BMC Genetics最新文献

Background: The complement cascade is increasingly implicated in development of a variety of diseases with strong immune contributions such as Alzheimer's disease and Systemic Lupus Erythematosus. Mouse models have been used to determine function of central components of the complement cascade such as C1q and C3. However, species differences in their gene structures mean that mice do not adequately replicate human complement regulators, including CR1 and CR2. Genetic variation in CR1 and CR2 have been implicated in modifying disease states but the mechanisms are not known.

Results: To decipher the roles of human CR1 and CR2 in health and disease, we engineered C57BL/6J (B6) mice to replace endogenous murine Cr2 with human complement receptors, CR1 and CR2 (B6.CR2CR1). CR1 has an array of allotypes in human populations and using traditional recombination methods (Flp-frt and Cre-loxP) two of the most common alleles (referred to here as CR1^long and CR1^short) can be replicated within this mouse model, along with a CR1 knockout allele (CR1^KO). Transcriptional profiling of spleens and brains identified genes and pathways differentially expressed between mice homozygous for either CR1^long, CR1^short or CR1^KO. Gene set enrichment analysis predicts hematopoietic cell number and cell infiltration are modulated by CR1^long, but not CR1^short or CR1^KO.

Conclusion: The B6.CR2CR1 mouse model provides a novel tool for determining the relationship between human-relevant CR1 alleles and disease.

Background: Canine progressive retinal atrophies are a group of hereditary retinal degenerations in dogs characterised by depletion of photoreceptor cells in the retina, which ultimately leads to blindness. PRA in the Lhasa Apso (LA) dog has not previously been clinically characterised or described in the literature, but owners in the UK are advised to have their dog examined through the British Veterinary Association/ Kennel Club/ International Sheep Dog Society (BVA/KC/ISDS) eye scheme annually, and similar schemes that are in operation in other countries. After the exclusion of 25 previously reported canine retinal mutations in LA PRA-affected dogs, we sought to identify the genetic cause of PRA in this breed.

Results: Analysis of whole-exome sequencing data of three PRA-affected LA and three LA without signs of PRA did not identify any exonic or splice site variants, suggesting the causal variant was non-exonic. We subsequently undertook a genome-wide association study (GWAS), which identified a 1.3 Mb disease-associated region on canine chromosome 33, followed by whole-genome sequencing analysis that revealed a long interspersed element-1 (LINE-1) insertion upstream of the IMPG2 gene. IMPG2 has previously been implicated in human retinal disease; however, until now no canine PRAs have been associated with this gene. The identification of this PRA-associated variant has enabled the development of a DNA test for this form of PRA in the breed, here termed PRA4 to distinguish it from other forms of PRA described in other breeds. This test has been used to determine the genotypes of over 900 LA dogs. A large cohort of genotyped dogs was used to estimate the allele frequency as between 0.07-0.1 in the UK LA population.

Conclusions: Through the use of GWAS and subsequent sequencing of a PRA case, we have identified a LINE-1 insertion in the retinal candidate gene IMPG2 that is associated with a form of PRA in the LA dog. Validation of this variant in 447 dogs of 123 breeds determined it was private to LA dogs. We envisage that, over time, the developed DNA test will offer breeders the opportunity to avoid producing dogs affected with this form of PRA.

Background: Associations between haplotypes and quantitative traits provide valuable information about the genetic basis of complex human diseases. Haplotypes also provide an effective way to deal with untyped SNPs. Two major challenges arise in haplotype-based association analysis of family data. First, haplotypes may not be inferred with certainty from genotype data. Second, the trait values within a family tend to be correlated because of common genetic and environmental factors.

Results: To address these challenges, we present an efficient likelihood-based approach to analyzing associations of quantitative traits with haplotypes or untyped SNPs. This approach properly accounts for within-family trait correlations and can handle general pedigrees with arbitrary patterns of missing genotypes. We characterize the genetic effects on the quantitative trait by a linear regression model with random effects and develop efficient likelihood-based inference procedures. Extensive simulation studies are conducted to examine the performance of the proposed methods. An application to family data from the Childhood Asthma Management Program Ancillary Genetic Study is provided. A computer program is freely available.

Conclusions: Results from extensive simulation studies show that the proposed methods for testing the haplotype effects on quantitative traits have correct type I error rates and are more powerful than some existing methods.

Background: C-to-U RNA editing is prevalent in the mitochondrial and chloroplast genes in plants. The biological functions of a fraction of C-to-U editing sites are continuously discovered by case studies. However, at genome-wide level, the cis and trans determinants affecting the occurrence or editing levels of these C-to-U events are relatively less studied. What is known is that the PPR (pentatricopeptide repeat) proteins are the main trans-regulatory elements responsible for the C-to-U conversion, but other determinants especially the cis-regulatory elements remain largely uninvestigated.

Results: By analyzing the transcriptome and translatome data in Arabidopsis thaliana roots and shoots, combined with RNA-seq data from hybrids of Arabidopsis thaliana and Arabidopsis lyrata, we perform genome-wide investigation on the cis elements and trans-regulatory elements that potentially affect C-to-U editing events. An upstream guanosine or double-stranded RNA (dsRNA) regions are unfavorable for editing events. Meanwhile, many genes including the transcription factors may indirectly play regulatory roles in trans.

Conclusions: The 5-prime thymidine facilitates editing and dsRNA structures prevent editing in cis. Many transcription factors affect editing in trans. Although the detailed molecular mechanisms underlying the cis and trans regulation remain to be experimentally verified, our findings provide novel aspects in studying the botanical C-to-U RNA editing events.

Background: R package mbend was developed for bending symmetric non-positive-definite matrices to positive-definite (PD). Bending is a procedure of transforming non-PD matrices to PD. The covariance matrices used in multi-trait best linear unbiased prediction (BLUP) should be PD. Two bending methods are implemented in mbend. The first is an unweighted bending with small positive values in a descending order replacing negative eigenvalues (LRS14), and the second method is a weighted (precision-based) bending with a custom small positive value (ϵ) replacing smaller eigenvalues (HJ03). Weighted bending is beneficial, as it relaxes low precision elements to change and it reduces or prohibits the change in high precision elements. Therefore, a weighted version of LRS14 was developed in mbend. In cases where the precision of matrix elements is unknown, the package provides an unweighted version of HJ03. Another unweighted bending method (DB88) was tested, by which all eigenvalues are changed (eigenvalues less than ϵ replaced with 100 × ϵ), and it is originally designed for correlation matrices.

Results: Different bending procedures were conducted on a 5 × 5 covariance matrix (V), V converted to a correlation matrix (C) and an ill-conditioned 1000 × 1000 genomic relationship matrix (G). Considering weighted distance statistics between matrix elements before and after bending, weighting considerably improved the bending quality. For weighted and unweighted bending of V and C, HJ03-4 (HJ03, ϵ = 10^-4) performed the best. HJ03-2 (HJ03, ϵ = 10^-2) ranked better than LRS14 for V, but not for C. Though the differences were marginal, LRS14 performed the best for G. DB88-4 (DB88, ϵ = 10^-4) was used for unweighted bending and it ranked the last. This method could perform considerably better with a lower ϵ.

Conclusions: R package mbend provides necessary tools for transforming symmetric non-PD matrices to PD, using different methods and parameters. There were benefits in both weighted bending and small positive values in a descending order replacing negative eigenvalues. Thus, weighted LRS14 was implemented in mbend. Different bending methods might be preferable for different matrices, depending on the matrix type (covariance vs. correlation), number and the magnitude of negative eigenvalues, and the matrix size.

Background: Myanmar cattle populations predominantly consist of native cattle breeds (Pyer Sein and Shwe), characterized by their geographical location and coat color, and the Holstein-Friesian crossbreed, which is highly adapted to the harsh tropical climates of this region. Here, we analyzed the diversity and genetic structure of the BoLA-DRB3 gene, a genetic locus that has been linked to the immune response, in Myanmar cattle populations.

Methods: Blood samples (n = 294) were taken from two native breeds (Pyer Sein, n = 163 and Shwe Ni, n = 69) and a cattle crossbreed (Holstein-Friesian, n = 62) distributed across six regions of Myanmar (Bago, n = 38; Sagaing, n = 77; Mandalay, n = 46; Magway, n = 46; Kayin, n = 43; Yangon, n = 44). In addition, a database that included 2428 BoLA-DRB3 genotypes from European (Angus, Hereford, Holstein, Shorthorn, Overo Negro, Overo Colorado, and Jersey), Zebuine (Nellore, Brahman and Gir), Asian Native from Japan and Philippine and Latin-American Creole breeds was also included. Furthermore, the information from the IPD-MHC database was also used in the present analysis. DNA was genotyped using the sequence-based typing method. DNA electropherograms were analyzed using the Assign 400ATF software.

Results: We detected 71 distinct alleles, including three new variants for the BoLA-DRB3 gene. Venn analysis showed that 11 of these alleles were only detected in Myanmar native breeds and 26 were only shared with Asian native and/or Zebu groups. The number of alleles ranged from 33 in Holstein-Friesians to 58 in Pyer Seins, and the observed versus unbiased expected heterozygosity were higher than 0.84 in all the three the populations analyzed. The F_ST analysis showed a low level of genetic differentiation between the two Myanmar native breeds (F_ST = 0.003), and between these native breeds and the Holstein-Friesians (F_ST <  0.021). The average F_ST value for all the Myanmar Holstein-Friesian crossbred and Myanmar native populations was 0.0136 and 0.0121, respectively. Principal component analysis (PCA) and tree analysis showed that Myanmar native populations grouped in a narrow cluster that diverged clearly from the Holstein-Friesian populations. Furthermore, the BoLA-DRB3 allele frequencies suggested that while some Myanmar native populations from Bago, Mandalay and Yangon regions were more closely related to Zebu breeds (Gir and Brahman), populations from Kayin, Magway and Sagaing regions were more related to the Philippines native breeds. On the contrary, PCA showed that the Holstein-Friesian populations demonstrated a high degree of dispersion, which is likely the result of the different degrees of native admixture in these populations.

Conclusion: This study is the first to report the genetic diversity of the BoLA-DRB3 gene in two native breeds and one exotic cattle crossbreed from M

Background: The Human Leukocyte Antigen G (HLA-G) protein is an immune tolerogenic molecule with 7 isoforms. The change of expression level and some polymorphisms of the HLA-G gene are involved in various pathologies. Therefore, this study aimed to predict the most deleterious missense non-synonymous single nucleotide polymorphisms (nsSNPs) in HLA-G isoforms via in silico analyses and to examine structural and functional effects of the predicted nsSNPs on HLA-G isoforms.

Results: Out of 301 reported SNPs in dbSNP, 35 missense SNPs in isoform 1, 35 missense SNPs in isoform 5, 8 missense SNPs in all membrane-bound HLA-G isoforms and 8 missense SNPs in all soluble HLA-G isoforms were predicted as deleterious by all eight servers (SIFT, PROVEAN, PolyPhen-2, I-Mutant 3.0, SNPs&GO, PhD-SNP, SNAP2, and MUpro). The Structural and functional effects of the predicted nsSNPs on HLA-G isoforms were determined by MutPred2 and HOPE servers, respectively. Consurf analyses showed that the majority of the predicted nsSNPs occur in conserved sites. I-TASSER and Chimera were used for modeling of the predicted nsSNPs. rs182801644 and rs771111444 were related to creating functional patterns in 5'UTR. 5 SNPs in 3'UTR of the HLA-G gene were predicted to affect the miRNA target sites. Kaplan-Meier analysis showed the HLA-G deregulation can serve as a prognostic marker for some cancers.

Conclusions: The implementation of in silico SNP prioritization methods provides a great framework for the recognition of functional SNPs. The results obtained from the current study would be called laboratory investigations.

Background: Waterlogging is one of the most serious abiotic stresses affecting wheat-growing regions in China. Considerable differences in waterlogging tolerance have been found among different wheat varieties, and the mechanisms governing the waterlogging tolerance of wheat seeds during germination have not been elucidated.

Results: The results showed no significant difference between the germination rate of 'Bainong 207' (BN207) (after 72 h of waterlogging treatment) and that of the control seeds. However, the degree of emulsification and the degradation rate of endosperm cells under waterlogging stress were higher than those obtained with the control treatment, and the number of amyloplasts in the endosperm was significantly reduced by waterlogging. Transcriptomic data were obtained from seed samples (a total of 18 samples) of three wheat varieties, 'Zhoumai 22' (ZM22), BN207 and 'Bainong 607' (BN607), subjected to the waterlogging and control treatments. A comprehensive analysis identified a total of 2775 differentially expressed genes (DEGs). In addition, an analysis of the correlations among the expression difference levels of DEGs and the seed germination rates of the three wheat varieties under waterlogging stress revealed that the relative expression levels of 563 and 398 genes were positively and negatively correlated with the germination rate of the wheat seeds, respectively. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that the difference in the waterlogging tolerance among the three wheat varieties was related to the abundance of key genes involved in the glycolysis pathway, the starch and sucrose metabolism pathway, and the lactose metabolism pathway. The alcohol dehydrogenase (ADH) gene in the endosperm of BN607 was induced immediately after short-term waterlogging, and the energy provided by the glycolysis pathway enabled the BN607 seeds to germinate as early as possible; in addition, the expression of the AP2/ERF transcription factor was upregulated to further enhance the waterlogging tolerance of this cultivar.

Conclusions: Taken together, the results of this study help elucidate the mechanisms through which different wheat varieties respond to waterlogging stress during germination.

Background: Triatoma brasiliensis Neiva, 1911 is the main vector of Trypanosoma cruzi in the caatinga of Northeastern Brazil. Despite of its epidemiological relevance, there are few studies on its genetic variability. Using microsatellite markers, we characterized the variability and dynamics of infestation and reinfestation of T. brasiliensis after residual insecticide spraying in five surveys conducted in a well-defined rural area located in the municipality of Tauá, Ceará, between 2009 and 2015. We evaluated: (1) general variability among local of captures; (2) variability along the time analysis (2009, 2010 and 2015); (3) and reinfestation process.

Results: On the analysis (1) global and pairwise F_ST values suggested absence of clusters among the area. AMOVA indicated that total variation is mainly represented by individual differences. Absence of clustering indicates a panmitic unit, with free gene flow. For (2), Pairwise F_ST indicated alterations in the genetic profile of the triatomines along the time. (3) Analysis of the reinfestation process showed that the domiciliary units investigated had different sources of infestation despite of its proximity.

Conclusions: Observed homogeneity can be explained by the great dispersal capacity of T. brasiliensis, overlapping the different environments. Persistent house infestation in Tauá may be attributed to the occurrence of postspraying residual foci and the invasion of triatomines from their natural habitats.

Background: G-protein subunit beta 1 like (GNB1L) encodes a G-protein beta-subunit-like polypeptide. Chicken GNB1L is upregulated in the breast muscle of high feed efficiency chickens, and its expression is 1.52-fold that in low feed efficiency chickens. However, no report has described the effects of GNB1L indels on the chicken carcass and growth traits.

Results: This study identified a 31-bp indel in the 5' untranslated region (UTR) of GNB1L and elucidated the effect of this gene mutation on the carcass and growth traits in chickens. The 31-bp indel showed a highly significant association with the body weight at 8 different stages and was significantly correlated with daily gains at 0 to 4 weeks and 4 to 8 weeks. Similarly, the mutation was significantly associated with small intestine length, breast width, breast depth and breast muscle weight. Moreover, DD and ID were superior genotypes for chicken growth and carcass traits.

Conclusions: These results show that the 31-bp indel of GNB1L significantly affects chicken body weight and carcass traits and can serve as a candidate molecular marker for chicken genetics and breeding programs.