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Chikungunya virus 3' untranslated region: adaptation to mosquitoes and a population bottleneck as major evolutionary forces.

Chen R, Wang E, Tsetsarkin KA, Weaver SC - PLoS Pathog. (2013)

Bottom Line: Given that a longer genome is usually associated with less efficient replication, we hypothesized that the fixation of these genetic changes in the Asian lineage 3'UTR was due to their beneficial effects on adaptation to vectors or hosts.Rather, it may have resulted from a population bottleneck during its introduction from Africa to Asia.Our results provide further evidence that the limited epidemic potential of the Asian CHIKV strains resulted from founder effects that reduced its fitness for efficient transmission by mosquitoes there.

View Article: PubMed Central - PubMed

Affiliation: Center for Tropical Diseases and Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America.

ABSTRACT
The 3' untranslated genome region (UTR) of arthropod-borne viruses is characterized by enriched direct repeats (DRs) and stem-loop structures. Despite many years of theoretical and experimental study, on-going positive selection on the 3'UTR had never been observed in 'real-time,' and the role of the arbovirus 3'UTR remains poorly understood. We observed a lineage-specific 3'UTR sequence pattern in all available Asian lineage of the mosquito-borne alphavirus, chikungunya virus (CHIKV) (1958-2009), including complicated mutation and duplication patterns of the long DRs. Given that a longer genome is usually associated with less efficient replication, we hypothesized that the fixation of these genetic changes in the Asian lineage 3'UTR was due to their beneficial effects on adaptation to vectors or hosts. Using reverse genetic methods, we examined the functional importance of each direct repeat. Our results suggest that adaptation to mosquitoes, rather than to mammalian hosts, is a major evolutionary force on the CHIKV 3'UTR. Surprisingly, the Asian 3'UTR appeared to be inferior to its predicted ancestral sequence for replication in both mammals and mosquitoes, suggesting that its fixation in Asia was not a result of directional selection. Rather, it may have resulted from a population bottleneck during its introduction from Africa to Asia. We propose that this introduction of a 3'UTR with deletions led to genetic drift and compensatory mutations associated with the loss of structural/functional constraints, followed by two independent beneficial duplications and fixation due to positive selection. Our results provide further evidence that the limited epidemic potential of the Asian CHIKV strains resulted from founder effects that reduced its fitness for efficient transmission by mosquitoes there.

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Hypothetical evolutionary pathway of CHIKV Asian lineage 3′UTR.Color blocks in this figure correspond to those in Fig. 1.
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ppat-1003591-g004: Hypothetical evolutionary pathway of CHIKV Asian lineage 3′UTR.Color blocks in this figure correspond to those in Fig. 1.

Mentions: Based on this, we propose an evolutionary path of the Asian CHIKV 3′UTR illustrated in Fig. 4. First, a deletion occurred that resulted in the loss of one copy each of DR1 and DR2. Compared to its inferred ECSA ancestor, this mutant strain was presumably debilitated in its fitness for infection and dissemination in its principal vector, A. aegypti although it may have had a slight fitness increase for replication in humans based on the murine model. In the large enzootic CHIKV populations that exist in Africa, this mutant could disappear quickly due to its low frequency. The rapid fixation of such a mutant in Asia can only be explained by a population bottleneck where stochastic events can facilitate the fixation of a beneficial allele, and even allow a mutant with reduced fitness to circumvent selection. It is possible that this mutation accompanied the intercontinental transmission from Africa to Asia, which probably involved one or a few infected persons; it is also possible that a CHIKV population bottleneck was influenced by a mosquito eradication campaign in Southeast Asia (1955–1969). Although this effort was designed to eliminate malaria [41], [42], it included the use of DDT inside homes, which also reduced populations of A. aegypti responsible for urban CHIKV transmission. The use of DDT was also instrumental in the eradication of A. aegypti in many parts of the Americas during the 1950s to1960s [43], [44]. The coincidence of our estimated year of the most recent common ancestor of currently circulating Asian CHIKV lineage (1948–1956) with this malaria eradication campaign suggests a possible link.


Chikungunya virus 3' untranslated region: adaptation to mosquitoes and a population bottleneck as major evolutionary forces.

Chen R, Wang E, Tsetsarkin KA, Weaver SC - PLoS Pathog. (2013)

Hypothetical evolutionary pathway of CHIKV Asian lineage 3′UTR.Color blocks in this figure correspond to those in Fig. 1.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3757053&req=5

ppat-1003591-g004: Hypothetical evolutionary pathway of CHIKV Asian lineage 3′UTR.Color blocks in this figure correspond to those in Fig. 1.
Mentions: Based on this, we propose an evolutionary path of the Asian CHIKV 3′UTR illustrated in Fig. 4. First, a deletion occurred that resulted in the loss of one copy each of DR1 and DR2. Compared to its inferred ECSA ancestor, this mutant strain was presumably debilitated in its fitness for infection and dissemination in its principal vector, A. aegypti although it may have had a slight fitness increase for replication in humans based on the murine model. In the large enzootic CHIKV populations that exist in Africa, this mutant could disappear quickly due to its low frequency. The rapid fixation of such a mutant in Asia can only be explained by a population bottleneck where stochastic events can facilitate the fixation of a beneficial allele, and even allow a mutant with reduced fitness to circumvent selection. It is possible that this mutation accompanied the intercontinental transmission from Africa to Asia, which probably involved one or a few infected persons; it is also possible that a CHIKV population bottleneck was influenced by a mosquito eradication campaign in Southeast Asia (1955–1969). Although this effort was designed to eliminate malaria [41], [42], it included the use of DDT inside homes, which also reduced populations of A. aegypti responsible for urban CHIKV transmission. The use of DDT was also instrumental in the eradication of A. aegypti in many parts of the Americas during the 1950s to1960s [43], [44]. The coincidence of our estimated year of the most recent common ancestor of currently circulating Asian CHIKV lineage (1948–1956) with this malaria eradication campaign suggests a possible link.

Bottom Line: Given that a longer genome is usually associated with less efficient replication, we hypothesized that the fixation of these genetic changes in the Asian lineage 3'UTR was due to their beneficial effects on adaptation to vectors or hosts.Rather, it may have resulted from a population bottleneck during its introduction from Africa to Asia.Our results provide further evidence that the limited epidemic potential of the Asian CHIKV strains resulted from founder effects that reduced its fitness for efficient transmission by mosquitoes there.

View Article: PubMed Central - PubMed

Affiliation: Center for Tropical Diseases and Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America.

ABSTRACT
The 3' untranslated genome region (UTR) of arthropod-borne viruses is characterized by enriched direct repeats (DRs) and stem-loop structures. Despite many years of theoretical and experimental study, on-going positive selection on the 3'UTR had never been observed in 'real-time,' and the role of the arbovirus 3'UTR remains poorly understood. We observed a lineage-specific 3'UTR sequence pattern in all available Asian lineage of the mosquito-borne alphavirus, chikungunya virus (CHIKV) (1958-2009), including complicated mutation and duplication patterns of the long DRs. Given that a longer genome is usually associated with less efficient replication, we hypothesized that the fixation of these genetic changes in the Asian lineage 3'UTR was due to their beneficial effects on adaptation to vectors or hosts. Using reverse genetic methods, we examined the functional importance of each direct repeat. Our results suggest that adaptation to mosquitoes, rather than to mammalian hosts, is a major evolutionary force on the CHIKV 3'UTR. Surprisingly, the Asian 3'UTR appeared to be inferior to its predicted ancestral sequence for replication in both mammals and mosquitoes, suggesting that its fixation in Asia was not a result of directional selection. Rather, it may have resulted from a population bottleneck during its introduction from Africa to Asia. We propose that this introduction of a 3'UTR with deletions led to genetic drift and compensatory mutations associated with the loss of structural/functional constraints, followed by two independent beneficial duplications and fixation due to positive selection. Our results provide further evidence that the limited epidemic potential of the Asian CHIKV strains resulted from founder effects that reduced its fitness for efficient transmission by mosquitoes there.

Show MeSH
Related in: MedlinePlus