The SPANX gene family of cancer/testis-specific antigens: Rapid evolution and amplification in African great apes and hominids

Abstract

, encoding cancer͞testis-specific antigens that are potential targets for cancer immunotherapy. These highly similar paralogous genes cluster on the X chromosome at Xq27. We isolated and sequenced primate genomic clones homologous to human SPANX. Analysis of these clones and search of the human genome sequence revealed an uncharacterized group of genes, SPANX-N, which are present in all primates as well as in mouse and rat. In humans, four SPANX-N genes comprise a series of tandem duplicates at Xq27; a fifth member of this subfamily is located at Xp11. Similarly to SPANX-A͞D, human SPANX-N genes are expressed in normal testis and some melanoma cell lines; testis-specific expression of SPANX is also conserved in mouse. Analysis of the taxonomic distribution of the long and short forms of the intron indicates that SPANX-N is the ancestral form, from which the SPANX-A͞D subfamily evolved in the common ancestor of the hominoid lineage. Strikingly, the coding sequences of the SPANX genes evolved much faster than the intron and the 5 untranslated region. There is a strong correlation between the rates of evolution of synonymous and nonsynonymous codon positions, both of which are accelerated 2-fold or more compared to the noncoding sequences. Thus, evolution of the SPANX family appears to have involved positive selection that affected not only the protein sequence but also the synonymous sites in the coding sequence. T he sperm protein associated with the nucleus on the X chromosome (SPANX) multigene family encodes proteins whose expression is restricted to the normal testis and certain tumors (1, 2). These postmeiotically transcribed genes comprise one of the few examples of haploid expression from X-linked genes (3). Antibodies against SPANX recognized spermatozoa craters and cytoplasmic droplets in ejaculated spermatozoa. Spermatozoa craters correspond to indentations on the nuclear surface and to vacuoles within the condensed chromatin in spermatozoa nuclei. Nuclear vacuoles are believed to be derived from the nucleolus of spermatocytes and spermatids (ref. 4 and references therein). The presence of these craters usually is linked to reduced fertility in mammals (5). However, the correlation between fertility and large nuclear craters in human spermatozoa remains controversial (6, 7).SPANX genes encode small proteins migrating as a broad band of 15-20 kDa under reducing electrophoresis conditions. In spermatozoa, SPANX proteins are found in the form of dimers or complexes with other proteins (1, 3). The SPANX cluster on chromosome X consists of five genes. These genes reside in the Xq26.3-Xq27.3 region, within Ϸ20 kb, highly similar tandem duplications. All SPANX genes consist of two exons separated by an Ϸ650-bp intron containing a solo retroviral LTR sequence (8). SPANX genes are divided into two groups, the SPANX-Aand -B-like subfamilies (8). Classification of SPANX genes is based on the presence of diagnostic amino acid substitutions.The SPANX-A-like subfamily consists of four members, SPANX-A1, -A2, -C, and -...

Evolutionary biology of cancer

“…Recently, a suite of genes involved in carcinogenesis have been shown to exhibit signatures of positive selection [44][45][46] and, in each case, this selection appears to involve evolutionary antagonisms, such as those seen in parent-offspring conflict, sexual conflict, sexually selected conflict or intragenomic conflict [46][47][48].…”

Dynamic structure of the SPANX gene cluster mapped to the prostate cancer susceptibility locus HPCX at Xq27

“…However, neither the size nor the homology of the duplicated regions was determined because of the lack of the complete sequence of Xq27-28 at that time. The completion of the human genome, along with a new information on the organization of the SPANX genes in nonhuman primates (Kouprina et al 2004;Ross et al 2005), allowed us to analyze SDs within the gene cluster. Figure 1 illustrates organization of the SPANX-A/D gene cluster.…”

“…1). The SPANX (Sperm Protein Associated with the Nucleus on the X chromosome) multigene family encodes proteins whose expression is restricted to the normal testis, a few nongametogenic tissues, and certain tumors (Zendman et al 1999(Zendman et al , 2003Westbrook et al 2000Westbrook et al , 2004Goydos et al 2002;Wang et al 2003;Kouprina et al 2004). SPANX genes encode small unfolded proteins (∼100 amino acid residues), to some extent resembling the high mobility group A (HMGA) proteins involved in the formation of various nucleoprotein complexes.…”

“…A recent analysis of SPANX gene homologs in nonhuman primates revealed that SPANX-A/D genes arose ∼7 million years ago and that their expansion is an ongoing process in hominids (Kouprina et al 2004). In addition, this study led to the discovery of a new subfamily of SPANX genes (SPANX-N1-N5) in the human genome.…”

“…The fifth member of the SPANX-N subfamily, SPANX-N5, is located on the short arm of the chromosome at Xp11. Similar to other genes involved in reproduction, SPANX genes appear to have evolved under strong positive selection (Kouprina et al 2004).…”