A population genetics study of the Familial Mediterranean Fever gene: evidence of balancing selection under an overdominance regime

Fumagalli, Matteo; Cagliani, Rachele; Pozzoli, Uberto; Riva, Stefania; Comi, Giacomo P.; Menozzi, Giorgia; Bresolin, Nereo; Sironi, Manuela

doi:10.1038/gene.2009.59

Cited by 21 publications

(24 citation statements)

References 82 publications

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“…Remarkably, all genes in that category with signatures of balancing selection in both Europeans and Africans are included in the IL1 or TNF family (Figure 1). Moreover MEFV also shows an excess of intermediate variants in one of the neutrality tests in Europeans, and signatures of balancing selection have been previously reported [12,13]. The complement proteins also show a significant enrichment for genes under balancing selection in Africans (Fisher's exact test P = 0.01).…”

Section: Resultssupporting

confidence: 52%

Genetic adaptation of the antibacterial human innate immunity network

et al. 2011

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BackgroundPathogens have represented an important selective force during the adaptation of modern human populations to changing social and other environmental conditions. The evolution of the immune system has therefore been influenced by these pressures. Genomic scans have revealed that immune system is one of the functions enriched with genes under adaptive selection.ResultsHere, we describe how the innate immune system has responded to these challenges, through the analysis of resequencing data for 132 innate immunity genes in two human populations. Results are interpreted in the context of the functional and interaction networks defined by these genes. Nucleotide diversity is lower in the adaptors and modulators functional classes, and is negatively correlated with the centrality of the proteins within the interaction network. We also produced a list of candidate genes under positive or balancing selection in each population detected by neutrality tests and showed that some functional classes are preferential targets for selection.ConclusionsWe found evidence that the role of each gene in the network conditions the capacity to evolve or their evolvability: genes at the core of the network are more constrained, while adaptation mostly occurred at particular positions at the network edges. Interestingly, the functional classes containing most of the genes with signatures of balancing selection are involved in autoinflammatory and autoimmune diseases, suggesting a counterbalance between the beneficial and deleterious effects of the immune response.

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Section: Resultssupporting

confidence: 52%

Genetic adaptation of the antibacterial human innate immunity network

et al. 2011

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“…The existence of a unique, common polymorphism (A1696G) and significant shift in genotype frequencies (rs3775073 and rs3821985) are additional indicators [5]. There is also significantly reduced heterozygosity in TLR6 in the Ugandan population, further reflecting selective pressure [19]. The novel TLR6 SNP in the South African population (T34A) is also quite common.…”

Section: Discussionmentioning

confidence: 99%

Genetic Variation in TLR Genes in Ugandan and South African Populations and Comparison with HapMap Data

et al. 2012

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Genetic epidemiological studies of complex diseases often rely on data from the International HapMap Consortium for identification of single nucleotide polymorphisms (SNPs), particularly those that tag haplotypes. However, little is known about the relevance of the African populations used to collect HapMap data for study populations conducted elsewhere in Africa. Toll-like receptor (TLR) genes play a key role in susceptibility to various infectious diseases, including tuberculosis. We conducted full-exon sequencing in samples obtained from Uganda (n = 48) and South Africa (n = 48), in four genes in the TLR pathway: TLR2, TLR4, TLR6, and TIRAP. We identified one novel TIRAP SNP (with minor allele frequency [MAF] 3.2%) and a novel TLR6 SNP (MAF 8%) in the Ugandan population, and a TLR6 SNP that is unique to the South African population (MAF 14%). These SNPs were also not present in the 1000 Genomes data. Genotype and haplotype frequencies and linkage disequilibrium patterns in Uganda and South Africa were similar to African populations in the HapMap datasets. Multidimensional scaling analysis of polymorphisms in all four genes suggested broad overlap of all of the examined African populations. Based on these data, we propose that there is enough similarity among African populations represented in the HapMap database to justify initial SNP selection for genetic epidemiological studies in Uganda and South Africa. We also discovered three novel polymorphisms that appear to be population-specific and would only be detected by sequencing efforts.

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“…Aside from the classical example of the S ‐gene involved in sickle‐cell disease and malaria resistance, overdominance has been suggested to be implicated in the evolution of immune‐related genes such as MEFV , the gene responsible for familial Mediterranean fever in humans (Fumagalli et al . ) and MHC genes (Kekalainen et al . ), especially in cases of multipathogen infections (Oliver et al .…”

Section: Mechanisms Underlying Local Polymorphismmentioning

confidence: 99%

Genetic architecture and balancing selection: the life and death of differentiated variants

2017

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Balancing selection describes any form of natural selection, which results in the persistence of multiple variants of a trait at intermediate frequencies within populations. By offering up a snapshot of multiple co-occurring functional variants and their interactions, systems under balancing selection can reveal the evolutionary mechanisms favouring the emergence and persistence of adaptive variation in natural populations. We here focus on the mechanisms by which several functional variants for a given trait can arise, a process typically requiring multiple epistatic mutations. We highlight how balancing selection can favour specific features in the genetic architecture and review the evolutionary and molecular mechanisms shaping this architecture. First, balancing selection affects the number of loci underlying differentiated traits and their respective effects. Control by one or few loci favours the persistence of differentiated functional variants by limiting intergenic recombination, or its impact, and may sometimes lead to the evolution of supergenes. Chromosomal rearrangements, particularly inversions, preventing adaptive combinations from being dissociated are increasingly being noted as features of such systems. Similarly, due to the frequency of heterozygotes maintained by balancing selection, dominance may be a key property of adaptive variants. High heterozygosity and limited recombination also influence associated genetic load, as linked recessive deleterious mutations may be sheltered. The capture of deleterious elements in a locus under balancing selection may reinforce polymorphism by further promoting heterozygotes. Finally, according to recent genomewide scans, balanced polymorphism might be more pervasive than generally thought. We stress the need for both functional and ecological studies to characterize the evolutionary mechanisms operating in these systems.

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A population genetics study of the Familial Mediterranean Fever gene: evidence of balancing selection under an overdominance regime

Cited by 21 publications

References 82 publications

Genetic adaptation of the antibacterial human innate immunity network

Genetic adaptation of the antibacterial human innate immunity network

Genetic Variation in TLR Genes in Ugandan and South African Populations and Comparison with HapMap Data

Genetic architecture and balancing selection: the life and death of differentiated variants

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