Genome-wide association study of four composite reproductive traits in Iranian fat-tailed sheep.

Composite reproductive traits are a combination of growth and reproductive traits. They have the advantage of being better attuned to the market drivers since producers are paid on a per kilogram basis and not on a per head basis. In this study, 124 Lori---Bakhtiari ewes were genotyped using the medium-density Illumina Ovine SNP50 array. A genome-wide association study was performed on estimated breeding values of four composite reproductive traits and genetic parameters were also estimated. The traits were litter mean weight at birth, litter mean weight at weaning, total litter weight at birth and total litter weight at weaning. Several suggestive and associated single nucleotide polymorphisms (SNPs) were identified. Neighbouring the top SNPs there were five genes, inhibin ß E subunit (INHBE), inhibin ß C subunit (INHBC), testis expressed 12 (TEX12), ß-carotene oxygenase 2 (BCO2) and WD Repeat Domain 70 (WDR70) identified as possible candidate genes for composite reproductive traits of the Lori-Bakhtiari sheep. These genes are in pathways known to be relevant to fertility and growth characteristics. The results provide new information for the functional annotation of genes associated with fertility traits and add new evidence towards a consensus of quantitative trait loci associated with reproductive traits in sheep.

Genome-wide association study of birth weight in sheep.

Birth weight is the earliest available growth trait with considerable impacts on lamb survivability and growth performance traits. This study was conducted to perform a genome-wide association study of birth weight in a meat-type sheep. A total of 132 Lori-Bakhtiari sheep were selected based on estimated of breeding values (EBVs) for BW analyses. The selected animals were genotyped using Illumina Ovine SNP50 Bead Chip. After quality control, a total of 41 323 single-nucleotide polymorphisms (SNPs) and 130 sheep were used for subsequent analyses. Plink 1.90 beta software was used for the analyses. Seven SNPs on chromosomes 1, 16, 19 and 22 were detected based on genome-wide unadjusted P-values (P <10-6), which jointly accounted for 1.2% of total genetic variation. However, based on Bonferroni-adjusted P-values, only three SNPs on chromosome 1 had significant associations with EBVs for birth weight (P <0.05), which jointly explained 0.8% of total genetic variation. A total of seven genes were found in 50 kb intervals from the three significant SNPs on chromosome 1, but only three genes, including RAB6B (a member of RAS oncogene family), Tf serotransferrin and GIGYF2 (a GRB10 interacting GYF protein 2), could be considered as candidate genes for birth weight in future studies. The results of this study may facilitate potential use of the genes involving in growth and production traits for genetic improvement of productivity in sheep.

Genome-wide association study to identify genomic regions affecting prolificacy in Lori-Bakhtiari sheep.

Several causative mutations in candidate genes affecting prolificacy have been detected in various sheep breeds. A genome-wide association study was performed on estimated breeding values for litter size in Lori-Bakhtiari sheep. Prolific ewes with twinning records and others with only singleton records were genotyped using the medium-density Illumina Ovine SNP50 array. Four single nucleotide polymorphisms (SNPs) associated with litter size were identified on chromosomes 3, 6 and 22. The region on sheep chromosome 3 between 75 739 167 and 75 745 152 bp included two significant SNPs (s52383.1 and OAR3_80038014_X.1) in high linkage disequilibrium with each other. The region that surrounds these SNPs contains a novel putative candidate gene: luteinizing hormone/choriogonadotropin receptor (LHCGR), known to be involved in ovarian steroidogenesis and organism-specific biosystem pathways in sheep. Known prolificacy genes BMPR1B, BMP15 and GDF9 were not associated with litter size in Lori-Bakhtiari sheep, suggesting that other biological mechanisms could be responsible for the trait's variation in this breed.

A review on prolificacy genes in sheep.

Ovulation rate and litter size are important reproduction traits in sheep and are of high economic value. Reproduction traits typically have low to medium heritabilities and do not exhibit a noticeable response to phenotypic selection. Therefore, inclusion of genetic information of the genes associated with reproductive ability could efficiently enhance the selection response. The most important major genes affecting prolificacy and their genetic diversities in different sheep breeds were reviewed. Different causative mutations with major effects on reproductive traits including ovulation rate and litter size have been found in various sheep breeds around the world. A general overview of the studies on main prolificacy genes showed that some alleles may express different phenotypic effects in different breeds, and thus, further studies on epistatic effects are necessary for more understanding of genetic control of reproductivity in sheep. Regarding the polygenic control of fertility traits, application of new high-throughput technologies to find new variants is essential for future studies. Moreover, genomewide association studies and genomic best linear unbiased predictions of breeding values are likely to be effective tools for genetic improvement of sheep reproductive performance traits.

Serine protease inhibitor-6 differentially affects the survival of effector and memory alloreactive CD8-T cells.

The clonal expansion of effector T cells and subsequent generation of memory T cells are critical in determining the outcome of transplantation. While cytotoxic T lymphocytes induce direct cytolysis of target cells through secretion of Granzyme-B (GrB), they also express cytoplasmic serine protease inhibitor-6 (Spi6) to protect themselves from GrB that has leaked from granules. Here, we studied the role of GrB/Spi6 axis in determining clonal expansion of alloreactive CD8-T cells and subsequent generation of memory CD8-T cells in transplantation. CD8-T cells from Spi6(-/-) mice underwent more GrB mediated apoptosis upon alloantigen stimulation in vitro and in vivo following adoptive transfer into an allogeneic host. Interestingly, while OT1.Spi6(-/-) CD8 T cells showed significantly lower clonal expansion following skin transplants from OVA mice, there was no difference in the size of the effector memory CD8-T cells long after transplantation. Furthermore, lack of Spi6 resulted in a decrease of short-lived-effector-CD8-cells but did not impact the pool of memory-precursor-effector-CD8-cells. Similar results were found in heart transplant models. Our findings suggest that the final alloreactive CD8-memory-pool-size is independent from the initial clonal-proliferation as memory precursors express low levels of GrB and therefore are independent of Spi6 for survival. These data advance our understanding of memory T cells generation in transplantation and provide basis for Spi6 based strategies to target effector T cells.

T Helper Cells Fate Mapping by Co-stimulatory Molecules and its Functions in Allograft Rejection and Tolerance.

T cell differentiation is dictated by a combination of T cell receptor (TCR) interaction with an antigen-bound major histocompatibility complex (MHC), and co-stimulatory molecules signal. The co-stimulatory signal can be positive or negative, and amplifying or diminishing the initial signal. However, the secondary co-stimulatory signal is not obligatory and its necessity is dictated, in part, by the stage of T cell development. In the field of transplantation, directing the T cell differentiation process can lead to therapeutic possibilities that promote allograft tolerance, and hinder unfavorable alloimmune responses. Therefore, understanding the details of T cell differentiation process, including the influence of co-stimulatory signals, is of paramount importance. It is important to note there is functional overlap between co-stimulatory molecules. It has been observed that some co-stimulatory signals have different effects on different T cell subsets. Hence, blockade of a co-stimulatory signal pathway, as part of a therapeutic regimen in transplantation, may have far reaching effects beyond the initial therapeutic intent and inhibit co-stimulatory signals necessary for desirable regulatory responses. In this review, co-stimulatory molecules involved in the differentiation of naïve T cells into T helper 1 (Th1), T helper 2 (Th2), T helper 17 (Th17), inducible regulatory T cells (iTregs), and T helper 9 (Th9) cells and their overlap are discussed.

Association of BMPR-1B and GDF9 genes polymorphisms and secondary protein structure changes with reproduction traits in Mehraban ewes.

BMPR-1B and GDF9 genes are well known due to their important effects on litter size and mechanisms controlling ovulation rate in sheep. In the present study, polymorphisms of BMPR-1B gene exon 8 and GDF9 gene exon 1 were detected by single strand conformational polymorphism (SSCP) analysis and DNA sequencing methods in 100 Mehraban ewes. The PCR reaction forced to amplify 140 and 380-bp fragments of BMPR-1B and GDF9 genes, respectively. Two single nucleotide polymorphisms (SNPS) were identified in two different SSCP patterns of BMPR-1B gene (CC and CA genotypes) that deduced one amino acid exchange. Also, two SNPS were identified in three different SSCP patterns of GDF9 gene (AA, AG and GG genotypes) that deduced one amino acid exchanges. Two different secondary structures of protein were predicted for BMPR-1B exon 8, but the secondary protein structures predicted for GDF9 exon 1 were similar together. The evaluation of the associations between the SSCP patterns and the protein structure changes with reproduction traits showed that BMPR-1B exon 8 genotypes have significant effects on some of reproduction traits but the GDF9 genotypes did not have any significant effect. The CA genotype of BMPR-1B exon 8 had a significant positive effect on reproduction performance and could be considered as an important and new mutation, affecting the ewes reproduction performance. Marker assisted selection using BMPR-IB gene could be noticed to improve the reproduction traits in Mehraban sheep.

A comparison of different feature extraction methods for diagnosis of valvular heart diseases using PCG signals.

This article presents a novel method for diagnosis of valvular heart disease (VHD) based on phonocardiography (PCG) signals. Application of the pattern classification and feature selection and reduction methods in analysing normal and pathological heart sound was investigated. After signal preprocessing using independent component analysis (ICA), 32 features are extracted. Those include carefully selected linear and nonlinear time domain, wavelet and entropy features. By examining different feature selection and feature reduction methods such as principal component analysis (PCA), genetic algorithms (GA), genetic programming (GP) and generalized discriminant analysis (GDA), the four most informative features are extracted. Furthermore, support vector machines (SVM) and neural network classifiers are compared for diagnosis of pathological heart sounds. Three valvular heart diseases are considered: aortic stenosis (AS), mitral stenosis (MS) and mitral regurgitation (MR). An overall accuracy of 99.47% was achieved by proposed algorithm.