A question of scale: Human migrations writ large and small

Several recent papers illustrate the importance of migration and gene flow in molding the patterns of genetic variation observed in humans today. We place the varied demographic processes covered by these terms into a more general framework, and discuss some of the challenges facing attempts to reconstruct past human mobility and determine its influence on our genetic heritage

A Genealogical Interpretation of Principal Components Analysis

Principal components analysis, PCA, is a statistical method commonly used in population genetics to identify structure in the distribution of genetic variation across geographical location and ethnic background. However, while the method is often used to inform about historical demographic processes, little is known about the relationship between fundamental demographic parameters and the projection of samples onto the primary axes. Here I show that for SNP data the projection of samples onto the principal components can be obtained directly from considering the average coalescent times between pairs of haploid genomes. The result provides a framework for interpreting PCA projections in terms of underlying processes, including migration, geographical isolation, and admixture. I also demonstrate a link between PCA and Wright's fst and show that SNP ascertainment has a largely simple and predictable effect on the projection of samples. Using examples from human genetics, I discuss the application of these results to empirical data and the implications for inference

The Druze: A Population Genetic Refugium of the Near East

BACKGROUND: Phylogenetic mitochondrial DNA haplogroups are highly partitioned across global geographic regions. A unique exception is the X haplogroup, which has a widespread global distribution without major regions of distinct localization. PRINCIPAL FINDINGS: We have examined mitochondrial DNA sequence variation together with Y-chromosome-based haplogroup structure among the Druze, a religious minority with a unique socio-demographic history residing in the Near East. We observed a striking overall pattern of heterogeneous parental origins, consistent with Druze oral tradition, together with both a high frequency and a high diversity of the mitochondrial DNA (mtDNA) X haplogroup within a confined regional subpopulation. Furthermore demographic modeling indicated low migration rates with nearby populations. CONCLUSIONS: These findings were enabled through the use of a paternal kindred based sampling approach, and suggest that the Galilee Druze represent a population isolate, and that the combination of a high frequency and diversity of the mtDNA X haplogroup signifies a phylogenetic refugium, providing a sample snapshot of the genetic landscape of the Near East prior to the modern age

The FLASSH study: protocol for a randomised controlled trial evaluating falls prevention after stroke and two sub-studies

This randomised controlled trial aims to evaluate the effectiveness of a multi-factorial falls prevention program for stroke survivors who are at high risk of falling when they return home after rehabilitation. Intervention will consist of a home exercise program as well as individualised falls prevention and injury minimisation strategies based on identified risk factors for falls. Additionally, two sub-studies will be implemented in order to explore other key areas related to falls in this population. The first of these is a longitudinal study evaluating the relationship between fear of falling, falls and function over twelve months, and the second evaluates residual impairment in gait stability and obstacle crossing twelve months after discharge from rehabilitation

A Three-Stage Colonization Model for the Peopling of the Americas

Background: We evaluate the process by which the Americas were originally colonized and propose a three-stage model that integrates current genetic, archaeological, geological, and paleoecological data. Specifically, we analyze mitochondrial and nuclear genetic data by using complementary coalescent models of demographic history and incorporating nongenetic data to enhance the anthropological relevance of the analysis. Methodology/Findings: Bayesian skyline plots, which provide dynamic representations of population size changes over time, indicate that Amerinds went through two stages of growth <40,000 and <15,000 years ago separated by a long period of population stability. Isolation-with-migration coalescent analyses, which utilize data from sister populations to estimate a divergence date and founder population sizes, suggest an Amerind population expansion starting <15,000 years ago. Conclusions/Significance: These results support a model for the peopling of the New World in which Amerind ancestors diverged from the Asian gene pool prior to 40,000 years ago and experienced a gradual population expansion as they moved into Beringia. After a long period of little change in population size in greater Beringia, Amerinds rapidly expanded into the Americas <15,000 years ago either through an interior ice-free corridor or along the coast. This rapid colonization of the New World was achieved by a founder group with an effective population size of <1,000–5,400 individuals. Our model presents a detailed scenario for the timing and scale of the initial migration to the Americas, substantially refines th

Noncanonical DNA Motifs as Transactivation Targets by Wild Type and Mutant p53

Sequence-specific binding by the human p53 master regulator is critical to its tumor suppressor activity in response to environmental stresses. p53 binds as a tetramer to two decameric half-sites separated by 0–13 nucleotides (nt), originally defined by the consensus RRRCWWGYYY (n = 0–13) RRRCWWGYYY. To better understand the role of sequence, organization, and level of p53 on transactivation at target response elements (REs) by wild type (WT) and mutant p53, we deconstructed the functional p53 canonical consensus sequence using budding yeast and human cell systems. Contrary to early reports on binding in vitro, small increases in distance between decamer half-sites greatly reduces p53 transactivation, as demonstrated for the natural TIGER RE. This was confirmed with human cell extracts using a newly developed, semi–in vitro microsphere binding assay. These results contrast with the synergistic increase in transactivation from a pair of weak, full-site REs in the MDM2 promoter that are separated by an evolutionary conserved 17 bp spacer. Surprisingly, there can be substantial transactivation at noncanonical ½-(a single decamer) and ¾-sites, some of which were originally classified as biologically relevant canonical consensus sequences including PIDD and Apaf-1. p53 family members p63 and p73 yielded similar results. Efficient transactivation from noncanonical elements requires tetrameric p53, and the presence of the carboxy terminal, non-specific DNA binding domain enhanced transactivation from noncanonical sequences. Our findings demonstrate that RE sequence, organization, and level of p53 can strongly impact p53-mediated transactivation, thereby changing the view of what constitutes a functional p53 target. Importantly, inclusion of ½- and ¾-site REs greatly expands the p53 master regulatory network

Use of an innovative model to evaluate mobility in seniors with lower-limb amputations of vascular origin: a pilot study

<p>Abstract</p> <p>Background</p> <p>The mobility of older individuals has often been only partially assessed, without considering all important aspects such as potential (available) versus effective (used) mobilities and the physical and psychosocial factors that modulate them. This study proposes a new model for evaluating mobility that considers all important aspects, applied here to lower-limb amputees with vascular origin. This model integrates the concepts of potential mobility (e.g. balance, speed of movement), effective mobility (e.g. life habits, movements in living areas) and factors that modulate these two types of mobility (e.g. strength, sensitivity, social support, depression). The main objective was to characterize potential and effective mobility as well as mobility modulators in a small sample of people with lower-limb amputations of vascular origin with different characteristics. The second objective of this pilot study was to assess the feasibility of measuring all variables in the model in a residential context.</p> <p>Methods</p> <p>An observational and transversal design was used with a heterogeneous sample of 10 participants with a lower-limb amputation of vascular origin, aged 51 to 83, assessed between eight and 18 months after discharge from an acute care hospital. A questionnaire of participant characteristics and 16 reliable and valid measurements were used.</p> <p>Results</p> <p>The results show that the potential mobility indicators do not accurately predict effective mobility, i.e., participants who perform well on traditional measures done in the laboratory or clinic are not always those who perform well in the real world. The model generated 4 different profiles (categories) of participants ranging from reduced to excellent potential mobility and low to excellent effective mobility, and characterized the modulating factors. The evaluations were acceptable in terms of the time taken (three hours) and the overall measurements, with a few exceptions, which were modified to optimize the data collected and the classification of the participants. For the population assessed, the results showed that some of the negative modulators (particularly living alone, no rehabilitation, pain, limited social support, poor muscle strength) played an important role in reducing effective mobility.</p> <p>Conclusion</p> <p>The first use of the model revealed interesting data that add to our understanding of important aspects linked to potential and effective mobility as well as modulators. The feasibility of measuring all variables in the model in a residential context was demonstrated. A study with a large number of participants is now warranted to rigorously characterize mobility levels of lower-limb amputees with vascular origin.</p