Allele frequency divergence reveals ubiquitous influence of positive selection in Drosophila

Resolving the role of natural selection is a basic objective of evolutionary biology. It is generally difficult to detect the influence of selection because ubiquitous non-selective stochastic change in allele frequencies (genetic drift) degrades evidence of selection. As a result, selection scans typically only identify genomic regions that have undergone episodes of intense selection. Yet it seems likely such episodes are the exception; the norm is more likely to involve subtle, concurrent selective changes at a large number of loci. We develop a new theoretical approach that uncovers a previously undocumented genome-wide signature of selection in the collective divergence of allele frequencies over time. Applying our approach to temporally resolved allele frequency measurements from laboratory and wild Drosophila populations, we quantify the selective contribution to allele frequency divergence and find that selection has substantial effects on much of the genome. We further quantify the magnitude of the total selection coefficient (a measure of the combined effects of direct and linked selection) at a typical polymorphic locus, and find this to be large (of order 1%) even though most mutations are not directly under selection. We find that selective allele frequency divergence is substantially elevated at intermediate allele frequencies, which we argue is most parsimoniously explained by positive—not negative—selection. Thus, in these populations most mutations are far from evolving neutrally in the short term (tens of generations), including mutations with neutral fitness effects, and the result cannot be explained simply as an ongoing purging of deleterious mutations.

Allele frequency divergence reveals ubiquitous influence of positive selection in Drosophila

Resolving the role of natural selection is a basic objective of evolutionary biology. It is generally difficult to detect the influence of selection because ubiquitous non-selective stochastic change in allele frequencies (genetic drift) degrades evidence of selection. As a result, selection scans typically only identify genomic regions that have undergone episodes of intense selection. Yet it seems likely such episodes are the exception; the norm is more likely to involve subtle, concurrent selective changes at a large number of loci. We develop a new theoretical approach that uncovers a previously undocumented genome-wide signature of selection in the collective divergence of allele frequencies over time. Applying our approach to temporally-resolved allele frequency measurements from laboratory and wild Drosophila populations, we quantify the selective contribution to allele frequency divergence and find that selection has substantial effects on much of the genome. We further quantify the magnitude of the total selection coefficient (a measure of the combined effects of direct and linked selection) at a typical polymorphic locus, and find this to be large (of order 1%) even though most mutations are not directly under selection. We find that selective allele frequency divergence is substantial at intermediate allele frequencies, which we argue is most parsimoniously explained by positive --- not purifying --- selection. Thus, in these populations most mutations are far from evolving neutrally in the short term (tens of generations), including mutations with neutral fitness effects, and the result cannot be explained simply as a purging of deleterious mutations.

Genetic counselling for unaffected family members

This chapter focuses on aspects of genetic counselling for those at 50 per cent risk for Huntington’s disease (HD). There are various options including not being tested. Predictive testing for HD is described together with some perspectives from patients. There are four types of results from a predictive test: normal, intermediate allele, reduced penetrance, and abnormal. The implications of these are discussed. Options regarding testing in pregnancy are discussed which include: no testing and accepting a risk, invasive tests such as chorion villus sampling or amniocentesis and preimplantation genetic diagnosis. Finally, the issue of testing someone at 25 per cent risk is discussed.

Parkinsonism with a Hint of Huntington’s from 29 CAG Repeats in HTT

Huntington’s disease is caused by at least 36 cytosine-adenine-guanine (CAG) repeats in an HTT gene allele, but repeat tracts in the intermediate range (27–35 repeats) also display a subtle phenotype. This patient had a slightly elongated CAG repeat tract (29 repeats), a prominent family history of Parkinson’s disease (PD), and a clinical phenotype mostly consistent with PD, but early dystonia and poor levodopa response. Neurophysiological test results were more consistent with Huntington’s disease (HD) than PD. It is suggested that the intermediate allele modulated the clinical phenotype of PD in this patient.

A simple genetic basis of adaptation to a novel thermal environment results in complex metabolic rewiring in Drosophila

Population genetic theory predicts that rapid adaptation is largely driven by complex traits encoded by many loci of small effect. Because large effect loci are quickly fixed in natural populations, they should not contribute much to rapid adaptation. To investigate the genetic architecture of thermal adaptation - a highly complex trait - we performed experimental evolution on a natural Drosophila simulans population. Transcriptome and respiration measurements revealed extensive metabolic rewiring after only ∼60 generations in a hot environment. Analysis of genome-wide polymorphisms identified two interacting selection targets, Sestrin and SNF4Aγ, pointing to AMPK, a central metabolic switch, as a key factor for thermal adaptation. Our results demonstrate that large-effect loci segregating at intermediate allele frequencies can allow natural populations to rapidly respond to selection. Because SNF4Aγ also exhibits clinal variation in various Drosophila species, we suggest that this large effect polymorphism is maintained by temporal and spatial temperature variation in natural environments.