INTRODUCTION
Many human genetic disorders, including those related to developmental delay and intellectual disabilities, are well-known to show sex bias (Neul and Zoghbi, 2004; Rinehart et al., 2011). Recombination rates are also known to be different in males and females (Broman et al., 1998; Fledel-Alon et al., 2011). Furthermore, it has been shown that many human imprinted chromosomal regions are involved in sex-specific recombination (Paldi et al., 1995; Sandovici et al., 2006), and parent-of-origin deletion of imprinted regions are known to cause genetic diseases (Soejima and Wagstaff, 2005). As non-allelic homologous recombination takes place between interspersed duplicated sequences, it is proposed that copy number variation (CNV), the gain and/or loss of genomic materials, occurs through non-allelic homologous recombination (Hastings et al., 2009) suggesting a direct connection between CNV and recombination. Thus these various observations hint to the likelihood of a link between gender and CNV in normal people, as well as, those with genetic disorders, which are both the subjects of this study.
However, the scope of this study was not set at the genomic level, rather a large gene family, with genome-wide representations. Thus the possible role of sex in CNV among olfactory receptor (OR) gene family was investigated. OR genes (Buck and Axel, 1991; Rouquier et al., 1998) comprise the largest gene family in the human genome, with nearly 900 members (Glusman et al., 2001; Hasin-Brumshtein et al., 2009) and also have been extensively studied, with regard to CNV (Trask et al., 1998; Waszak et al., 2010).
OR gene family is also well-known to have a large number of pseudogenes (about 50%) among its members (Glusman et al., 2001). More recently with newly developed bioinformatics algorithms, many new pseudogenes have been identified in the human genome (Menashe et al., 2006) establishing them as regular constituents of the genomic architecture. Also during the last decade many more studies have indicated specific regulatory functions for pseudogenes (Balakirev and Ayala, 2003; Wen et al., 2011, 2012). Therefore should the results of this study show sex bias among OR pseudogenes, it could be another indication that at least some of them are functional, lending more support to the argument that this large family of genes probably has other functions besides olfaction, like serving as regulatory agents in early embryonic development (Dreyer, 1998).
Using publicly available CNV data for 791 OR loci (Waszak et al., 2010) obtained from 150 phenotypically normal individuals (57 males and 93 females) from the 1000 Genome Project, a total of 3872 CNVs with assigned copy number genotypes (ranging from zero to nine) was extensively analyzed for this population genomics study, which was conducted at three levels: among all 150 individuals, and within and between three diverse populations comprising these 150 individuals. The focal point was to investigate the role of gender in various aspects of CNV among OR gene family, including being more prevalent in pseudogenes or genes, in common or uncommon variants, and in copy number loss or gain. The results portray an unexpectedly complex yet fascinating picture of the effects of gender on the CNV of OR gene family. This complexity entailed some speculations about an indirect role of olfaction system in the development of a bigger brain in humans. Additionally, to examine the clinical relevance of these results, sex bias was assessed in the CNV of children with intellectual disabilities and birth defects, using a public database.