Single nucleotide variations of the canine RAD51 domains, which directly binds PALB2 and BRCA2

Tumors of the mammary glands are the most common tumors to affect entire female dogs representing between 50-70% of all tumors types, which is three times higher rate of incidence than humans. No other animal species has such high probability of onset of mammary tumors. Homologous recombination (HR) is the most important double-strand breaks (DSBs) repair mechanisms of DNA and RAD51 plays an important role in this repair mechanism. The tumor suppressors RAD51, BRCA2 and PALB2 act together to initiate the chromosomal lesions repair. BRCA2 and PALB2 mutations lead to destabilization of the genome and engender cancer risk. PALB2 binds to DNA and associates with the RAD51 recombinase. In this study we investigate the genetic variations in RAD51 gene, which directly interactions with PALB2 and BRCA2 domains. From a total of 64 canine patients with mammary tumors, 31 mammary tumors with benign and malign carcinomas and the 3 normal mammary glands were used for the study. We have identified 2 SNPs (Single Nucleotide Polymorphisms) and 7 SNVs (Single Nucleotide Variants) in canine RAD51 exon 7- intron 9 regions, among them 7 SNVs and 1 SNPs were detected for the first time in this study

The Combined Effect of Prostaglandin Administration and Ram Introduction in Multiparous and Nulliparous Sheep in Anestrous Period on Prolificacy

In the study it was aimed to investigate and compare the combined effectiveness of ram introduction (ram effect) and prostaglandin F2 alpha (PGF2 alpha) administration in multiparous and nulliparous Kangal White Karaman ewes during the out of breeding season. The ewes were first divided into two main groups: non-lactating multiparous (Group M, n=104) and nulliparous (Group N, n=101). The multiparous and nulliparous animals were further divided in to two subgroups. Group MRP (n=50 multiparous) and NRP (n=51 nulliparous) were injected with a single dose of PGF2 alpha on the first day of ram introduction. And the Group MR (n=54) and NR (n=50) served as controls with ram introduction but no PGF2 alpha injection. In all of the groups, adult, purebred and fertile rams stayed with the ewes for 45 days. The blood samples were collected at 3-day intervals for 18 days after ram introduction from subsets of ewes (n=17 per group) to monitor the serum progesterone concentration. The total lambing ratios in multiparous and nulliparous animals were 72.1% (75/104) and 44.6% (45/101), respectively (P0.05). We concluded that being multiparous contributes to the success of PGF2 alpha administration in combination with ram introduction in the anestrous period in ewes. Furthermore, PGF2 alpha administration together with ram introduction positively affects the lambing rate in nulliparous ewes

Nradd Acts as a Negative Feedback Regulator of Wnt/beta-Catenin Signaling and Promotes Apoptosis

Wnt/beta-catenin signaling controls many biological processes for the generation and sustainability of proper tissue size, organization and function during development and homeostasis. Consequently, mutations in the Wnt pathway components and modulators cause diseases, including genetic disorders and cancers. Targeted treatment of pathway-associated diseases entails detailed understanding of the regulatory mechanisms that fine-tune Wnt signaling. Here, we identify the neurotrophin receptor-associated death domain (Nradd), a homolog of p75 neurotrophin receptor (p75(NTR)), as a negative regulator of Wnt/beta-catenin signaling in zebrafish embryos and in mammalian cells. Nradd significantly suppresses Wnt8-mediated patterning of the mesoderm and neuroectoderm during zebrafish gastrulation. Nradd is localized at the plasma membrane, physically interacts with the Wnt receptor complex and enhances apoptosis in cooperation with Wnt/beta-catenin signaling. Our functional analyses indicate that the N-glycosylated N-terminus and the death domain-containing C-terminus regions are necessary for both the inhibition of Wnt signaling and apoptosis. Finally, Nradd can induce apoptosis in mammalian cells. Thus, Nradd regulates cell death as a modifier of Wnt/beta-catenin signaling during development

Phenotypic expansion illuminates multilocus pathogenic variation

Purpose: Multilocus variation-pathogenic variants in two or more disease genes-can potentially explain the underlying genetic basis for apparent phenotypic expansion in cases for which the observed clinical features extend beyond those reported in association with a "known" disease gene. Methods: Analyses focused on 106 patients, 19 for whom apparent phenotypic expansion was previously attributed to variation at known disease genes. We performed a retrospective computational reanalysis of whole-exome sequencing data using stringent Variant Call File filtering criteria to determine whether molecular diagnoses involving additional disease loci might explain the observed expanded phenotypes. Results: Multilocus variation was identified in 31.6% (6/19) of families with phenotypic expansion and 2.3% (2/87) without phenotypic expansion. Intrafamilial clinical variability within two families was explained by multilocus variation identified in the more severely affected sibling. Conclusion: Our findings underscore the role of multiple rare variants at different loci in the etiology of genetically and clinically heterogeneous cohorts. Intrafamilial phenotypic and genotypic variability allowed a dissection of genotype-phenotype relationships in two families. Our data emphasize the critical role of the clinician in diagnostic genomic analyses and demonstrate that apparent phenotypic expansion may represent blended phenotypes resulting from pathogenic variation at more than one locus

High prevalence of multilocus pathogenic variation in neurodevelopmental disorders in the Turkish population

Neurodevelopmental disorders (NDD5) are clinically and genetically heterogenous; many such disorders are secondary to perturbation in brain development and/or function. The prevalence of NDD5 is > 3%, resulting in significant sociocultural and economic challenges to society. With recent advances in family-based genomics, rare-variant analyses, and further exploration of the Clan Genomics hypothesis, there has been a logarithmic explosion in neurogenetic "disease-associated genes" molecular etiology and biology of NDD5; however, the majority of NDD5 remain molecularly undiagnosed. We applied genome-wide screening technologies, including exome sequencing (ES) and whole-genome sequencing (WGS), to identify the molecular etiology of 234 newly enrolled subjects and 20 previously unsolved Turkish NDD families. In 176 of the 234 studied families (75.2%), a plausible and genetically parsimonious molecular etiology was identified. Out of 176 solved families, deleterious variants were identified in 218 distinct genes, further documenting the enormous genetic heterogeneity and diverse perturbations in human biology underlying NDD5. We propose 86 candidate disease-trait-associated genes for an NDD phenotype. Importantly, on the basis of objective and internally established variant prioritization criteria, we identified 51 families (51/176 = 28.9%) with multilocus pathogenic variation (MPV), mostly driven by runs of homozygosity (ROH5) - reflecting genomic segments/haplotypes that are identical-by-descent. Furthermore, with the use of additional bioinformatic tools and expansion of ES to additional family members, we established a molecular diagnosis in 5 out of 20 families (25%) who remained undiagnosed in our previously studied NDD cohort emanating from Turkey.United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Human Genome Research Institute (NHGRI) ; United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Heart Lung & Blood Institute (NHLBI) ; International Rett Syndrome Foundation (IRS