Evidence of widespread selection on standing variation in Europe at height-associated SNPs.

Strong signatures of positive selection at newly arising genetic variants are well documented in humans(1-8), but this form of selection may not be widespread in recent human evolution(9). Because many human traits are highly polygenic and partly determined by common, ancient genetic variation, an alternative model for rapid genetic adaptation has been proposed: weak selection acting on many pre-existing (standing) genetic variants, or polygenic adaptation(10-12). By studying height, a classic polygenic trait, we demonstrate the first human signature of widespread selection on standing variation. We show that frequencies of alleles associated with increased height, both at known loci and genome wide, are systematically elevated in Northern Europeans compared with Southern Europeans (P < 4.3 × 10(-4)). This pattern mirrors intra-European height differences and is not confounded by ancestry or other ascertainment biases. The systematic frequency differences are consistent with the presence of widespread weak selection (selection coefficients ∼10(-3)-10(-5) per allele) rather than genetic drift alone (P < 10(-15))

Evidence of Widespread Selection on Standing Variation in Europe at Height-Associated SNPs

Strong signatures of positive selection at newly arising genetic variants are well-documented in humans, but this form of selection may not be widespread in recent human evolution. Because many human traits are highly polygenic and partly determined by common, ancient genetic variation, an alternative model for rapid genetic adaptation has been proposed: weak selection acting on many pre-existing (standing) genetic variants, or polygenic adaptation. By studying height, a classic polygenic trait, we demonstrate the first human signature of widespread selection on standing variation. We show that frequencies of alleles associated with increased height, both at known loci and genome-wide, are systematically elevated in Northern Europeans compared with Southern Europeans $(p<4.3×10^{−4})$. This pattern mirrors intra-European height differences and is not confounded by ancestry or other ascertainment biases. The systematic frequency differences are consistent with the presence of widespread weak selection (selection coefficients $~10^{−3}–10^{−5}$ per allele) rather than genetic drift alone $(p<10^{−15})$

Prevalence and factors affecting home blood pressure documentation in routine clinical care: a retrospective study

<p>Abstract</p> <p>Background</p> <p>Home blood pressure (BP) is closely linked to patient outcomes. However, the prevalence of its documentation has not been examined. The objective of this study was to analyze the prevalence and factors affecting documentation of home BP in routine clinical care.</p> <p>Methods</p> <p>A retrospective study of 142,973 encounters of 9,840 hypertensive patients with diabetes from 2000 to 2005 was performed. The prevalence of recorded home BP and the factors associated with its documentation were analyzed. We assessed validity of home BP information by comparing the difference between home and office BP to previously published prospective studies.</p> <p>Results</p> <p>Home BP was documented in narrative notes for 2.08% of encounters where any blood pressure was recorded and negligibly in structured data (EMR flowsheets). Systolic and diastolic home BP in narrative notes were lower than office BP readings by 9.6 and 2.5 mm Hg, respectively (p < 0.0001 for both), consistent with prospective data. Probability of home BP documentation increased by 23.0% for each 10 mm Hg of office systolic BP (p < 0.0001), by 6.2% for each $10,000 in median income of zip code (p = 0.0055), and by 17.7% for each decade in the patient's age (p < 0.0001).</p> <p>Conclusions</p> <p>Home BP readings provide a valid representation of the patient's condition, yet are seldom documented despite their potential utility in both patient care and research. Strong association between higher patient income and home BP documentation suggests that the cost of the monitors may be a limiting factor; reimbursement of home BP monitoring expenses should be pursued.</p

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Why Did Memetics Fail? Comparative Case Study

Although the theory of memetics appeared highly promising at the beginning, it is no longer considered a scientific theory among contemporary evolutionary scholars. This study aims to compare the genealogy of memetics with the historically more successful gene-culture coevolution theory. This comparison is made in order to determine the constraints that emerged during the internal development of the memetics theory that could bias memeticists to work on the ontology of meme units as opposed to hypotheses testing, which was adopted by the gene-culture scholars. I trace this problem back to the diachronic development of memetics to its origin in the gene-centered anti-group-selectionist argument of George C. Williams and Richard Dawkins. The strict adoption of this argument predisposed memeticists with the a priori idea that there is no evolution without discrete units of selection, which in turn, made them dependent on the principal separation of biological and memetic fitness. This separation thus prevented memeticists from accepting an adaptationist view of culture which, on the contrary, allowed gene-culture theorists to attract more scientists to test the hypotheses, creating the historical success of the gene-culture coevolution theory

Bayesian Estimation of Animal Movement from Archival and Satellite Tags

The reliable estimation of animal location, and its associated error is fundamental to animal ecology. There are many existing techniques for handling location error, but these are often ad hoc or are used in isolation from each other. In this study we present a Bayesian framework for determining location that uses all the data available, is flexible to all tagging techniques, and provides location estimates with built-in measures of uncertainty. Bayesian methods allow the contributions of multiple data sources to be decomposed into manageable components. We illustrate with two examples for two different location methods: satellite tracking and light level geo-location. We show that many of the problems with uncertainty involved are reduced and quantified by our approach. This approach can use any available information, such as existing knowledge of the animal's potential range, light levels or direct location estimates, auxiliary data, and movement models. The approach provides a substantial contribution to the handling uncertainty in archival tag and satellite tracking data using readily available tools

Pitfalls of predicting complex traits from SNPs

The success of genome-wide association studies (GWASs) has led to increasing interest in making predictions of complex trait phenotypes, including disease, from genotype data. Rigorous assessment of the value of predictors is crucial before implementation. Here we discuss some of the limitations and pitfalls of prediction analysis and show how naive implementations can lead to severe bias and misinterpretation of results

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years