The Population Genetic Signature of Polygenic Local Adaptation

Adaptation in response to selection on polygenic phenotypes may occur via subtle allele frequencies shifts at many loci. Current population genomic techniques are not well posed to identify such signals. In the past decade, detailed knowledge about the specific loci underlying polygenic traits has begun to emerge from genome-wide association studies (GWAS). Here we combine this knowledge from GWAS with robust population genetic modeling to identify traits that may have been influenced by local adaptation. We exploit the fact that GWAS provide an estimate of the additive effect size of many loci to estimate the mean additive genetic value for a given phenotype across many populations as simple weighted sums of allele frequencies. We first describe a general model of neutral genetic value drift for an arbitrary number of populations with an arbitrary relatedness structure. Based on this model we develop methods for detecting unusually strong correlations between genetic values and specific environmental variables, as well as a generalization of $Q_{ST}/F_{ST}$ comparisons to test for over-dispersion of genetic values among populations. Finally we lay out a framework to identify the individual populations or groups of populations that contribute to the signal of overdispersion. These tests have considerably greater power than their single locus equivalents due to the fact that they look for positive covariance between like effect alleles, and also significantly outperform methods that do not account for population structure. We apply our tests to the Human Genome Diversity Panel (HGDP) dataset using GWAS data for height, skin pigmentation, type 2 diabetes, body mass index, and two inflammatory bowel disease datasets. This analysis uncovers a number of putative signals of local adaptation, and we discuss the biological interpretation and caveats of these results.Comment: 42 pages including 8 figures and 3 tables; supplementary figures and tables not included on this upload, but are mostly unchanged from v

A general hospital experience of polymyalgia rheumatica and giant cell arteritis

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A Morse index theorem for elliptic operators on bounded domains

Given a selfadjoint, elliptic operator $L$, one would like to know how the spectrum changes as the spatial domain $\Omega \subset \mathbb{R}^d$ is deformed. For a family of domains $\{\Omega_t\}_{t\in[a,b]}$ we prove that the Morse index of $L$ on $\Omega_a$ differs from the Morse index of $L$ on $\Omega_b$ by the Maslov index of a path of Lagrangian subspaces on the boundary of $\Omega$. This is particularly useful when $\Omega_a$ is a domain for which the Morse index is known, e.g. a region with very small volume. Then the Maslov index computes the difference of Morse indices for the "original" problem (on $\Omega_b$) and the "simplified" problem (on $\Omega_a$). This generalizes previous multi-dimensional Morse index theorems that were only available on star-shaped domains or for Dirichlet boundary conditions. We also discuss how one can compute the Maslov index using crossing forms, and present some applications to the spectral theory of Dirichlet and Neumann boundary value problems.Comment: 21 pages; weaker regularity assumptions than in the first versio

The Generic Approximation Lemma

The approximation lemma is a simplification of the well-known take lemma, and is used to prove properties of programs that produce lists of values. We show how the approximation lemma, unlike the take lemma, can naturally be generalised from lists to a large class of datatypes, and present a generic approximation lemma that is parametric in the datatype to which it applies. As a useful by-product, we find that generalising the approximation lemma in this way also simplifies its proof

Voluntary Euthanasia and 'Assisted Dying' in Tasmania: A Response to Giddings and McKim

This paper provides a consolidated response to the Honourable Lara Giddings (MP) and the Honourable Nick McKim (MP), offering analysis and critique of their ‘Voluntary Assisted Dying - A Proposal for Tasmania' (2013) paper. Their paper puts forward a radical proposal that, if legislated, would make Tasmania one of a very small number of jurisdictions in the world to legalise voluntary euthanasia and assisted suicide. From close examination of their paper and proposed model, it is argued that while a number of their claims are evidence based, others are unsubstantiated. Their claims often represent one perspective or type of response to complex issues and questions -- the answers to which may never be agreed upon by relevant stakeholders. This paper draws on international literature as well as insights from well-credentialed Tasmanian practitioners to analyse Giddings and McKim' (2013) representation of what has (and has not) happened elsewhere and to critique their bid for euthanasia law reform in Tasmania. We conclude that the paper produced by Ms Giddings and Mr McKim does not constitute a compelling evidence-based case for changing the law. The risks of proceeding with the model that they propose are not justified