the assessment of progression of keratoconus.

Genome-scale sequencing and analysis of human, wolf, and bison DNA from 25,000-year-old sediment.

Cave sediments have been shown to preserve ancient DNA but so far have not yielded the genome-scale information of skeletal remains. We retrieved and analyzed human and mammalian nuclear and mitochondrial environmental "shotgun" genomes from a single 25,000-year-old Upper Paleolithic sediment sample from Satsurblia cave, western Georgia:first, a human environmental genome with substantial basal Eurasian ancestry, which was an ancestral component of the majority of post-Ice Age people in the Near East, North Africa, and parts of Europe; second, a wolf environmental genome that is basal to extant Eurasian wolves and dogs and represents a previously unknown, likely extinct, Caucasian lineage; and third, a European bison environmental genome that is basal to present-day populations, suggesting that population structure has been substantially reshaped since the Last Glacial Maximum. Our results provide new insights into the Late Pleistocene genetic histories of these three species and demonstrate that direct shotgun sequencing of sediment DNA, without target enrichment methods, can yield genome-wide data informative of ancestry and phylogenetic relationships.

Evaluation of SSTR2 Expression in SI-NETs and Relation to Overall Survival after PRRT.

(1) Purpose: Small intestinal neuroendocrine tumors (SI-NETs) often present with distant metastases at diagnosis. Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogues is a systemic treatment that increases overall survival (OS) in SI-NET patients with stage IV disease. However, the treatment response after PRRT, which targets somatostatin receptor 2 (SSTR2), is variable and predictive factors have not been established. This exploratory study aims to evaluate if SSTR2 expression in SI-NETs could be used to predict OS after PRRT treatment. (2) Methods: Using a previously constructed Tissue Micro Array (TMA) we identified tissue samples from 42 patients that had received PRRT treatment during 2006-2017 at Sahlgrenska University hospital. Immunohistochemical expression of SSTR2, Ki-67 and neuroendocrine markers synaptophysin and Chromogranin A (CgA) were assessed. A retrospective estimation of 177Lu-DOTATATE uptake in 33 patients was performed. Data regarding OS and non-surgical treatment after PRRT were collected. Another subgroup of 34 patients with paired samples from 3 tumor sites (primary tumor, lymph node and liver metastases) was identified in the TMA. The SSTR2 expression was assessed in corresponding tissue samples (n = 102). (3) Results: The patients were grouped into Low SSTR2 or High SSTR2 groups based upon on levels of SSTR2 expression. There was no significant difference in 177Lu-DOTATATE uptake between the groups. The patients in the Low SSTR2 group had significantly longer OS after PRRT than the patients in the High SSTR2 group (p = 0.049). PRRT treated patients with low SSTR2 expression received less additional treatment compared with patients with high SSTR2 expression. SSTR2 expression did not vary between tumor sites but correlated within patients. (4) Conclusion: The results from the present study suggest that retrospective evaluation of SSTR2 expression in resected tumors cannot be used to predict OS after PRRT.

Million-year-old DNA sheds light on the genomic history of mammoths.

Temporal genomic data hold great potential for studying evolutionary processes such as speciation. However, sampling across speciation events would, in many cases, require genomic time series that stretch well back into the Early Pleistocene subepoch. Although theoretical models suggest that DNA should survive on this timescale1, the oldest genomic data recovered so far are from a horse specimen dated to 780-560 thousand years ago2. Here we report the recovery of genome-wide data from three mammoth specimens dating to the Early and Middle Pleistocene subepochs, two of which are more than one million years old. We find that two distinct mammoth lineages were present in eastern Siberia during the Early Pleistocene. One of these lineages gave rise to the woolly mammoth and the other represents a previously unrecognized lineage that was ancestral to the first mammoths to colonize North America. Our analyses reveal that the Columbian mammoth of North America traces its ancestry to a Middle Pleistocene hybridization between these two lineages, with roughly equal admixture proportions. Finally, we show that the majority of protein-coding changes associated with cold adaptation in woolly mammoths were already present one million years ago. These findings highlight the potential of deep-time palaeogenomics to expand our understanding of speciation and long-term adaptive evolution.

Origins of modern human ancestry.

New finds in the palaeoanthropological and genomic records have changed our view of the origins of modern human ancestry. Here we review our current understanding of how the ancestry of modern humans around the globe can be traced into the deep past, and which ancestors it passes through during our journey back in time. We identify three key phases that are surrounded by major questions, and which will be at the frontiers of future research. The most recent phase comprises the worldwide expansion of modern humans between 40 and 60 thousand years ago (ka) and their last known contacts with archaic groups such as Neanderthals and Denisovans. The second phase is associated with a broadly construed African origin of modern human diversity between 60 and 300 ka. The oldest phase comprises the complex separation of modern human ancestors from archaic human groups from 0.3 to 1 million years ago. We argue that no specific point in time can currently be identified at which modern human ancestry was confined to a limited birthplace, and that patterns of the first appearance of anatomical or behavioural traits that are used to define Homo sapiens are consistent with a range of evolutionary histories.

The Interday Repeatability of Parameters for the Assessment of Progressive Disease in Subjects With Less Advanced Keratoconus.

PURPOSE: To evaluate the interday repeatability in the measurement of parameters used for the detection of progression of keratoconus by prediction limits (PL) for single measurements, and the repeatability coefficient (RC) for the mean of replicate measurements. DESIGN: Prospective reliability analysis for cases and control eyes. METHODS: Twenty-five eyes in 25 subjects with KC and 25 eyes in 25 healthy controls were included. Four consecutive measurements were made, 3 days apart, with a Pentacam HR tomographic instrument (denoted the Pentacam) and a Nidek ARK 560-A auto-keratometer (denoted the keratometer). Main outcome measures were the intra- and interday RC of parameters used in the detection of progression of keratoconus. RESULTS: The most repeatable parameter obtained with the Pentacam was the curvature power of the central flat meridian (K1, 0.44 D [RC], -0.55 to 0.60 diopter [D] [PL]), followed by the central steep meridian (K2, 0.72 D [RC], -0.90 to 0.94 D [PL]). The interday repeatability of K1 and K2 was similar when using the keratometer (K1, 0.32 D [RC], -0.66 to 0.57 D [PL], K2, 0.93 D [RC], -1.36 to 1.08 D [PL]). The interday repeatability of the curvature power of the steepest point (Kmax, 0.84 D [RC], -0.90 to 1.11 D [PL]) would benefit from being stratified: RC = 0.44 D and PL = -0.49 to 0.67 D for Kmax < 49.0 D, and RC = 1.08 D and PL = -1.19 to 1.42 D for Kmax ≥ 49.0 D. CONCLUSIONS: The interday repeatability of measurements, single or replicate, in subjects with keratoconus should be considered when diagnosing progressive disease. K1 exhibited the best intraday repeatability. Kmax benefits from being stratified according to disease severity.

Archaeological Central American maize genomes suggest ancient gene flow from South America.

Maize (Zea mays ssp. mays) domestication began in southwestern Mexico ∼9,000 calendar years before present (cal. BP) and humans dispersed this important grain to South America by at least 7,000 cal. BP as a partial domesticate. South America served as a secondary improvement center where the domestication syndrome became fixed and new lineages emerged in parallel with similar processes in Mesoamerica. Later, Indigenous cultivators carried a second major wave of maize southward from Mesoamerica, but it has been unclear until now whether the deeply divergent maize lineages underwent any subsequent gene flow between these regions. Here we report ancient maize genomes (2,300-1,900 cal. BP) from El Gigante rock shelter, Honduras, that are closely related to ancient and modern maize from South America. Our findings suggest that the second wave of maize brought into South America hybridized with long-established landraces from the first wave, and that some of the resulting newly admixed lineages were then reintroduced to Central America. Direct radiocarbon dates and cob morphological data from the rock shelter suggest that more productive maize varieties developed between 4,300 and 2,500 cal. BP. We hypothesize that the influx of maize from South America into Central America may have been an important source of genetic diversity as maize was becoming a staple grain in Central and Mesoamerica.

Learning Curve and One-Year Outcome of XEN 45 Gel Stent Implantation in a Swedish Population.

PURPOSE: Evaluation of 1-year-outcome of XEN 45 gel stent surgery in a Swedish cohort with regard to clinical success, complications, and learning curve. PATIENTS AND METHODS: This was a retrospective study of glaucoma patients undergoing glaucoma XEN-stent surgery alone or combined with phacoemulsification between December 2015 and May 2017. Intraocular pressure (IOP), number of medical agents, and adverse events were assessed. Clinical success rate was defined as achieving individual target pressure with/without medication. RESULTS: A total of 113 eyes were included in the final statistics. Mean age was 70.8±11.8 years. Primary open angle glaucoma (POAG) accounted for 46.9% and exfoliative glaucoma (PEXG) for 40.7%. Mean preoperative IOP was 23.8±6.2 mmHg and mean number of agents 3.4. After 1 year, mean IOP was reduced to 16.1±4.7 mmHg and medication to 1.34 substances on average. Failure rate at 1-year follow-up was 34% with no significant difference between POAG and PEXG. There was a trend of higher success rate for combined cases (P=0.116). Stents with malpositioned or curved appearance had significantly worse outcome. The failure rate of the most productive surgeon dropped from 33% to 10% from the first implantations. Temporary hypotony (19.5%) and choroidal detachment (9.7%) were the most common complications. Blockage of the inner stent lumen was common (8.8%), with a high proportion of failure. CONCLUSION: XEN-stent surgery is a surgical option in uncontrolled glaucoma in both POAG and PEXG. A XEN-stent can reduce both IOP and the number of antiglaucoma medications needed. The learning curve is significant and stent positioning is crucial for optimal results. Combined XEN-cataract surgery is not inferior to stand-alone procedures. The long-time effectiveness is still to be proven.

Origins and genetic legacy of prehistoric dogs.

Dogs were the first domestic animal, but little is known about their population history and to what extent it was linked to humans. We sequenced 27 ancient dog genomes and found that all dogs share a common ancestry distinct from present-day wolves, with limited gene flow from wolves since domestication but substantial dog-to-wolf gene flow. By 11,000 years ago, at least five major ancestry lineages had diversified, demonstrating a deep genetic history of dogs during the Paleolithic. Coanalysis with human genomes reveals aspects of dog population history that mirror humans, including Levant-related ancestry in Africa and early agricultural Europe. Other aspects differ, including the impacts of steppe pastoralist expansions in West and East Eurasia and a near-complete turnover of Neolithic European dog ancestry.

Population Structure, Stratification, and Introgression of Human Structural Variation.

Structural variants contribute substantially to genetic diversity and are important evolutionarily and medically, but they are still understudied. Here we present a comprehensive analysis of structural variation in the Human Genome Diversity panel, a high-coverage dataset of 911 samples from 54 diverse worldwide populations. We identify, in total, 126,018 variants, 78% of which were not identified in previous global sequencing projects. Some reach high frequency and are private to continental groups or even individual populations, including regionally restricted runaway duplications and putatively introgressed variants from archaic hominins. By de novo assembly of 25 genomes using linked-read sequencing, we discover 1,643 breakpoint-resolved unique insertions, in aggregate accounting for 1.9 Mb of sequence absent from the GRCh38 reference. Our results illustrate the limitation of a single human reference and the need for high-quality genomes from diverse populations to fully discover and understand human genetic variation.