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Ancient and recent selective pressures shaped genetic diversity at AIM2-like nucleic acid sensors.

Cagliani R, Forni D, Biasin M, Comabella M, Guerini FR, Riva S, Pozzoli U, Agliardi C, Caputo D, Malhotra S, Montalban X, Bresolin N, Clerici M, Sironi M - Genome Biol Evol (2014)

Bottom Line: Data herein indicate that ALRs have been repeatedly targeted by natural selection.The balancing selection region in IFI16 carries a variant with opposite risk effect for distinct autoimmune diseases, suggesting antagonistic pleiotropy.We propose that the underlying scenario is the result of an ancestral and still ongoing host-pathogen arms race and that the maintenance of susceptibility alleles for autoimmune diseases at IFI16 represents an evolutionary trade-off.

View Article: PubMed Central - PubMed

Affiliation: Bioinformatics Laboratory, Scientific Institute IRCCS E. Medea, Bosisio Parini (LC), Italy.

ABSTRACT
AIM2-like receptors (ALRs) are a family of nucleic acid sensors essential for innate immune responses against viruses and bacteria. We performed an evolutionary analysis of ALR genes (MNDA, PYHIN1, IFI16, and AIM2) by analyzing inter- and intraspecies diversity. Maximum-likelihood analyses indicated that IFI16 and AIM2 evolved adaptively in primates, with branch-specific selection at the catarrhini lineage for IFI16. Application of a population genetics-phylogenetics approach also allowed identification of positive selection events in the human lineage. Positive selection in primates targeted sites located at the DNA-binding interface in both IFI16 and AIM2. In IFI16, several sites positively selected in primates and in the human lineage were located in the PYD domain, which is involved in protein-protein interaction and is bound by a human cytomegalovirus immune evasion protein. Finally, positive selection was found to target nuclear localization signals in IFI16 and the spacer region separating the two HIN domains. Population genetic analysis in humans revealed that an IFI16 genic region has been a target of long-standing balancing selection, possibly acting on two nonsynonymous polymorphisms located in the spacer region. Data herein indicate that ALRs have been repeatedly targeted by natural selection. The balancing selection region in IFI16 carries a variant with opposite risk effect for distinct autoimmune diseases, suggesting antagonistic pleiotropy. We propose that the underlying scenario is the result of an ancestral and still ongoing host-pathogen arms race and that the maintenance of susceptibility alleles for autoimmune diseases at IFI16 represents an evolutionary trade-off.

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Related in: MedlinePlus

FST analysis of the ALR gene cluster. Data from the 1000 Genomes Pilot Project were used to calculate FST in sliding windows of 20 SNPs moving along the ALR gene cluster (NCBI/hg18, chr1:157063927–157317926) with a step of three SNPs (upper panel). Color codes refer to population comparisons: red, YRI/CEU; blue, YRI/AS; and green, CEU/AS. Horizontal dashed lines represent the 95th percentile in the distribution of FST calculated for sliding windows deriving from 2,000 randomly selected human genes. SNPs genotyped in the HGDP-CEPH panel are represented as gray circles (no unusual FST value among continental groups) or black circles (FST outliers); a SNP associated to rheumatoid arthritis and celiac disease is reported in red. The resequenced IFI16 region is shaded in gray. The blue and cyan boxes represent the segmental duplication of exon 7. In the bottom panel, LD analysis for the IFI16 resequenced region (5 kb) is shown. LD analysis was performed with the Haploview software using resequencing data, and blocks were identified through the implemented confidence interval algorithm (see Materials and Methods). Variants within the first LD block were used for Network and GENETREE analyses.
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evu066-F3: FST analysis of the ALR gene cluster. Data from the 1000 Genomes Pilot Project were used to calculate FST in sliding windows of 20 SNPs moving along the ALR gene cluster (NCBI/hg18, chr1:157063927–157317926) with a step of three SNPs (upper panel). Color codes refer to population comparisons: red, YRI/CEU; blue, YRI/AS; and green, CEU/AS. Horizontal dashed lines represent the 95th percentile in the distribution of FST calculated for sliding windows deriving from 2,000 randomly selected human genes. SNPs genotyped in the HGDP-CEPH panel are represented as gray circles (no unusual FST value among continental groups) or black circles (FST outliers); a SNP associated to rheumatoid arthritis and celiac disease is reported in red. The resequenced IFI16 region is shaded in gray. The blue and cyan boxes represent the segmental duplication of exon 7. In the bottom panel, LD analysis for the IFI16 resequenced region (5 kb) is shown. LD analysis was performed with the Haploview software using resequencing data, and blocks were identified through the implemented confidence interval algorithm (see Materials and Methods). Variants within the first LD block were used for Network and GENETREE analyses.

Mentions: As shown in figure 3, three variants (rs856090:A>G, rs1614254:T>C, rs947275:T>C) were found to be outliers among HGDP continental groups in FST distribution values (ranks = 0.965, 0.951, and 0.981, respectively). Two of them are within the IFI16 gene, and they are located in a peak of significantly high FST in all pairwise comparisons (YRI/CEU, YRI/AS, and CEU/AS), as assessed from the 1000 Genomes Pilot project data. Interestingly, susceptibility alleles for rheumatoid arthritis and for celiac disease (rs1772408:T>C) were identified in this region through a genome-wide association study (GWAS) (Zhernakova et al. 2011). Also, the FST outliers flank the exon 7 duplication allele (fig. 3).Fig. 3.—


Ancient and recent selective pressures shaped genetic diversity at AIM2-like nucleic acid sensors.

Cagliani R, Forni D, Biasin M, Comabella M, Guerini FR, Riva S, Pozzoli U, Agliardi C, Caputo D, Malhotra S, Montalban X, Bresolin N, Clerici M, Sironi M - Genome Biol Evol (2014)

FST analysis of the ALR gene cluster. Data from the 1000 Genomes Pilot Project were used to calculate FST in sliding windows of 20 SNPs moving along the ALR gene cluster (NCBI/hg18, chr1:157063927–157317926) with a step of three SNPs (upper panel). Color codes refer to population comparisons: red, YRI/CEU; blue, YRI/AS; and green, CEU/AS. Horizontal dashed lines represent the 95th percentile in the distribution of FST calculated for sliding windows deriving from 2,000 randomly selected human genes. SNPs genotyped in the HGDP-CEPH panel are represented as gray circles (no unusual FST value among continental groups) or black circles (FST outliers); a SNP associated to rheumatoid arthritis and celiac disease is reported in red. The resequenced IFI16 region is shaded in gray. The blue and cyan boxes represent the segmental duplication of exon 7. In the bottom panel, LD analysis for the IFI16 resequenced region (5 kb) is shown. LD analysis was performed with the Haploview software using resequencing data, and blocks were identified through the implemented confidence interval algorithm (see Materials and Methods). Variants within the first LD block were used for Network and GENETREE analyses.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4007548&req=5

evu066-F3: FST analysis of the ALR gene cluster. Data from the 1000 Genomes Pilot Project were used to calculate FST in sliding windows of 20 SNPs moving along the ALR gene cluster (NCBI/hg18, chr1:157063927–157317926) with a step of three SNPs (upper panel). Color codes refer to population comparisons: red, YRI/CEU; blue, YRI/AS; and green, CEU/AS. Horizontal dashed lines represent the 95th percentile in the distribution of FST calculated for sliding windows deriving from 2,000 randomly selected human genes. SNPs genotyped in the HGDP-CEPH panel are represented as gray circles (no unusual FST value among continental groups) or black circles (FST outliers); a SNP associated to rheumatoid arthritis and celiac disease is reported in red. The resequenced IFI16 region is shaded in gray. The blue and cyan boxes represent the segmental duplication of exon 7. In the bottom panel, LD analysis for the IFI16 resequenced region (5 kb) is shown. LD analysis was performed with the Haploview software using resequencing data, and blocks were identified through the implemented confidence interval algorithm (see Materials and Methods). Variants within the first LD block were used for Network and GENETREE analyses.
Mentions: As shown in figure 3, three variants (rs856090:A>G, rs1614254:T>C, rs947275:T>C) were found to be outliers among HGDP continental groups in FST distribution values (ranks = 0.965, 0.951, and 0.981, respectively). Two of them are within the IFI16 gene, and they are located in a peak of significantly high FST in all pairwise comparisons (YRI/CEU, YRI/AS, and CEU/AS), as assessed from the 1000 Genomes Pilot project data. Interestingly, susceptibility alleles for rheumatoid arthritis and for celiac disease (rs1772408:T>C) were identified in this region through a genome-wide association study (GWAS) (Zhernakova et al. 2011). Also, the FST outliers flank the exon 7 duplication allele (fig. 3).Fig. 3.—

Bottom Line: Data herein indicate that ALRs have been repeatedly targeted by natural selection.The balancing selection region in IFI16 carries a variant with opposite risk effect for distinct autoimmune diseases, suggesting antagonistic pleiotropy.We propose that the underlying scenario is the result of an ancestral and still ongoing host-pathogen arms race and that the maintenance of susceptibility alleles for autoimmune diseases at IFI16 represents an evolutionary trade-off.

View Article: PubMed Central - PubMed

Affiliation: Bioinformatics Laboratory, Scientific Institute IRCCS E. Medea, Bosisio Parini (LC), Italy.

ABSTRACT
AIM2-like receptors (ALRs) are a family of nucleic acid sensors essential for innate immune responses against viruses and bacteria. We performed an evolutionary analysis of ALR genes (MNDA, PYHIN1, IFI16, and AIM2) by analyzing inter- and intraspecies diversity. Maximum-likelihood analyses indicated that IFI16 and AIM2 evolved adaptively in primates, with branch-specific selection at the catarrhini lineage for IFI16. Application of a population genetics-phylogenetics approach also allowed identification of positive selection events in the human lineage. Positive selection in primates targeted sites located at the DNA-binding interface in both IFI16 and AIM2. In IFI16, several sites positively selected in primates and in the human lineage were located in the PYD domain, which is involved in protein-protein interaction and is bound by a human cytomegalovirus immune evasion protein. Finally, positive selection was found to target nuclear localization signals in IFI16 and the spacer region separating the two HIN domains. Population genetic analysis in humans revealed that an IFI16 genic region has been a target of long-standing balancing selection, possibly acting on two nonsynonymous polymorphisms located in the spacer region. Data herein indicate that ALRs have been repeatedly targeted by natural selection. The balancing selection region in IFI16 carries a variant with opposite risk effect for distinct autoimmune diseases, suggesting antagonistic pleiotropy. We propose that the underlying scenario is the result of an ancestral and still ongoing host-pathogen arms race and that the maintenance of susceptibility alleles for autoimmune diseases at IFI16 represents an evolutionary trade-off.

Show MeSH
Related in: MedlinePlus