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Population genetic evidence for positive and purifying selection acting at the human IFN-? locus in Africa.

ABSTRACT: Despite its critical role in the defense against microbial infection and tumor development, little is known about the range of nucleotide and haplotype variation at IFN-?, or the evolutionary forces that have shaped patterns of diversity at this locus. To address this gap in knowledge, we examined sequence data from the IFN-? gene in 1461 individuals from 15 worldwide populations. Our analyses uncovered novel patterns of variation in distinct African populations, including an excess of high frequency-derived alleles, unusually long haplotype structure surrounding the IFN-? gene, and a "star-like" genealogy of African-specific haplotypes carrying variants previously associated with infectious disease. We also inferred a deep time to coalescence of variation at IFN-? (~?0.8 million years ago) and ancient ages for common polymorphisms predating the evolution of modern humans. Taken together, these results are congruent with a model of positive selection on standing variation in African populations. Furthermore, we inferred that common variants in intron 3 of IFN-? are the likely targets of selection. In addition, we observed a paucity of non-synonymous substitutions relative to synonymous changes in the exons of IFN-? in African and non-African populations, suggestive of strong purifying selection. Therefore, we contend that positive and purifying selection have influenced levels of diversity in different regions of IFN-?, implying that these distinct genic regions are, or have been, functionally important. Overall, this study provides additional insights into the evolutionary events that have contributed to the frequency and distribution of alleles having a role in human health and disease.

SUBMITTER: Campbell MC

PROVIDER: S-EPMC7089600 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Population genetic evidence for positive and purifying selection acting at the human IFN-γ locus in Africa.

Campbell Michael C MC Smith Lunden T LT Harvey Jayla J

Genes and immunity 20180329 2

Despite its critical role in the defense against microbial infection and tumor development, little is known about the range of nucleotide and haplotype variation at IFN-γ, or the evolutionary forces that have shaped patterns of diversity at this locus. To address this gap in knowledge, we examined sequence data from the IFN-γ gene in 1461 individuals from 15 worldwide populations. Our analyses uncovered novel patterns of variation in distinct African populations, including an excess of high freq ...[more]

PMID: 29599512

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Project description:BACKGROUND: The ?-lactamase (bla) locus, which confers resistance to penicillins only, may control the transcription of mecA, the central element of methicillin resistance, which is embedded in a polymorphic heterelogous chromosomal cassette (the SCCmec element). In order to assess the eventual correlation between bla allotypes and genetic lineages, SCCmec types and/or ?-lactam resistance phenotypes, the allelic variation on the bla locus was evaluated in a representative collection of 54 international epidemic methicillin-resistant Staphylococcus aureus (MRSA) clinical strains and, for comparative purposes, also in 24 diverse methicillin-susceptible S. aureus (MSSA) strains. RESULTS: Internal fragments of blaZ (the ?-lactamase structural gene) were sequenced for all strains. A subset of strains, representative of blaZ allotypes, was further characterized by sequencing of internal fragments of the blaZ transcriptional regulators, blaI and blaR1. Thirteen allotypes for blaZ, nine for blaI and 12 for blaR1 were found. In a total of 121 unique single-nucleotide polymorphisms (SNP) detected, no frameshift mutations were identified and only one nonsense mutation within blaZ was found in a MRSA strain. On average, blaZ alleles were more polymorphic among MSSA than in MRSA (14.7 vs 11.4 SNP/allele). Overall, blaR1 was the most polymorphic gene with an average of 24.8 SNP/allele. No correlation could be established between bla allotypes and genetic lineages, SCCmec types and/or ?-lactam resistance phenotypes. In order to estimate the selection pressure acting on the bla locus, the average dN/dS values were computed. In the three genes and in both collections dN/dS ratios were significantly below 1. CONCLUSIONS: The data strongly suggests the existence of a purifying selection to maintain the bla locus fully functional even on MRSA strains. Although, this is in agreement with the notion that in most clinical MRSA strains mecA gene is under the control of the bla regulatory genes, these findings also suggest that the apparently redundant function of blaZ gene for the MRSA resistant phenotype is still important for these strains. In addition, the data shows that the sensor-inducer blaR1 is the primary target for the accumulation of mutations in the bla locus, presumably to modulate the response to the presence of ?-lactam antibiotic.

Dataset Information

Population genetic evidence for positive and purifying selection acting at the human IFN-? locus in Africa.

Publications

Population genetic evidence for positive and purifying selection acting at the human IFN-γ locus in Africa.

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