Fine Mapping of Genetic Loci on Bos taurus autosome 18 associated with Functional Traits and Conformation Traits in German Holstein cattle

In this study separate and combined linkage and linkage disequilibrium analyses were performed to map genetic loci on Bos taurus chromosome 18 in the German Holstein population. Quantitative trait loci affecting udder health, calving performance, udder conformation and body conformation traits were identified. Continuative analyses of maternally inherited marker alleles indicated the two-marker-haplotype BB710 - PVRL2_c.392G>A and microsatellite marker DIK4234 to be in population-wide linkage disequilibrium to the causal mutations affecting udder health or calving performance, respectively

Identification of a two-marker-haplotype on Bos taurus autosome 18 associated with somatic cell score in German Holstein cattle

<p>Abstract</p> <p>Background</p> <p>The somatic cell score (SCS) is implemented in routine sire evaluations in many countries as an indicator trait for udder health. Somatic cell score is highly correlated with clinical mastitis, and in the German Holstein population quantitative trait loci (QTL) for SCS have been repeatedly mapped on <it>Bos taurus </it>autosome 18 (BTA18). In the present study, we report a refined analysis of previously detected QTL regions on BTA18 with the aim of identifying marker and marker haplotypes in linkage disequilibrium with SCS. A combined linkage and linkage disequilibrium approach was implemented, and association analyses of marker genotypes and maternally inherited two-marker-haplotypes were conducted to identify marker and haplotypes in linkage disequilibrium with a locus affecting SCS in the German Holstein population.</p> <p>Results</p> <p>We detected a genome-wide significant QTL within marker interval 9 (<it>HAMP_c.366+109G>A </it>- <it>BMS833</it>) in the middle to telomeric region on BTA18 and a second putative QTL in marker interval 12-13 (<it>BB710 </it>- <it>PVRL2_c.392G>A</it>). Association analyses with genotypes of markers flanking the most likely QTL positions revealed the microsatellite marker <it>BMS833 </it>(interval 9) to be associated with a locus affecting SCS within the families investigated. A further analysis of maternally inherited two-marker haplotypes and effects of maternally inherited two-marker-interval gametes indicated haplotype <it>249-G </it>in marker interval 12-13 (<it>BB710 </it>- <it>PVRL2_c.392G>A</it>) to be associated with SCS in the German Holstein population.</p> <p>Conclusion</p> <p>Our results confirmed previous QTL mapping results for SCS and support the hypothesis that more than one locus presumably affects udder health in the middle to telomeric region of BTA18. However, a subsequent investigation of the reported QTL regions is necessary to verify the two-QTL hypothesis and confirm the association of two-marker-haplotype <it>249-G </it>in marker interval 12-13 (<it>BB710 </it>- <it>PVRL2_c.392G>A</it>) with SCS. For this purpose, higher marker density and multiple-trait and multiple-QTL models are required to narrow down the position of the causal mutation or mutations affecting SCS in German Holstein cattle.</p

Erratum to: Adrenal cortex expression quantitative trait loci in a German Holstein × Charolais cross

BACKGROUND: The importance of the adrenal gland in regard to lactation and reproduction in cattle has been recognized early. Caused by interest in animal welfare and the impact of stress on economically important traits in farm animals the adrenal gland and its function within the stress response is of increasing interest. However, the molecular mechanisms and pathways involved in stress-related effects on economically important traits in farm animals are not fully understood. Gene expression is an important mechanism underlying complex traits, and genetic variants affecting the transcript abundance are thought to influence the manifestation of an expressed phenotype. We therefore investigated the genetic background of adrenocortical gene expression by applying an adaptive linear rank test to identify genome-wide expression quantitative trait loci (eQTL) for adrenal cortex transcripts in cattle. RESULTS: A total of 10,986 adrenal cortex transcripts and 37,204 single nucleotide polymorphisms (SNPs) were analysed in 145 F2 cows of a Charolais × German Holstein cross. We identified 505 SNPs that were associated with the abundance of 129 transcripts, comprising 482 cis effects and 17 trans effects. These SNPs were located on all chromosomes but X, 16, 24 and 28. Associated genes are mainly involved in molecular and cellular functions comprising free radical scavenging, cellular compromise, cell morphology and lipid metabolism, including genes such as CYP27A1 and LHCGR that have been shown to affect economically important traits in cattle. CONCLUSIONS: In this study we showed that adrenocortical eQTL affect the expression of genes known to contribute to the phenotypic manifestation in cattle. Furthermore, some of the identified genes and related molecular pathways were previously shown to contribute to the phenotypic variation of behaviour, temperament and growth at the onset of puberty in the same population investigated here. We conclude that eQTL analysis appears to be a useful approach providing insight into the molecular and genetic background of complex traits in cattle and will help to understand molecular networks involved

Comparative expression profiling of E. coli and S. aureus inoculated primary mammary gland cells sampled from cows with different genetic predispositions for somatic cell score

BACKGROUND: During the past ten years many quantitative trait loci (QTL) affecting mastitis incidence and mastitis related traits like somatic cell score (SCS) were identified in cattle. However, little is known about the molecular architecture of QTL affecting mastitis susceptibility and the underlying physiological mechanisms and genes causing mastitis susceptibility. Here, a genome-wide expression analysis was conducted to analyze molecular mechanisms of mastitis susceptibility that are affected by a specific QTL for SCS on Bos taurus autosome 18 (BTA18). Thereby, some first insights were sought into the genetically determined mechanisms of mammary gland epithelial cells influencing the course of infection. METHODS: Primary bovine mammary gland epithelial cells (pbMEC) were sampled from the udder parenchyma of cows selected for high and low mastitis susceptibility by applying a marker-assisted selection strategy considering QTL and molecular marker information of a confirmed QTL for SCS in the telomeric region of BTA18. The cells were cultured and subsequently inoculated with heat-inactivated mastitis pathogens Escherichia coli and Staphylococcus aureus, respectively. After 1, 6 and 24 h, the cells were harvested and analyzed using the microarray expression chip technology to identify differences in mRNA expression profiles attributed to genetic predisposition, inoculation and cell culture. RESULTS: Comparative analysis of co-expression profiles clearly showed a faster and stronger response after pathogen challenge in pbMEC from less susceptible animals that inherited the favorable QTL allele 'Q' than in pbMEC from more susceptible animals that inherited the unfavorable QTL allele 'q'. Furthermore, the results highlighted RELB as a functional and positional candidate gene and related non-canonical Nf-kappaB signaling as a functional mechanism affected by the QTL. However, in both groups, inoculation resulted in up-regulation of genes associated with the Ingenuity pathways 'dendritic cell maturation' and 'acute phase response signaling', whereas cell culture affected biological processes involved in 'cellular development'. CONCLUSIONS: The results indicate that the complex expression profiling of pathogen challenged pbMEC sampled from cows inheriting alternative QTL alleles is suitable to study genetically determined molecular mechanisms of mastitis susceptibility in mammary epithelial cells in vitro and to highlight the most likely functional pathways and candidate genes underlying the QTL effect

Association of CLEC16A with human common variable immunodeficiency disorder and role in murine B cells

Common variable immunodeficiency disorder (CVID) is the most common symptomatic primary immunodeficiency in adults, characterized by B-cell abnormalities and inadequate antibody response. CVID patients have considerable autoimmune comorbidity and we therefore hypothesized that genetic susceptibility to CVID may overlap with autoimmune disorders. Here, in the largest genetic study performed in CVID to date, we compare 778 CVID cases with 10, 999 controls across 123, 127 single-nucleotide polymorphisms (SNPs) on the Immunochip. We identify the first non-HLA genome-wide significant risk locus at CLEC16A (rs17806056, P = 2.0 x 10(-9)) and confirm the previously reported human leukocyte antigen (HLA) associations on chromosome 6p21 (rs1049225, P = 4.8 x 10(-16)). Clec16a knockdown (KD) mice showed reduced number of B cells and elevated IgM levels compared with controls, suggesting that CLEC16A may be involved in immune regulatory pathways of relevance to CVID. In conclusion, the CLEC16A associations in CVID represent the first robust evidence of non-HLA associations in this immunodeficiency condition

Recommendations for accelerating open preprint peer review to improve the culture of science

Peer review is an important part of the scientific process, but traditional peer review at journals is coming under increased scrutiny for its inefficiency and lack of transparency. As preprints become more widely used and accepted, they raise the possibility of rethinking the peer-review process. Preprints are enabling new forms of peer review that have the potential to be more thorough, inclusive, and collegial than traditional journal peer review, and to thus fundamentally shift the culture of peer review toward constructive collaboration. In this Consensus View, we make a call to action to stakeholders in the community to accelerate the growing momentum of preprint sharing and provide recommendations to empower researchers to provide open and constructive peer review for preprints