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Understanding Rare and Common Diseases in the Context of Human Evolution Lluis Quintana-Murci1,2,3

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Understanding Rare and Common Diseases in the Context of Human Evolution Lluis Quintana-Murci1,2,3 Quintana-Murci Genome Biology (2016) 17:225 DOI 10.1186/s13059-016-1093-y REVIEW Open Access Understanding rare and common diseases in the context of human evolution Lluis Quintana-Murci1,2,3 Abstract (e.g., migration, admixture, and changes in population size), and natural selection. The wealth of available genetic information is allowing The plethora of genetic information generated in the the reconstruction of human demographic and adaptive last ten years, thanks largely to the publication of se- history. Demography and purifying selection affect the quencing datasets for both modern human populations purge of rare, deleterious mutations from the human and ancient DNA samples [14–18], is making it possible population, whereas positive and balancing selection to reconstruct the genetic history of our species, and to can increase the frequency of advantageous variants, define the parameters characterizing human demographic improving survival and reproductioninspecific history: expansion out of Africa, the loss of genetic diversity environmental conditions. In this review, I discuss with increasing distance from Africa (i.e., the “serial founder how theoretical and empirical population genetics effect”), demographic expansions over different time scales, studies, using both modern and ancient DNA data, and admixture with ancient hominins [16–21]. These stud- are a powerful tool for obtaining new insight into ies are also revealing the extent to which selection has acted the genetic basis of severe disorders and complex on the human genome, providing insight into the way in disease phenotypes, rare and common, focusing which selection removes deleterious variation and the po- particularly on infectious disease risk. tential of human populations to adapt to the broad range of climatic, nutritional, and pathogenic environments they have occupied [22–28]. It has thus become essential to Introduction dissect the role of selection, in its diverse forms and in- Intense research efforts have focused on identifying rare tensities, in shaping the patterns of population genetic and common variants that increase disease risk in humans, diversity (Fig. 1a), not only to improve our understanding for both rare and common diseases. Several, non-mutually of human evolutionary history, but also to obtain insight exclusive models have been proposed to explain the func- into phenotypic diversity and differences in the risk of de- tional properties of such variants and their contributions to veloping rare and common diseases [12, 13, 24, 29–32]. pathological conditions, and this topic has been reviewed elsewhere [1–10]. These studies implicated multiple vari- ants in disease susceptibility, but the relative importance of The removal of mutations deleterious to human rare and common variants in phenotypic diversity, both be- health nign and disease-related, has yet to be explored in detail Studies of the occurrence, frequency, and population [11]. We can use an evolutionary approach to tackle this distribution of deleterious mutations are of fundamental question, as population genetics models can predict the al- importance if we are to understand the genetic architec- lelic architecture of disease susceptibility [12, 13]. They are ture of human disease. Theoretical and empirical popula- able to do so because rare and common disease-risk alleles tion genetics studies have shown that most new mutations are a subset of global human genetic diversity, and their resulting in amino acid substitutions (non-synonymous) occurrence, frequency, and population distribution is gov- are rapidly culled from the population through purifying erned by evolutionary forces, such as mutation, genetic drift selection (Fig. 1a) [33, 34]. Indeed, the small number of non-synonymous variants observed relative to the rate of Correspondence: [email protected] non-synonymous mutation indicates that most non- 1 Human Evolutionary Genetics Unit, Department of Genomes & Genetics, synonymous mutations are lethal or highly deleterious, Institut Pasteur, Paris 75015, France 2Centre National de la Recherche Scientifique, URA3012, Paris 75015, France strongly compromising the reproductive success of their Full list of author information is available at the end of the article carriers [34–36]. Purifying selection—the most common © The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Quintana-Murci Genome Biology (2016) 17:225 Page 2 of 14 Fig. 1 Modes in which selection or admixture can remove, maintain, or increase genetic diversity. a Schematic representation of the different types of natural selection. Purifying selection removes deleterious alleles (in black) from the population, and genes evolving under strong purifying selection are usually associated with rare, severe disorders. Conversely, mutations conferring a selective advantage (e.g., increased resistanceto complex infectious disease) can increase in frequency in the population, or be maintained, through different forms of positive and balancing selection. Positive selection is represented here by the classic hard-sweep model where, following an environmental change, a newly arisen advantageous mutation or a mutation at very low frequency (in red) will be immediately targeted by positive selection and will ultimately reach fixation. Balancing selection is illustrated here by the case of heterozygote advantage (or overdominance), where the presence of heterozygotes (in blue) is favored in the population. b Long-term balancing selection. Advantageous genetic diversity can be maintained over long periods of time and survive speciation, resulting in “trans-species polymorphism” (represented by black and red arrows). In this example, a trans-species polymorphism that is present in the modern European population (where it has survived the known bottleneck out of Africa) is shared with other primates, such as chimpanzees and gorillas. c Modern humans can also acquire genetic diversity (whether advantageous or not) through admixture with other hominins, such as Neanderthals or Denisovans (Box 2). The green and blue arrows represent the direction and estimated magnitude of admixture between modern humans and Neanderthals and Denisovans, respectively (see [17]) Quintana-Murci Genome Biology (2016) 17:225 Page 3 of 14 form of selection—refers to the selective removal of alleles (GWAS), which focus on common variants, have been that are deleterious, such as those associated with severe only moderately successful in explaining the genetic basis Mendelian disorders, or their maintenance at low popula- of complex diseases [3]. Furthermore, theoretical studies tion frequencies (i.e., mutation–selection balance) [32, 37]. have shown that a large proportion of the so-called “miss- The efficacy of purifying selection for eliminating deleteri- ing heritability” is explained by rare variants, particularly ous mutations from a population depends not only on the those that affect fitness as well as causing disease [54]. selection coefficient(s), but also on population size (N), The increasing amount of sequence-based datasets which determines the magnitude of genetic drift. Unlike available, both in basic and medically oriented research, highly deleterious mutations, variants subject to weaker is accelerating the investigation into the contribution of selection (i.e., weakly deleterious mutations) behave like rare variants to disease susceptibility. In this context, di- “nearly neutral mutations”; they may, therefore, reach rela- verse variant annotation tools and predictive algorithms tively high population frequencies [38–40]. In large out- have been developed to systematically evaluate the po- bred populations, with low levels of drift, deleterious tential functional impacts of genetic variants (e.g., Poly- mutations will eventually be eliminated. By contrast, in Phen, SIFT, and GERP) [55–57], helping to prioritize the small populations, deleterious mutations behave very study of putative causal variants in further detail. These much like neutral mutations and may be subject to strong methods, which use different statistics and types of in- drift, resulting in moderate-to-high frequencies, or even formation, generally assess the “deleteriousness” of each fixation [39]. genetic variant by considering different measures, such as evolutionary conservation scores, changes in amino Rare variants are widespread in the human genome acid sequence, or potential effect on protein function Recent deep-sequencing studies are showing a surpris- and structure [58]. Novel methods are increasingly being ingly high proportion of rare and low-frequency variants developed, providing improved power and resolution. in different human populations [14, 15, 41–47]. The Ex- For example, CADD, which integrates both evolutionary ome Variant Server, for example, reports frequency in- and functional importance, generates a single prediction formation from 6515 exomes of individuals of African from multiple annotation
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