title: Two genetic determinants acquired late in Mus evolution regulate the inclusion of exon 5, which alters mouse APOBEC3 translation efficiency.
abstract: Mouse apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like editing complex 3 (mA3), an intracellular antiviral factor, has 2 allelic variations that are linked with different susceptibilities to beta- and gammaretrovirus infections among various mouse strains. In virus-resistant C57BL/6 (B6) mice, mA3 transcripts are more abundant than those in susceptible BALB/c mice both in the spleen and bone marrow. These strains of mice also express mA3 transcripts with different splicing patterns: B6 mice preferentially express exon 5-deficient (Δ5) mA3 mRNA, while BALB/c mice produce exon 5-containing full-length mA3 mRNA as the major transcript. Although the protein product of the Δ5 mRNA exerts stronger antiretroviral activities than the full-length protein, how exon 5 affects mA3 antiviral activity, as well as the genetic mechanisms regulating exon 5 inclusion into the mA3 transcripts, remains largely uncharacterized. Here we show that mA3 exon 5 is indeed a functional element that influences protein synthesis at a post-transcriptional level. We further employed in vitro splicing assays using genomic DNA clones to identify two critical polymorphisms affecting the inclusion of exon 5 into mA3 transcripts: the number of TCCT repeats upstream of exon 5 and the single nucleotide polymorphism within exon 5 located 12 bases upstream of the exon 5/intron 5 boundary. Distribution of the above polymorphisms among different Mus species indicates that the inclusion of exon 5 into mA3 mRNA is a relatively recent event in the evolution of mice. The widespread geographic distribution of this exon 5-including genetic variant suggests that in some Mus populations the cost of maintaining an effective but mutagenic enzyme may outweigh its antiviral function.
authors.affiliation: Department of Immunology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Hakata
authors.forename: Eri
authors.initials: E
authors.lastname: Takeda
authors.forename: Qingping
authors.initials: Q
authors.lastname: Liu
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Iwatani
authors.forename: Christine A
authors.initials: CA
authors.lastname: Kozak
authors.forename: Masaaki
authors.initials: M
authors.lastname: Miyazawa
mesh_terms: D000818:Animals; D005075:Biological Evolution; D002461:Cell Line, Transformed; D003564:Cytidine Deaminase / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D014176:Protein Biosynthesis / Q000235:genetics*; D055550:Protein Stability; D012326:RNA Splicing / Q000235:genetics*; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D038621:Regulatory Sequences, Ribonucleic Acid / Q000235:genetics*; D012190:Retroviridae / Q000502:physiology; D012192:Retroviridae Infections / Q000821:virology; D017384:Sequence Deletion; D013045:Species Specificity; D014412:Tumor Virus Infections / Q000821:virology
chemical_list: D012333:RNA, Messenger; D038621:Regulatory Sequences, Ribonucleic Acid; C503504:Apobec3 protein, mouse; D003564:Cytidine Deaminase