DNA secondary structures are associated with recombination in major Plasmodium falciparum variable surface antigen gene families

TY - JOUR

T1 - DNA secondary structures are associated with recombination in major Plasmodium falciparum variable surface antigen gene families

AU - Pedersen, Adam Frederik Sander

AU - Lavstsen, Thomas

AU - Rask, Thomas Salhøj

AU - Lisby, Michael

AU - Salanti, Ali

AU - Fordyce, Sarah L

AU - Jespersen, Jakob S

AU - Carter, Richard

AU - Deitsch, Kirk W

AU - Theander, Thor G

AU - Pedersen, Anders Gorm

AU - Arnot, David Edward

PY - 2014/2

Y1 - 2014/2

N2 - Many bacterial, viral and parasitic pathogens undergo antigenic variation to counter host immune defense mechanisms. In Plasmodium falciparum, the most lethal of human malaria parasites, switching of var gene expression results in alternating expression of the adhesion proteins of the Plasmodium falciparum-erythrocyte membrane protein 1 class on the infected erythrocyte surface. Recombination clearly generates var diversity, but the nature and control of the genetic exchanges involved remain unclear. By experimental and bioinformatic identification of recombination events and genome-wide recombination hotspots in var genes, we show that during the parasite's sexual stages, ectopic recombination between isogenous var paralogs occurs near low folding free energy DNA 50-mers and that these sequences are heavily concentrated at the boundaries of regions encoding individual Plasmodium falciparum-erythrocyte membrane protein 1 structural domains. The recombinogenic potential of these 50-mers is not parasite-specific because these sequences also induce recombination when transferred to the yeast Saccharomyces cerevisiae. Genetic cross data suggest that DNA secondary structures (DSS) act as inducers of recombination during DNA replication in P. falciparum sexual stages, and that these DSS-regulated genetic exchanges generate functional and diverse P. falciparum adhesion antigens. DSS-induced recombination may represent a common mechanism for optimizing the evolvability of virulence gene families in pathogens.

AB - Many bacterial, viral and parasitic pathogens undergo antigenic variation to counter host immune defense mechanisms. In Plasmodium falciparum, the most lethal of human malaria parasites, switching of var gene expression results in alternating expression of the adhesion proteins of the Plasmodium falciparum-erythrocyte membrane protein 1 class on the infected erythrocyte surface. Recombination clearly generates var diversity, but the nature and control of the genetic exchanges involved remain unclear. By experimental and bioinformatic identification of recombination events and genome-wide recombination hotspots in var genes, we show that during the parasite's sexual stages, ectopic recombination between isogenous var paralogs occurs near low folding free energy DNA 50-mers and that these sequences are heavily concentrated at the boundaries of regions encoding individual Plasmodium falciparum-erythrocyte membrane protein 1 structural domains. The recombinogenic potential of these 50-mers is not parasite-specific because these sequences also induce recombination when transferred to the yeast Saccharomyces cerevisiae. Genetic cross data suggest that DNA secondary structures (DSS) act as inducers of recombination during DNA replication in P. falciparum sexual stages, and that these DSS-regulated genetic exchanges generate functional and diverse P. falciparum adhesion antigens. DSS-induced recombination may represent a common mechanism for optimizing the evolvability of virulence gene families in pathogens.

KW - Antigenic Variation

KW - Antigens, Protozoan

KW - DNA, Protozoan

KW - Genes, Protozoan

KW - Multigene Family

KW - Nucleic Acid Conformation

KW - Plasmodium falciparum

KW - Protein Structure, Tertiary

KW - Protozoan Proteins

KW - Recombination, Genetic

KW - Saccharomyces cerevisiae

U2 - 10.1093/nar/gkt1174

DO - 10.1093/nar/gkt1174

M3 - Journal article

C2 - 24253306

SN - 0305-1048

VL - 42

SP - 2270

EP - 2281

JO - Nucleic Acids Research

JF - Nucleic Acids Research

IS - 4

ER -