And other double-domain enzymes is still lacking, but strong homology with the solved catalytic domain structures, including no significant insertions or deletions, indicates that they will have a similar overall structural organization. Positive selection and copy KF-89617 structure number variationAuthor Manuscript Author Manuscript Author Manuscript Author ManuscriptOne of the most fascinating hallmarks of the APOBEC family and a probable characteristic of all virus restriction factors is rapid evolution evidenced by elevated rates of amino acid substitution mutations and gene copy number variations (Harris et al., 2012; Johnson and Sawyer, 2009; Meyerson and Sawyer, 2011; Ortiz et al., 2006). A higher ratio of amino acid altering mutations relative to silent mutations is called positive selection. All of the A3 subfamily members show compelling evidence for positive selection (Duggal et al., 2013; Henry et al., 2012; Sawyer et al., 2004; Zhang and Webb, 2004), consistent with ancient and likely ongoing battles with viral pathogens. There is also tremendous variation in A3 gene copy number between branches of the mammalian phylogenetic tree (Conticello et al., 2005; Harris and Liddament, 2004; LaRue et al., 2009; LaRue et al., 2008; M k et al., 2008) (Figure 1C). For instance, humans, chimpanzees, and rhesus macaques, and most other primates share a similar seven gene A3 locus comprised of three single domain genes (A3A/C/H) and four double domain genes (A3B/D/F/G) (Hultquist et al., 2011; Schmitt et al., 2011; Virgen and Hatziioannou, 2007). In contrast, mice have just one double-domain A3 gene (Harris and Liddament, 2004; Li et al., 2012a; Sanville et al., 2010). Other present day mammals have different copy numbers and overall gene organizations (Conticello et al., 2005; Harris and Liddament, 2004; LaRue et al., 2009; LaRue et al., 2008; M k et al., 2008). Genomic sequences have enabled investigators to deduce that the origin of the mammalspecific A3 gene subfamily most likely occurred through duplication of an ancestral AID/ APOBEC1 locus (these genes are still located adjacent to one another in most vertebrates, but separated in others, such as primates, by a large chromosomal inversion) (Conticello et al., 2005; Harris and Liddament, 2004; LaRue et al., 2009; LaRue et al., 2008). The tandem head-to-tail organization of the ancestral A3 gene cluster provided the necessary substrate for rapid evolutionary diversification through multiple unequal crossing-over events, with some leading to gene expansions and POR-8 web others to contractions. Selective pressures from diverse viral infections most likely led to the expanded A3 gene repertoire observed in many present day mammals. Nevertheless, deletions are also common as observed by one A3 gene in rodents (due to a relatively ancient deletion early in the rodent lineage) and one in pigs (due to a relatively recent deletion specific to the Suidae lineage). Copy number and amino acid alternations also occur within a single species evidenced by the circulation of a commonVirology. Author manuscript; available in PMC 2016 May 01.Harris and DudleyPageA3B deletion in humans (Kidd et al., 2007), the existence of seven distinct A3H haplotypes in humans that encode stable or unstable proteins (OhAinle et al., 2008; Ooms et al., 2013; Refsland et al., 2014; Wang et al., 2011), two human A3A translation initiation sites (Henry et al., 2012; Stenglein et al., 2010; Thielen et al., 2010), multiple transcription initiation.And other double-domain enzymes is still lacking, but strong homology with the solved catalytic domain structures, including no significant insertions or deletions, indicates that they will have a similar overall structural organization. Positive selection and copy number variationAuthor Manuscript Author Manuscript Author Manuscript Author ManuscriptOne of the most fascinating hallmarks of the APOBEC family and a probable characteristic of all virus restriction factors is rapid evolution evidenced by elevated rates of amino acid substitution mutations and gene copy number variations (Harris et al., 2012; Johnson and Sawyer, 2009; Meyerson and Sawyer, 2011; Ortiz et al., 2006). A higher ratio of amino acid altering mutations relative to silent mutations is called positive selection. All of the A3 subfamily members show compelling evidence for positive selection (Duggal et al., 2013; Henry et al., 2012; Sawyer et al., 2004; Zhang and Webb, 2004), consistent with ancient and likely ongoing battles with viral pathogens. There is also tremendous variation in A3 gene copy number between branches of the mammalian phylogenetic tree (Conticello et al., 2005; Harris and Liddament, 2004; LaRue et al., 2009; LaRue et al., 2008; M k et al., 2008) (Figure 1C). For instance, humans, chimpanzees, and rhesus macaques, and most other primates share a similar seven gene A3 locus comprised of three single domain genes (A3A/C/H) and four double domain genes (A3B/D/F/G) (Hultquist et al., 2011; Schmitt et al., 2011; Virgen and Hatziioannou, 2007). In contrast, mice have just one double-domain A3 gene (Harris and Liddament, 2004; Li et al., 2012a; Sanville et al., 2010). Other present day mammals have different copy numbers and overall gene organizations (Conticello et al., 2005; Harris and Liddament, 2004; LaRue et al., 2009; LaRue et al., 2008; M k et al., 2008). Genomic sequences have enabled investigators to deduce that the origin of the mammalspecific A3 gene subfamily most likely occurred through duplication of an ancestral AID/ APOBEC1 locus (these genes are still located adjacent to one another in most vertebrates, but separated in others, such as primates, by a large chromosomal inversion) (Conticello et al., 2005; Harris and Liddament, 2004; LaRue et al., 2009; LaRue et al., 2008). The tandem head-to-tail organization of the ancestral A3 gene cluster provided the necessary substrate for rapid evolutionary diversification through multiple unequal crossing-over events, with some leading to gene expansions and others to contractions. Selective pressures from diverse viral infections most likely led to the expanded A3 gene repertoire observed in many present day mammals. Nevertheless, deletions are also common as observed by one A3 gene in rodents (due to a relatively ancient deletion early in the rodent lineage) and one in pigs (due to a relatively recent deletion specific to the Suidae lineage). Copy number and amino acid alternations also occur within a single species evidenced by the circulation of a commonVirology. Author manuscript; available in PMC 2016 May 01.Harris and DudleyPageA3B deletion in humans (Kidd et al., 2007), the existence of seven distinct A3H haplotypes in humans that encode stable or unstable proteins (OhAinle et al., 2008; Ooms et al., 2013; Refsland et al., 2014; Wang et al., 2011), two human A3A translation initiation sites (Henry et al., 2012; Stenglein et al., 2010; Thielen et al., 2010), multiple transcription initiation.