Relationship between H1 and H2 haplotypes of the 17q21 inversion and pregnancy loss in Bosnian population: A case - control study

Background: The 17q21.31 band is one of the most structurally complex and evolutionarily dynamic region of the genome. Frequencies of two SNPs: rs9468 and rs1800547 determine worldwide distribution of H1 and H2 haplotypes. Recent studies have demonstrated that H2 haplotype is ancestral in hominoids and under positive selection in European populations. The role of non-inverted orientation (H1 haplotype) and inverted orientation (H2) remains unclear, i.a. it is suggested that mothers who are H1H2 heterozygotes, tend to have more children than H2H2 homozygotes on average. Materials and methods: We investigated the prevalence of haplotypes of the 17q21 inversion in 154 women with pregnancy loss and 154 mothers with at last one live-born child, mean age: 33.0 (±5.4) y/o and 31.4 (±6.7) y/o, respectively. Following DNA extraction from buccal swabs, the genotyping was performed. All tests were performed using the R CRAN statistical software. Haplotypes were compared between groups. Results: In women with and without pregnancy loss we identified: 74.7% and 79.2% H1H1, 24.0% and 17.5% H1H2 and 1.3% and 3.3% H2H2 of haplotypes, respectively. There were no significant differences between the distributions of haplotypes in women with and without pregnancy loss. Statistically significant difference between the average number of children in women with H1H2 haplotype (navg. = 1.54) compared to women with H2H2 haplotype (navg. = 1.29), was not found. Conclusion: Haplotype H2 of the 17q21.31 inversion was not linked to pregnancy loss and number of children in Bosnian women.

Sam68 binds Alu-rich introns in SMN and promotes pre-mRNA circularization

The Spinal Muscular Atrophy (SMA) gene SMN was recently duplicated (SMN1 and SMN2) in higher primates. Furthermore, invasion of the locus by repetitive elements almost doubled its size with respect to mouse Smn, in spite of an almost identical protein-coding sequence. Herein, we found that SMN ranks among the human genes with highest density of Alus, which are evolutionary conserved in primates and often occur in inverted orientation. Inverted repeat Alus (IRAlus) negatively regulate splicing of long introns within SMN, while promoting widespread alternative circular RNA (circRNA) biogenesis. Bioinformatics analyses revealed the presence of ultra-conserved Sam68 binding sites in SMN IRAlus. Cross-link-immunoprecipitation (CLIP), mutagenesis and silencing experiments showed that Sam68 binds in proximity of intronic Alus in the SMN pre-mRNA, thus favouring circRNA biogenesis in vitro and in vivo. These findings highlight a novel layer of regulation in SMN expression, uncover the crucial impact exerted by IRAlus and reveal a role for Sam68 in SMN circRNA biogenesis.

Inverted Face with Upright Body: Evidence for Face Inversion Effect in Japanese Macaques (Macaca fuscata) under the Preferential Looking Procedure

Young Japanese macaques (Macaca fuscata) looked at the photographs that contained faces of the two species of macaques (M. fuscata and M. mulatta) for longer time when they were presented at upright orientation than inverted orientation, and that species discrimination was deteriorated when the photographs were presented at inverted orientation [16]. The present experiment further explored the factor affecting the inversion effect observed in the previous experiments. Five young laboratory-born Japanese macaques looked at the photographs by pressing the lever under the conjugate schedule of sensory reinforcement, that is, successive preferential looking procedure. Photographs of macaques were scrambled and made up two types of the bizarre photographs: upright face with upright body (orientation consistent) and inverted face with upright body (orientation inconsistent). These two types of photographs were presented at upright and inverted orientations. The monkeys looked longer when the face was upright than inverted. Orientation of body and background had no effect on looking time duration. The present results strongly suggest that inversion effect found in macaques is face-specific.

Structure of Fam20A reveals a pseudokinase featuring a unique disulfide pattern and inverted ATP-binding

Mutations in FAM20A cause tooth enamel defects known as Amelogenesis Imperfecta (AI) and renal calcification. We previously showed that Fam20A is a secretory pathway pseudokinase and allosterically activates the physiological casein kinase Fam20C to phosphorylate secreted proteins important for biomineralization (Cui et al., 2015). Here we report the nucleotide-free and ATP-bound structures of Fam20A. Fam20A exhibits a distinct disulfide bond pattern mediated by a unique insertion region. Loss of this insertion due to abnormal mRNA splicing interferes with the structure and function of Fam20A, resulting in AI. Fam20A binds ATP in the absence of divalent cations, and strikingly, ATP is bound in an inverted orientation compared to other kinases. Fam20A forms a dimer in the crystal, and residues in the dimer interface are critical for Fam20C activation. Together, these results provide structural insights into the function of Fam20A and shed light on the mechanism by which Fam20A mutations cause disease.