Efficient Moment-Based Inference of Admixture Parameters and Sources of Gene Flow

The recent explosion in available genetic data has led to significant advances in understanding the demographic histories of and relationships among human populations. It is still a challenge, however, to infer reliable parameter values for complicated models involving many populations. Here, we present MixMapper, an efficient, interactive method for constructing phylogenetic trees including admixture events using single nucleotide polymorphism (SNP) genotype data. MixMapper implements a novel two-phase approach to admixture inference using moment statistics, first building an unadmixed scaffold tree and then adding admixed populations by solving systems of equations that express allele frequency divergences in terms of mixture parameters. Importantly, all features of the model, including topology, sources of gene flow, branch lengths, and mixture proportions, are optimized automatically from the data and include estimates of statistical uncertainty. MixMapper also uses a new method to express branch lengths in easily interpretable drift units. We apply MixMapper to recently published data for Human Genome Diversity Cell Line Panel individuals genotyped on a SNP array designed especially for use in population genetics studies, obtaining confident results for 30 populations, 20 of them admixed. Notably, we confirm a signal of ancient admixture in European populations—including previously undetected admixture in Sardinians and Basques—involving a proportion of 20–40% ancient northern Eurasian ancestry

Objective Quantification of Neuromotor Symptoms in Parkinson's Disease: Implementation of a Portable, Computerized Measurement Tool

Quantification of neuromotor symptoms with device-based measures provides a useful supplement to clinical evaluation. Research using the CATSYS has established its utility as a computerized measurement system to quantify neuromotor function. The primary objective of this study is to provide technical guidance on the use of the CATSYS in Parkinson's disease (PD). Forty-four patients with idiopathic PD and 28 healthy controls were prospectively recruited and evaluated with CATSYS, a portable, Windows-based system consisting of a data logger and four different sensors (tremor pen, touch recording plate, reaction time handle, and force plate for balance recording) for quantification of neuromotor functions. CATSYS discriminated between PD and controls on measurements of rest/postural tremor, pronation/supination, finger tapping, simple reaction time, and postural sway intensity and velocity. CATSYS measurements using the proposed test battery were associated with relevant clinician-rated Unified Parkinson's disease rating scale (UPDRS) items assessing tremor and bradykinesia. More work is warranted to establish CATSYS as a diagnostic/monitoring instrument in movement disorders using the proposed technical approaches

Dementia and Stroke Risk Associated with Brain Artery Luminal Diameters

Background: It is unclear whether brain artery diameters measured on conventional T2-weighted brain MRI images relate to dementia and stroke outcomes across distinct populations. We aimed this study to evaluate the association of T2-weighted brain artery luminal diameters with dementia and stroke in three distinct population‑based studies. Methods: Three longitudinal population-based studies with 8420 adults \u3e40 years old (Northern Manhattan Study [NOMAS] from the United States, and the Rotterdam Study [RS], from the Netherlands, and Three-City, from France) with brain MRI scans obtained between 1999 and 2015. The median follow-up time for clinical events ranged between 7 and 12.5 years. We tested our hypothesis in each cohort separately due to local data‑sharing regulations. The exposure variable was brain carotid and basilar artery luminal diameters measured on MRI axial T2‑weighted scans. Multivariable hazard ratios (HRs) and their 95% confidence intervals (CI) expressed the risk of dementia and stroke (primary outcomes) associated with the lowest (\u3c5th) and highest (\u3e95th) percentiles of the rank‑normalized brain artery diameters compared to a reference group defined as the diameters distributed between the 5th and 95th percentiles. Secondary outcomes included total and vascular mortality, and fatal and nonfatal cardiovascular and coronary end points. Results: Among the three cohorts (mean age ranged from 65 to 73 y, ≥57% women), 335 participants developed dementia and 331 strokes. Compared with the reference group, participants with arterial diameters \u3e95th percentile had a higher risk of dementia (HR range 1.15-4.50) and any stroke (HR range 1.29-2.03). For secondary outcomes, participants with arterial diameters \u3e95th percentile had a consistent higher risk of coronary outcomes, vascular mortality and a composite of any vascular events. The results were less supportive of a higher risk of events among participants with arterial diameters \u3c5th percentile except for vascular mortality. Conclusions: Individuals with dilated brain arteries are at higher risk of dementia and vascular events. Our findings were consistency across distinct populations in spite of using a non-enhanced, conventional T2-weighted MRI sequence. Understanding the underlying physiopathology of the reported associations, particularly with dementia and stroke, might reveal novel vascular contributions to dementi

A global sampling approach to designing and reengineering RNA secondary structures

The development of algorithms for designing artificial RNA sequences that fold into specific secondary structures has many potential biomedical and synthetic biology applications. To date, this problem remains computationally difficult, and current strategies to address it resort to heuristics and stochastic search techniques. The most popular methods consist of two steps: First a random seed sequence is generated; next, this seed is progressively modified (i.e. mutated) to adopt the desired folding properties. Although computationally inexpensive, this approach raises several questions such as (i) the influence of the seed; and (ii) the efficiency of single-path directed searches that may be affected by energy barriers in the mutational landscape. In this article, we present RNA-ensign, a novel paradigm for RNA design. Instead of taking a progressive adaptive walk driven by local search criteria, we use an efficient global sampling algorithm to examine large regions of the mutational landscape under structural and thermodynamical constraints until a solution is found. When considering the influence of the seeds and the target secondary structures, our results show that, compared to single-path directed searches, our approach is more robust, succeeds more often and generates more thermodynamically stable sequences. An ensemble approach to RNA design is thus well worth pursuing as a complement to existing approaches. RNA-ensign is available at http://csb.cs.mcgill.ca/RNAensign.National Science Foundation (U.S.). Graduate Research Fellowship ProgramNatural Sciences and Engineering Research Council of Canada (NSERC) (RGPIN ) (386596-10)Fonds québécois de la recherche sur la nature et les technologies (PR-146375)National Institutes of Health (U.S.) (Grant GM081871)Natural Sciences and Engineering Research Council of Canada (NSERC)National Institutes of Health (U.S.