[Show abstract][Hide abstract] ABSTRACT: Interferons (IFNs) are cytokines that play a key role in innate and adaptive immune responses. Despite the large number of immunological studies of these molecules, the relative contributions of the numerous IFNs to human survival remain largely unknown. Here, we evaluated the extent to which natural selection has targeted the human IFNs and their receptors, to provide insight into the mechanisms that govern host defense in the natural setting. We found that some IFN-α subtypes, such as IFN-α6, IFN-α8, IFN-α13, and IFN-α14, as well as the type II IFN-γ, have evolved under strong purifying selection, attesting to their essential and nonredundant function in immunity to infection. Conversely, selective constraints have been relaxed for other type I IFNs, particularly for IFN-α10 and IFN-ε, which have accumulated missense or nonsense mutations at high frequencies within the population, suggesting redundancy in host defense. Finally, type III IFNs display geographically restricted signatures of positive selection in European and Asian populations, indicating that genetic variation at these genes has conferred a selective advantage to the host, most likely by increasing resistance to viral infection. Our population genetic analyses show that IFNs differ widely in their biological relevance, and highlight evolutionarily important determinants of host immune responsiveness.
Journal of Experimental Medicine 12/2011; 208(13):2747-59. DOI:10.1084/jem.20111680 · 12.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: APOBEC3 genes encode cytidine deaminases endowed with the ability to inhibit retroviruses and retrotransposons. These genes have been targets of natural selection throughout primate evolutionary history. We analyzed their selection pattern in human populations observing that APOBEC3F and 3G are neutrally evolving. Conversely, nucleotide diversity was extremely high for APOBEC3H, and most tests rejected the hypothesis of selective neutrality in Eurasian populations. Haplotype analysis and the derived intraallelic nucleotide diversity test indicated that positive selection has driven the increase in frequency of one haplotype (Hap I) outside Africa. Consistently, population genetic differentiation between African and non-African populations was higher than expected under neutrality. A case-control association analysis indicated that Hap I is associated with protection from sexually transmitted HIV-1 infection. Hap I carries a protein-destabilizing variant and a residue conferring resistance to Vif-mediated degradation. Data herein suggest that lower protein stability might have been traded-off with a higher ability to circumvent Vif-mediated hijacking. Alternatively, transcription regulatory variants might represent the selection target. Our data represent an example of how the selective pressures exerted by extinct or unknown viral agents can be exploited to provide valuable information on the allelic determinants of susceptibility to modern infections.
[Show abstract][Hide abstract] ABSTRACT: Previous genome-wide scans of positive natural selection in humans have identified a number of non-neutrally evolving genes that play important roles in skin pigmentation, metabolism, or immune function. Recent studies have also shown that a genome-wide pattern of local adaptation can be detected by identifying correlations between patterns of allele frequencies and environmental variables. Despite these observations, the degree to which natural selection is primarily driven by adaptation to local environments, and the role of pathogens or other ecological factors as selective agents, is still under debate. To address this issue, we correlated the spatial allele frequency distribution of a large sample of SNPs from 55 distinct human populations to a set of environmental factors that describe local geographical features such as climate, diet regimes, and pathogen loads. In concordance with previous studies, we detected a significant enrichment of genic SNPs, and particularly non-synonymous SNPs associated with local adaptation. Furthermore, we show that the diversity of the local pathogenic environment is the predominant driver of local adaptation, and that climate, at least as measured here, only plays a relatively minor role. While background demography by far makes the strongest contribution in explaining the genetic variance among populations, we detected about 100 genes which show an unexpectedly strong correlation between allele frequencies and pathogenic environment, after correcting for demography. Conversely, for diet regimes and climatic conditions, no genes show a similar correlation between the environmental factor and allele frequencies. This result is validated using low-coverage sequencing data for multiple populations. Among the loci targeted by pathogen-driven selection, we found an enrichment of genes associated to autoimmune diseases, such as celiac disease, type 1 diabetes, and multiples sclerosis, which lends credence to the hypothesis that some susceptibility alleles for autoimmune diseases may be maintained in human population due to past selective processes.
[Show abstract][Hide abstract] ABSTRACT: Contrasting results have been reported concerning the association of a splice-site polymorphism (rs10774671) in OAS1 with multiple sclerosis (MS). We analysed two OAS1 regions encompassing alternatively spliced exons. While the region carrying the splice-site variant is neutrally evolving, a signature of long-standing balancing selection was observed across an alternative exon 7. Analysis of variants in this exon identified an insertion/deletion polymorphism (rs11352835, A/-) that originates predicted products with distinct C termini. This variant is located along the major branch of the haplotype genealogy, suggesting that it may represent the selection target. A case/control study for MS indicated that rs11352835 is associated with disease susceptibility (for an allelic model with the deleted allele predisposing to MS, OR 1.27, 95% CI 1.072-1.513, p = 0.010). No association was found between rs10774671 and MS. As the two SNPs are in linkage disequilibrium in Europeans, the previously reported association between rs10774671 and MS susceptibility might be driven by rs11352835, possibly explaining the contrasting results previously observed for the splice-site polymorphism. Thus, we describe a novel susceptibility variant for MS in OAS1 and show that population genetic analyses can be instrumental to the identification of selection targets and, consequently, of functional polymorphisms with an effect on phenotypic traits.
Human Genetics 07/2011; 131(1):87-97. DOI:10.1007/s00439-011-1053-2 · 4.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Several susceptibility genetic variants for autoimmune diseases have been identified. A subset of these polymorphisms displays an opposite risk profile in different autoimmune conditions. This observation open interesting questions on the evolutionary forces shaping the frequency of these alleles in human populations.We aimed at testing the hypothesis whereby balancing selection has shaped the frequency of opposite risk alleles.
Since balancing selection signatures are expected to extend over short genomic portions, we focused our analyses on 11 regions carrying putative functional polymorphisms that may represent the disease variants (and the selection targets). No exceptional nucleotide diversity was observed for ZSCAN23, HLA-DMB, VARS2, PTPN22, BAT3, C6orf47, and IL10; summary statistics were consistent with evolutionary neutrality for these gene regions. Conversely, CDSN/PSORS1C1, TRIM10/TRIM40, BTNL2, and TAP2 showed extremely high nucleotide diversity and most tests rejected neutrality, suggesting the action of balancing selection. For TAP2 and BTNL2 these signatures are not secondary to linkage disequilibrium with HLA class II genes. Nonetheless, with the exception of variants in TRIM40 and CDSN, our data suggest that opposite risk SNPs are not selection targets but rather have accumulated as neutral variants.
Data herein indicate that balancing selection is common within the extended MHC region and involves several non-HLA loci. Yet, the evolutionary history of most SNPs with an opposite effect for autoimmune diseases is consistent with evolutionary neutrality. We suggest that variants with an opposite effect on autoimmune diseases should not be considered a distinct class of disease alleles from the evolutionary perspective and, in a few cases, the opposite effect on distinct diseases may derive from complex haplotype structures in regions with high genetic diversity.
[Show abstract][Hide abstract] ABSTRACT: The human RAC2 gene encodes a small GTP-binding protein with a pivotal role in immune activation and in the induction of peripheral immune tolerance through restimulation-induced cell death (RICD). Different human pathogens target the protein product of RAC2, suggesting that the gene may be subject to natural selection, and that variants in RAC2 may affect immunological phenotypes in humans. We scanned the genomic region encompassing the entire transcription unit for the presence of putative noncoding regulatory elements conserved across mammals. This information was used to select two RAC2 gene regions and analyze their intraspecific genetic diversity. Results suggest that a region covering the 3' untranslated region has been a target of multiallelic balancing selection (or diversifying selection), and three major RAC2 haplogroups occur in human populations. Haplotypes belonging to one of these clades are associated with increased susceptibility to multiple sclerosis (P = 0.022) and earlier onset of disease symptoms (P = 0.025). This same haplogroup is significantly more common in patients with Crohn's disease compared with healthy controls (P = 0.048). These data reinforce recent evidences that susceptibility alleles/haplotypes are shared among multiple autoimmune disorders and support a causal "role for RAC2" variants in the pathogenesis of autoimmune diseases. Other genes with a role in RICD have previously been associated with autoimmunity in humans, suggesting that this pathway and RAC2 may represent novel therapeutic targets in autoimmune disorders.
[Show abstract][Hide abstract] ABSTRACT: We propose a C++ class library developed to the purpose of making the implementation of sequence analysis algorithms easier and faster when genomic annotations and variations need to be considered. The library provides a class hierarchy to seamlessly bind together annotations of genomic elements to sequences and to algorithm results; it allows to evaluate the effect of mutations/variations in terms of both element position shifts and of algorithm results, limiting recalculation to the minimum. Particular care has been posed to keep memory and time overhead into acceptable limits. AVAILABILITY AND IMPLEMENTATION: A complete tutorial as well as a detailed doxygen generated documentation and source code is freely available at http://bioinformatics.emedea.it/geco, under the GPL license. The library was written in standard ISO C++, and does not depend on external libraries.
[Show abstract][Hide abstract] ABSTRACT: The human TRIM5 genes encodes a retroviral restriction factor (TRIM5α). Evolutionary analyses of this gene in mammals have revealed a complex and multifaceted scenario, suggesting that TRIM5 has been the target of exceptionally strong selective pressures, possibly exerted by recurrent waves of retroviral infections. TRIM5 displays inter-individual expression variability in humans and high levels of TRIM5 mRNA have been associated with a reduced risk of HIV-1 infection. We resequenced TRIM5 in chimpanzees and identified two polymorphisms in intron 1 that are shared with humans. Analysis of the gene region encompassing the two trans-specific variants in human populations identified exceptional nucleotide diversity levels and an excess of polymorphism compared to fixed divergence. Most tests rejected the null hypothesis of neutral evolution for this region and haplotype analysis revealed the presence of two deeply separated clades. Calculation of the time to the most recent common ancestor (TMRCA) for TRIM5 haplotypes yielded estimates ranging between 4 and 7 million years. Overall, these data indicate that long-term balancing selection, an extremely rare process outside MHC genes, has maintained trans-specific polymorphisms in the first intron of TRIM5. Bioinformatic analyses indicated that variants in intron 1 may affect transcription factor-binding sites and, therefore, TRIM5 transcriptional activity. Data herein confirm an extremely complex evolutionary history of TRIM5 genes in primates and open the possibility that regulatory variants in the gene modulate the susceptibility to HIV-1.
Human Genetics 12/2010; 128(6):577-88. DOI:10.1007/s00439-010-0884-6 · 4.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Human ERAP1 and ERAP2 encode two endoplasmic reticulum aminopeptidases. These enzymes trim peptides to optimal size for loading onto major histocompatibility
complex class I molecules and shape the antigenic repertoire presented to CD8+ T cells. Therefore, ERAP1 and ERAP2 may be considered potential selection targets and modulators of infection susceptibility. We resequenced two genic regions
in ERAP1 and ERAP2 in three HapMap populations. In both cases, we observed high levels of nucleotide variation, an excess of intermediate-frequency
alleles, and reduced population genetic differentiation. The genealogy of ERAP1 and ERAP2 haplotypes was split into two major branches with deep coalescence times. These features suggest that long-standing balancing
selection has acted on these genes. Analysis of the Lys528Arg (rs30187 in ERAP1) and Asn392Lys (rs2549782 in ERAP2) variants in an Italian population of HIV-1-exposed seronegative (ESN) individuals and a larger number of Italian controls
indicated that rs2549782 significantly deviates from Hardy–Weinberg equilibrium (HWE) in ESN but not in controls. Technical
errors were excluded and a goodness-of-fit test indicated that a recessive model with only genetic effects adequately explains
HWE deviation. The genotype distribution of rs2549782 is significantly different in the two cohorts (P = 0.004), mainly as the result of an over-representation of Lys/Lys genotypes in the ESN sample (P-value for a recessive model: 0.00097). Our data suggest that genetic diversity in ERAP1 and ERAP2 has been maintained by balancing selection and that variants in ERAP2 confer resistance to HIV-1 infection possibly via the presentation of a distinctive peptide repertoire to CD8+ T cells.
Human Molecular Genetics 12/2010; 19(23):4705-14. DOI:10.1093/hmg/ddq401 · 6.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The human interferon induced with helicase C domain 1 (IFIH1) gene encodes a sensor of double-strand RNA involved in innate immunity against viruses, indicating that this gene is a likely target of virus-driven selective pressure. Notably, IFIH1 also plays a role in autoimmunity, as common and rare polymorphisms in this gene have been associated with type 1 diabetes (T1D). We analyzed the evolutionary history of IFIH1 in human populations. Results herein suggest that two major IFIH1 haplotype clades originated from ancestral population structure (or balancing selection) in the African continent and that local selective pressures have acted on the gene. Specifically, directional selection in Europe and Asia resulted in the spread of a common IFIH1 haplotype carrying a derived His460 allele. This variant changes a highly conserved arginine residue in the helicase domain, possibly conferring altered specificity in viral recognition. An alternative common haplotype has swept to high frequency in South Americans as a result of recent positive selection. Previous studies suggested that a portion of risk alleles for autoimmune diseases could have been maintained in humans as they conferred a selective advantage against infections. This is not the case for IFIH1, as population genetic differentiation and haplotype analyses indicated that the T1D susceptibility alleles behaved as neutral or nearly neutral polymorphisms. Our findings suggest that variants in IFIH1 confer different susceptibility to diverse viral infections and provide insight into the relationship between adaptation to past infection and predisposition to autoimmunity in modern populations.
[Show abstract][Hide abstract] ABSTRACT: More than 2 billion individuals worldwide suffer from helminth infections. The highest parasite burdens occur in children and helminth infection during pregnancy is a risk factor for preterm delivery and reduced birth weight. Therefore, helminth infections can be regarded as a strong selective pressure.
Here we propose that candidate susceptibility genes for parasitic worm infections can be identified by searching for SNPs that display a strong correlation with the diversity of helminth species/genera transmitted in different geographic areas. By a genome-wide search we identified 3478 variants that correlate with helminth diversity. These SNPs map to 810 distinct human genes including loci involved in regulatory T cell function and in macrophage activation, as well as leukocyte integrins and co-inhibitory molecules. Analysis of functional relationships among these genes identified complex interaction networks centred around Th2 cytokines. Finally, several genes carrying candidate targets for helminth-driven selective pressure also harbour susceptibility alleles for asthma/allergy or are involved in airway hyper-responsiveness, therefore expanding the known parallelism between these conditions and parasitic infections.
Our data provide a landscape of human genes that modulate susceptibility to helminths and indicate parasitic worms as one of the major selective forces in humans.
[Show abstract][Hide abstract] ABSTRACT: In previous studies, we identified a locus for schizophrenia on 6q23.3 and proposed the Abelson helper integration site 1 (AHI1) as the candidate gene. AHI1 is expressed in the brain and plays a key role in neurodevelopment, is involved in Joubert syndrome, and has been recently associated with autism. The neurodevelopmental role of AHI1 fits with etiological hypotheses of schizophrenia. To definitively confirm our hypothesis, we searched for associations using a dense map of the region. Our strongest findings lay within the AHI1 gene: single-nucleotide polymorphisms rs11154801 and rs7759971 showed significant associations (P=6.23E-06; P=0.84E-06) and haplotypes gave P values in the 10E-8 to 10E-10 range. The second highest significant region maps close to AHI1 and includes the intergenic region between BC040979 and PDE7B (rs2038549 at P=9.70E-06 and rs1475069 at P=6.97E-06), and PDE7B and MAP7. Using a sample of Palestinian Arab families to confirm these findings, we found isolated signals. While these results did not retain their significance after correction for multiple testing, the joint analysis across the 2 samples supports the role of AHI1, despite the presence of heterogeneity. Given the hypothesis of positive selection of schizophrenia genes, we resequenced a 11 kb region within AHI1 in ethnically defined populations and found evidence for a selective sweep. Network analysis indicates 2 haplotype clades, with schizophrenia-susceptibility haplotypes clustering within the major clade. In conclusion, our data support the role of AHI1 as a susceptibility gene for schizophrenia and confirm it has been subjected to positive selection, also shedding light on new possible candidate genes, MAP7 and PDE7B.
The FASEB Journal 04/2010; 24(8):3066-82. DOI:10.1096/fj.09-152611 · 5.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The CPB2 gene encodes thrombin-activatable fibrinolysis inhibitor (TAFI), a hepatically secreted zymogen acting as a molecular link among coagulation, fibrinolysis, and inflammation. Variants in CPB2 have been associated with several human conditions. We resequenced and analyzed the two regions carrying previously known nonsynonimous single-nucleotide polymorphisms (Ala147Thr and Ile325Thr) and variants affecting transcript stability. Our data indicate that whereas the gene portion extending from exon 9 to the 3' untranslated region fits a model of neutral evolution, variants in the region encompassing exons 6-7 have been maintained by balancing selection. Indeed, we verified that the region displays high nucleotide diversity, many intermediate frequency variants, and an excess of polymorphism compared with interspecific divergence. Consistently, haplotype analysis indicated the presence of two major haplotype clades separated by deep branches. Transcript analysis revealed that in both HepG2 cells and human liver samples, CPB2 exon 7 undergoes haplotype-preferential skipping. Therefore, we indicate that balancing selection has been maintaining functional variants that promote alternative exon 7 splicing. Although transcripts lacking exon 7 represent a minority of total CPB2 products, the effect on antifibrinolytic activity might be much greater as the intrinsic instability of TAFI is a major determinant of its antifibrinolytic potential. These data highlight the contribution of population genetics approaches to the analysis of functional genetic variation and may orient further biochemical and genetics studies on the pathophysiologic role of CPB2 gene products.
[Show abstract][Hide abstract] ABSTRACT: Protozoa exert a strong selective pressure in humans. The selection signatures left by these pathogens can be exploited to identify genetic modulators of infection susceptibility. We show that protozoa diversity in different geographic locations is a good measure of protozoa-driven selective pressure; protozoa diversity captured selection signatures at known malaria resistance loci and identified several selected single nucleotide polymorphisms in immune and hemolytic anemia genes. A genome-wide search enabled us to identify 5180 variants mapping to 1145 genes that are subjected to protozoa-driven selective pressure. We provide a genome-wide estimate of protozoa-driven selective pressure and identify candidate susceptibility genes for protozoa-borne diseases.
Trends in Genetics 03/2010; 26(3):95-9. DOI:10.1016/j.tig.2009.12.010 · 9.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Author Summary
Viruses have represented a constant threat to human communities throughout their history, therefore, human genes involved in anti-viral response can be thought of as targets of virus-driven selective pressure. Here we utilized the marks left by selection to identify viral infection-associated allelic variants. We analyzed more than 660,000 single nucleotide polymorphisms (SNPs) genotyped in 52 human populations, and we used virus diversity (the number of different viruses in a geographic region) to measure virus-driven selective pressure. Results showed that genes involved in immune response and in the biosynthesis of glycan structures functioning as viral receptors display more variants associated with virus diversity than expected by chance. The same holds true for genes encoding proteins that directly interact with viral components. Genome-wide analysis identified 441 variants, mapping to 139 human genes, significantly associated with virus-diversity. We analyzed the functional relationships among genes subjected to virus-driven selective pressure and identified a complex interaction network enriched in viral products-interacting proteins. Therefore, we describe a novel approach for the identification of gene variants that may be involved in the susceptibility to viral infections.
[Show abstract][Hide abstract] ABSTRACT: The hygiene hypothesis relies on the assumption that humans have adapted to a pathogen-rich environment that no longer exists in industrialized societies. Recent advances in molecular immunology and population genetics allow deeper insight into the evolution and co-evolution of host-pathogen interactions and, therefore, into the foundations of the hygiene hypothesis.
Microbes and Infection 02/2010; 12(6):421-7. DOI:10.1016/j.micinf.2010.02.002 · 2.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Angiotensin-converting enzyme plays a critical role in the maintenance of cardiovascular homeostasis. Extensive research has aimed at identifying ACE genetic variants responsible for variation in enzyme plasma concentrations and associated with human diseases. These efforts have been hampered by the extensive linkage disequilibrium across the gene and the identity or location of the functional polymorphism(s) is at presently unknown. The aim of our study was to verify whether the Alu insertion/deletion (Alu I/D) polymorphism or any linked variant has been maintained by natural selection in human populations.
We resequenced a gene region surrounding the Alu I/D polymorphism in four human populations; we applied population neutrality tests and performed haplotype analysis for this region.
We observed high levels of nucleotide diversity, an excess of intermediate frequency alleles and, at least in African populations, a higher level of within-species diversity compared with interspecific divergence. Analysis of haplotype genealogy indicated the presence of two major clades separated by deep branches with a coalescence time older than 1.5 million years. All these features strongly suggest the action of balancing selection and we verified that the selection signature is restricted to the gene region surrounding the Alu I/D.
Our data imply the presence of a functional polymorphism in the Alu I/D region and illustrate the contribution of evolutionary models to classic single nucleotide polymorphism-phenotype association approaches by providing information about the localization of candidate functional variants.
Pharmacogenetics and Genomics 02/2010; 20(2):131-4. DOI:10.1097/FPC.0b013e3283333532 · 3.48 Impact Factor