resolving a 150 year old paternity case in mormon history using dtc autosomal dna testing of distant relatives

Abstract Although autosomal DNA testing has been available for a number of years, its use to reconstruct genetic profiles of people that lived centuries in the past is relatively recent and there are no published cases where it was employed to verify a kinship relation, likely to be an alleged paternity, that occurred one and a half century ago. DNA testing has already been employed to study the ancestry and posterity of Joseph Smith Jr., founder of the Latter-day Saint (Mormon) movement. Thanks to information found on the paternally inherited Y chromosome, a number of alleged paternities have been disproved, but obviously this analysis is not effective for alleged daughters. Likewise, his reconstructed mitogenome sequence, reported here for the first time, provides information about his maternal ancestry, but is useless in any paternity questions due to the strict maternal inheritance. Among all the children attributed to Joseph Smith Jr., Josephine Lyon, born in 1844, is perhaps the most frequently mentioned. In the current study, 56 individuals, mostly direct descendants of Joseph Smith Jr. and Josephine Lyon, had their autosomal DNA tested to verify Josephine's biological paternity. Nearly 600,000 autosomal SNPs from each subject were typed and detailed genealogical data were compiled. The absence of shared DNA between Josephine's grandson and Joseph Smith Jr.'s five great-grandchildren together with various amounts of autosomal DNA shared by the same individual with four other relatives of Windsor Lyon is a clear indication that Josephine was not related to the Smith, but to the Lyon's family. These inferences were also verified using kinship analyses and likelihood ratio calculations

On-sky single-mode fiber coupling measurements at the Large Binocular Telescope

The demonstration of efficient single-mode fiber (SMF) coupling is a key requirement for the development of a compact, ultra-precise radial velocity (RV) spectrograph. iLocater is a next generation instrument for the Large Binocular Telescope (LBT) that uses adaptive optics (AO) to inject starlight into a SMF. In preparation for commissioning iLocater, a prototype SMF injection system was installed and tested at the LBT in the Y-band (0.970-1.065 $\mu$m). This system was designed to verify the capability of the LBT AO system as well as characterize on-sky SMF coupling efficiencies. SMF coupling was measured on stars with variable airmasses, apparent magnitudes, and seeing conditions for six half-nights using the Large Binocular Telescope Interferometer. We present the overall optical and mechanical performance of the SMF injection system, including details of the installation and alignment procedure. A particular emphasis is placed on analyzing the instrument's performance as a function of telescope elevation to inform the final design of the fiber injection system for iLocater.Comment: 11 pages, 7 figure

Arrival of Paleo-Indians to the Southern Cone of South America: New Clues from Mitogenomes

With analyses of entire mitogenomes, studies of Native American mitochondrial DNA (mtDNA) variation have entered the final phase of phylogenetic refinement: the dissection of the founding haplogroups into clades that arose in America during and after human arrival and spread. Ages and geographic distributions of these clades could provide novel clues on the colonization processes of the different regions of the double continent. As for the Southern Cone of South America, this approach has recently allowed the identification of two local clades (D1g and D1j) whose age estimates agree with the dating of the earliest archaeological sites in South America, indicating that Paleo-Indians might have reached that region from Beringia in less than 2000 years. In this study, we sequenced 46 mitogenomes belonging to two additional clades, termed B2i2 (former B2l) and C1b13, which were recently identified on the basis of mtDNA control-region data and whose geographical distributions appear to be restricted to Chile and Argentina. We confirm that their mutational motifs most likely arose in the Southern Cone region. However, the age estimate for B2i2 and C1b13 (11–13,000 years) appears to be younger than those of other local clades. The difference could reflect the different evolutionary origins of the distinct South American-specific sub-haplogroups, with some being already present, at different times and locations, at the very front of the expansion wave in South America, and others originating later in situ, when the tribalization process had already begun. A delayed origin of a few thousand years in one of the locally derived populations, possibly in the central part of Chile, would have limited the geographical and ethnic diffusion of B2i2 and explain the present-day occurrence that appears to be mainly confined to the Tehuelche and Araucanian-speaking grou

Analysis of the human Y-chromosome haplogroup Q characterizes ancient population movements in Eurasia and the Americas

Background: Recent genome studies of modern and ancient samples have proposed that Native Americans derive from a subset of the Eurasian gene pool carried to America by an ancestral Beringian population, from which two well-differentiated components originated and subsequently mixed in different proportion during their spread in the Americas. To assess the timing, places of origin and extent of admixture between these components, we performed an analysis of the Y-chromosome haplogroup Q, which is the only Pan-American haplogroup and accounts for virtually all Native American Y chromosomes in Mesoamerica and South America. Results: Our analyses of 1.5 Mb of 152 Y chromosomes, 34 re-sequenced in this work, support a "coastal and inland routes scenario" for the first entrance of modern humans in North America. We show a major phase of male population growth in the Americas after 15 thousand years ago (kya), followed by a period of constant population size from 8 to 3 kya, after which a secondary sign of growth was registered. The estimated dates of the first expansion in Mesoamerica and the Isthmo-Colombian Area, mainly revealed by haplogroup Q-Z780, suggest an entrance in South America prior to 15 kya. During the global constant population size phase, local South American hints of growth were registered by different Q-M848 sub-clades. These expansion events, which started during the Holocene with the improvement of climatic conditions, can be ascribed to multiple cultural changes rather than a steady population growth and a single cohesive culture diffusion as it occurred in Europe. Conclusions: We established and dated a detailed haplogroup Q phylogeny that provides new insights into the geographic distribution of its Eurasian and American branches in modern and ancient samples

The phylogeny of the four pan-American MtDNA haplogroups: Implications for evolutionary and disease studies

Only a limited number of complete mitochondrial genome sequences belonging to Native American haplogroups were available until recently, which left America as the continent with the least of information about sequence variation of entire mitochondrial DNAs. In this study, a comprehensive overview of all available complete mitochondrial DNA (mtDNA) genomes of the four pan-American haplogroups A2, B2, C1, and D1 is provided by revising the information scattered throughout GenBank and the literature, and adding 14 novel mtDNA sequences. The phylogenies of haplogroups A2, B2, C1, and D1 reveal a large number of sub haplogroups but suggest that the ancestral Beringian population(s) contributed only six (successful) founder haplotypes to these haplogroups. The derived are overall starlike with coalescence times ranging from 18,000 to 21,000 years (with one exception) using the conventional calibration. The average of about 19,000 years somewhat contrast with the corresponding lower age of about 13,500 years that was recently proposed by employing a different calibration and estimation approach. Our estimate indicates a human entry and spread of the pan-American haplogroups into the Americas right after the peak of the Last Glacial Maximum and comfortably agrees with the undisputed ages of the earliest Paleoindians in South America. In addition, the phylogenetic approach also indicates that the pathogenic status proposed for various mtDNA mutations, which actually define branches of Native American haplogroups, was based on insufficient grounds.Instituto Multidisciplinario de Biología CelularFacultad de Ciencias Naturales y Muse

Automated echocardiographic detection of heart failure with preserved ejection fraction using artificial intelligence

Background: Detection of heart failure with preserved ejection fraction (HFpEF) involves integration of multiple imaging and clinical features which are often discordant or indeterminate. Objectives: We applied artificial intelligence (AI) to analyze a single apical four-chamber (A4C) transthoracic echocardiogram videoclip to detect HFpEF. Methods: A three-dimensional convolutional neural network was developed and trained on A4C videoclips to classify patients with HFpEF (diagnosis of HF, EF≥50%, and echocardiographic evidence of increased filling pressure; cases) versus without HFpEF (EF≥50%, no diagnosis of HF, normal filling pressure; controls). Model outputs were classified as HFpEF, no HFpEF, or non-diagnostic (high uncertainty). Performance was assessed in an independent multi-site dataset and compared to previously validated clinical scores. Results: Training and validation included 2971 cases and 3785 controls (validation holdout, 16.8% patients), and demonstrated excellent discrimination (AUROC:0.97 [95%CI:0.96-0.97] and 0.95 [0.93-0.96] in training and validation, respectively). In independent testing (646 cases, 638 controls), 94 (7.3%) were non-diagnostic; sensitivity (87.8%; 84.5-90.9%) and specificity (81.9%; 78.2-85.6%) were maintained in clinically relevant subgroups, with high repeatability and reproducibility. Of 701 and 776 indeterminate outputs from the HFA-PEFF and H2FPEF scores, the AI HFpEF model correctly reclassified 73.5 and 73.6%, respectively. During follow-up (median [IQR]:2.3 [0.5-5.6] years), 444 (34.6%) patients died; mortality was higher in patients classified as HFpEF by AI (hazard ratio [95%CI]:1.9 [1.5-2.4]). Conclusion: An AI HFpEF model based on a single, routinely acquired echocardiographic video demonstrated excellent discrimination of patients with versus without HFpEF, more often than clinical scores, and identified patients with higher mortality

‘Stop-go’ policy and the restriction of post-war British house-building

From the mid-1950s to the early 1980s the Treasury and Bank of England successfully advocated a policy of restricting both private and public sector house-building, as a key but covert instrument of their wider ‘stop-go’ macroeconomic policy framework. While the intensity of restrictions varied over the economic cycle, private house-building was restricted (through limiting mortgage availability) for almost all this period. This was achieved by keeping building society interest rates low relative to other interest rates and thus starving the building society movement of mortgage funds. Mortgage restriction was never publicly discussed and sometimes operated alongside ambitious housing targets and well-publicised policy initiatives to boost housing demand. This paper outlines the evolution of house-building restriction, together with its impacts on the housing sector and the wider economy. We review the evolution of the policy framework and its consequences, compare the level and stability of British house-building during this period - historically and relative to other countries, and undertake time-series econometric analysis of its impacts on both house-building and house prices. Finally, implications for debates regarding stop-go policy, Britain’s housing problem, and the distributional consequences of government macroeconomic policy are discussed

Diagnosing Mitochondrial Disorders Remains Challenging in the Omics Era

Objective: We hypothesized that novel investigative pathways are needed to decrease diagnostic odysseys in pediatric mitochondrial disease and sought to determine the utility of clinical exome sequencing in a large cohort with suspected mitochondrial disease and to explore whether any of the traditional indicators of mitochondrial disease predict a confirmed genetic diagnosis. Methods: We investigated a cohort of 85 pediatric patients using clinical exome sequencing and compared the results with the outcome of traditional diagnostic tests, including biochemical testing of routine parameters (lactate, alanine, and proline), neuroimaging, and muscle biopsy with histology and respiratory chain enzyme activity studies. Results: We established a genetic diagnosis in 36.5% of the cohort and report 20 novel disease-causing variants (1 mitochondrial DNA). Counterintuitively, routine biochemical markers were more predictive of mitochondrial disease than more invasive and elaborate muscle studies. Conclusions: We propose using biochemical markers to support the clinical suspicion of mitochondrial disease and then apply first-line clinical exome sequencing to identify a definite diagnosis. Muscle biopsy studies should only be used in clinically urgent situations or to confirm an inconclusive genetic result. Classification of Evidence: This is a Class II diagnostic accuracy study showing that the combination of CSF and plasma biochemical tests plus neuroimaging could predict the presence or absence of exome sequencing confirmed mitochondrial disorders

Y-chromosome Short Tandem Repeat DYS458.2 Non-consensus Alleles Occur Independently in Both Binary Haplogroups J1-M267 and R1b3-M405

Cilj: Odrediti haploskupinsku osnovu “non-consensus” kratkih udvojenih sljedova (engl., short tandem repeat, STR) alela DYS458.2 na kromosomu Y i procijeniti njihov filogenetski podustroj i učestalost u reprezentativnim uzorcima sa Srednjega Istoka, Europe i Pakistana. Postupci: Molekularna karakterizacija povezanosti i konstrukcija haplotipova provedena je kombinacijom dvaju pristupa – analizom binarnog polimorfizma koji definira haploskupinu kromosoma Y i analizom do 37 lokusa STR, uključujući i DYS388. Za utvrđivanje povezanosti kromosoma Y koji sadrže slijed DYS458.2, rabljeno je sekvencioniranje DNA lokusa DYS458 i mrežna analiza udaljenosti od medijana. Rezultati Pokazali smo da je novi alel DYS458.2 nastao nezavisno na najmanje dvije osnove binarnih haploskupina, a možda i na trećoj. U svim haploskupinama kromosoma J1 koje su pregledane, uključivši i njegove poznate a malobrojne pod-haploskupine, nađen je fiksan dužinski uzorak parcijalnoga alela. U alternativnom M405 povezanom s R1b3 definiranoj pod-haploskupini nađene su i DYS458.0 i DYS458.2 alelne klase. Pojedinačni kromosom također se mogao svrstati u R1b3-M269*(xM405) klasu. Fizički smještaj djelomične nsercije/delecije u normalnom slijedu tetramera jasno se razlikovao u kontekstu svake haploskupine. Zaključak: Iako neobični aleli DYS458.2 pružaju korisne informacije, prilikom zaključivanja o haploskupinskoj osnovi i uobičajenom nasljeđivanju potrebne su dodatne informacije o drugim vezanim polimorfnim lokusima.Aim: To determine the human Y-chromosome haplogroup backgrounds of non-consensus DYS458.2 short tandem repeat alleles and evaluate their phylogenetic substructure and frequency in representative samples from the Middle East, Europe, and Pakistan. Methods: Molecular characterization of lineages was achieved using a combination of Y-chromosome haplogroup defining binary polymorphisms and up to 37 short tandem repeat loci, including DYS388 to construct haplotypes. DNA sequencing of the DYS458 locus and median-joining network analyses were used to evaluate Y-chromosome lineages displaying the DYS458.2 motif. Results: We showed that the DYS458.2 allelic innovation arose independently on at least two distinctive binary haplogroup backgrounds and possibly a third as well. The partial allele length pattern was fixed in all haplogroup J1 chromosomes examined, including its known rare sub-haplogroups. Within the alternative R1b3 associated M405 defined sub-haplogroup, both DYS458.0 and DYS458.2 allele classes occurred. A single chromosome also allocated to the R1b3-M269*(xM405) classification. The physical position of the partial insertion/deletion occurrence within the normal tetramer tract differed distinctly in each haplogroup context. Conclusions: While unusual DYS458.2 alleles are informative, additional information for other linked polymorphic loci is required when using such non-conforming alleles to infer haplogroup background and common ancestry