Population genetics models of common diseases Anna Di Rienzo The number and frequency of susceptibility alleles for common This is because the relevant fitness effects are those that diseases are important factors to consider in the efficient acted in ancestral human populations, whereas clinical design of disease association studies. These quantities are the phenotypes are assessed in contemporary populations. results of the joint effects of mutation, genetic drift and In addition, clinical severity does not necessarily imply selection. Hence, population genetics models, informed by effects on reproduction, viability and survival, especially empirical knowledge about patterns of disease variation, can for diseases with late age of onset. be used to make predictions about the allelic architecture of common disease susceptibility and to gain an overall Disease mapping strategies rely — implicitly or explicitly understanding about the evolutionary origins of such diseases. — on population genetics quantities, such as allelic Equilibrium models and empirical studies suggest a role for heterogeneity, allele frequency spectrum and inter-eth- both rare and common variants. In addition, increasing nic differentiation; for example, standard association evidence points to changes in selective pressures on methods are most powerful for detecting common sus- susceptibility genes for common diseases; these findings are ceptibility variants with limited heterogeneity. Likewise, likely to form the basis for further modeling studies. the evidence for association is most likely to be replicated in additional populations if the susceptibility variants are Addresses Department of Human Genetics, University of Chicago, Chicago, the same and similarly common across populations. IL 60637, USA Because these quantities are functions of the underlying population genetics model, modeling studies might help Corresponding author: Di Rienzo, Anna to optimize disease-mapping strategies to the outcomes of ([email protected]) specific evolutionary scenarios. Current Opinion in Genetics & Development 2006, 16:630–636 In general, modeling studies aim at analyzing a complex biological process (e.g. the evolution of disease suscep- This review comes from a themed issue on tibility) by reducing it to more basic components (e.g. Genomes and evolution Edited by Chris Tyler-Smith and Molly Przeworski mutation rate or strength of selection etc). The ultimate goal is to understand the properties of the process and to Available online 19th October 2006 make quantitative predictions about its outcomes. Even 0959-437X/$ – see front matter though most models are too simple to be realistic, they # 2006 Elsevier Ltd. All rights reserved. can still have practical utility. For example, they can generate hypotheses that can be tested by empirical DOI 10.1016/j.gde.2006.10.002 studies of genetic variation or they can point to new approaches to disease mapping. Conversely, as we learn more about genetic susceptibility variants, modeling stud- Introduction ies might use the available empirical information to fill in Alleles that contribute to the genetic susceptibility to the gaps of knowledge regarding the genetic architecture human diseases are the focus of intense attention in human of common diseases and how it was shaped by natural genetics. They can be studied by a variety of approaches selection. Hence, population genetics modeling informed (e.g. linkage analysis and case-control studies) that aim to by empirical studies of risk variation — and the reverse — identify their role in the etiology of clinically defined will be necessary if a comprehensive understanding of the phenotypes. Disease alleles are also a specific subset of genetic bases of common diseases is to be obtained. all genetic variation present in human populations. As such, their fate is influenced jointly by the history and Here, I review the results of modeling studies performed strength of the selective pressures acting in human popu- to date, in light of the available data on susceptibility lations as well as by demographic history, including popu- variants for common diseases. Several hypotheses have lation size changes and geographic structure. Therefore, also been formulated about how changes in selective the properties of disease alleles can also be investigated by pressures acted on susceptibility genes for common dis- population genetics modeling based on evolutionary prin- eases. These hypotheses are providing a framework for ciples. An important difference between disease mapping further empirical and modeling studies. and population genetics studies is that the latter focus on the effects of susceptibility alleles on evolutionary fitness Mutation–selection balance: models and data rather than focusing on parameters of clinical severity. Different types of population genetics models are Fitness is only loosely correlated with clinical severity. likely to apply to Mendelian versus common diseases. Current Opinion in Genetics & Development 2006, 16:630–636 www.sciencedirect.com Population genetics models of common diseases Di Rienzo 631 Mendelian diseases, which are usually due to highly In a related study, Reich and Lander [2] also modeled penetrant and deleterious alleles that segregate in susceptibility alleles as being (slightly) deleterious and families, probably fit relatively simple equilibrium models showed that, conditional on a specified total frequency of of mutation–selection balance in which disease alleles are the susceptibility allele class (20%) at a single locus and removed by purifying selection and continually replen- for a ‘typical’ disease mutation rate, there is a single ished through the mutation process. Mutation–selection predominant allele within the susceptibility class [6]. balance predicts high allelic heterogeneity and low dis- Importantly, this study focused on the role of population ease prevalence, which are both common features of growth on the dynamics of disease alleles. More specifi- Mendelian diseases. Models of positive selection also cally, the authors showed that, although the number of apply to a minority of Mendelian disease alleles, most disease alleles increases very quickly if the frequency of notably sickle cell anemia, G6PD deficiency and the the susceptibility class before the onset of growth is low, thalassemias, which are caused by the pleiotropic effects the allelic heterogeneity for loci with intermediate fre- of disease alleles on resistance to malaria. For other quencies also increases, but much more slowly. For diseases (e.g. cystic fibrosis), a selective advantage has plausible times for the onset of population growth, the been invoked, but generating definitive evidence has met increase in allelic heterogeneity for loci with intermediate with considerable difficulties [1–4]. equilibrium frequency is expected to be negligible. Hence, if indeed common diseases are due to suscep- When it comes to common diseases with complex pat- tibility loci with intermediate equilibrium frequencies, terns of inheritance, however, the formulation of evolu- the allelic heterogeneity is predicted to be relatively low. tionary models is more complicated. Owing to incomplete penetrance, late age of onset, gene-by-environment inter- Owing to the different parameterization, the conclusions actions and polygenic inheritance, the connection of these two studies cannot be directly compared. Never- between common disease susceptibility and fitness is theless, they highlight important issues in modeling the not clear. Moreover, although most recessive Mendelian evolution of common disease susceptibility, and they diseases are due to loss-of-function alleles, this expecta- indicate new directions for further investigation. One tion might not apply to common diseases, thus adding to important issue is the choice of parameter values. For the uncertainty regarding the rate at which susceptibility example, an obvious difference between the two studies variants are generated by the mutation process. Perhaps concerns the assumptions about the rate at which new more importantly, part of the selective pressures acting on susceptibility alleles are created by the mutation process. susceptibility alleles for common diseases might have Pritchard [1] considered a broad range of mutation rates changed dramatically during human history, as a result (i.e. 2.5 Â 10–6 to 1.25 Â 10–4 per gene per generation), of major cultural and/or environmental transitions, imply- whereas Reich and Lander [2] considered a single and low ing that non-equilibrium models might be needed. mutation rate (i.e. 3.2 Â 10–6). The rate at which suscept- ibility alleles are generated and the rate at which they are The first models of common disease susceptibility based repaired or compensated for depend on the functional on population genetics principles were formulated within effects of mutations causing common diseases, which in the mutation–selection balance framework. Pritchard [1] turn depend on a variety of factors, including the disease modeled the evolution of a disease susceptibility locus in pathophysiology and the biological function of the gene. a randomly mating population of constant size, incorpo- For example, the mutation rate for variants leading to loss rating the effects of mutation, genetic drift and selection of function is likely to be higher than the rate for variants [5]. An important aspect of this analysis is that the total resulting in gain of function. Moreover, partial or com- frequency