Genetic Analysis of White Facial and Leg Markings in the Swiss Franches-Montagnes Horse Breed

White markings and spotting patterns in animal species are thought to be a result of the domestication process. They often serve for the identification of individuals but sometimes are accompanied by complex pathological syndromes. In the Swiss Franches-Montagnes horse population, white markings increased vastly in size and occurrence during the past 30 years, although the breeding goal demands a horse with as little depigmented areas as possible. In order to improve selection and avoid more excessive depigmentation on the population level, we estimated population parameters and breeding values for white head and anterior and posterior leg markings. Heritabilities and genetic correlations for the traits were high (h2 > 0.5). A strong positive correlation was found between the chestnut allele at the melanocortin-1-receptor gene locus and the extent of white markings. Segregation analysis revealed that our data fit best to a model including a polygenic effect and a biallelic locus with a dominant-recessive mode of inheritance. The recessive allele was found to be the white trait-increasing allele. Multilocus linkage disequilibrium analysis allowed the mapping of the putative major locus to a chromosomal region on ECA3q harboring the KIT gen

Populationsstruktur und genetische Diversität von Schweizer Schafrassen

Das Jahr 2010 wurde von den Vereinten Nationen zum Jahr der Biodiversität erklärt. Der Schweizerische Schafzuchtverband stellte in diesem Kontext Herdebuchdaten der vier grössten Schweizer Schafrassen zur Analyse der genetischen Diversität zur Verfügung. Untersucht wur-den das Braunköpfige Fleischschaf (BFS; n=10 858), das Schwarzbraune Bergschaf (SBS; n=10 964), das Walliser Schwarznasenschaf (SN; n=14 371) und das Weisse Alpenschaf (WAS; n=32 169). Die Analysen beruhen auf allen Herdebuchtieren der Geburtsjahre 1996–2008 und ihren Ahnen bis und mit Geburtsjahr 1970. Ausgewertet wurden die Daten mit gängiger Software für populationsgenetische Fragestellungen. Die grösste Zunahme beim mittleren Inzuchtkoeffizienten konnte im untersuchten Zeitraum bei der Rasse SN (5,9 → 9,3 %) gefolgt von denRassen BFS (2,4 → 4,3 %), SBS (2,4 → 3,8 %) und WAS (1,4 → 2,5 %) beobachtet werden. Obwohl die Inzuchtraten im Zeitraum 1996 bis 2008 teilweise starke Schwankungen aufwiesen, zeigte sich bei allen vier Rassen grundsätzlich ein steigender Trend. Damit einher ging ein sinkender Trend bei der effektiven Populationsgrösse. Die grösste Anzahl an effektiven Gründertieren, Ahnen und Gründergenomen fanden sich beim weissen Alpenschaf. Bei allen vier Rassen war bei diesen drei Parametern im Laufe der Jahre eine sinkende Tendenz erkennbar, wobei die Abnahme bei der Rasse WAS im Vergleich mit den anderen Rassen viel ausgeprägter war. Ein weiterer Indikator für eine abnehmende genetische Vielfalt von 1996 bis 2008 ist der marginale Genanteil des wichtigsten Ahnen. Dieser ist bei allen vier Rassen angestiegen (SN 11,05 → 19,79 %; BFS 7,67 →11,27 %; SBS 4,45 → 5,19 %; WAS 2,84 →4,69 %).Aufgrund der Ergebnisse stellt sich die Frage nach gezielten Managementmassnahmen nur bei der SN-Population. Bei den anderen drei Rassen sollten die Trends der genetischen Diversitäts-parameter jedoch regelmässig überprüft werden

Züchterische Aspekte der Tiere im Projekt Weidekuh-Genetik

Auf der Suche nach der idealen Weidekuh lancierte die SHL Zollikofen zusammen mit der KTI, der IG Weidemilch, Swissgenetics und weiteren Partnern im Jahr 2007 das Projekt «Weidekuh-Genetik». In diesem Projekt werden aus Irland importierte Holstein-Kühe mit neuseeländischem Vater und Grossvater (Mutterseite) mit den drei Schweizer Milchviehrassen Braunvieh, Fleckvieh und Holstein bezüglich ihrer Vollweidetauglichkeit verglichen. In der vorliegenden Arbeit werden die Versuchstiere des Projekts hinsichtlich der Abstammung, des Exterieurs, des genetischen Leistungspotenzials sowie der Rangierung in ihrer Herkunftspopulation beschrieben. Die Auswahlkriterien und die hohen Häufigkeiten bei den Vätern und Grossvätern der importierten Tiere zeigen auf, dass es sich bei dieser Versuchsgruppe um eine selektierte Stichprobe handelt. Zudem liegen die irischen Gesamtzuchtwerte dieser Tiere deutlich über dem Durchschnitt der irischen Herdebuchpopulation. Aufgrund der selektiven Auswahl sind Rückschlüsse auf die gesamte irische oder gar neuseeländische Herdebuchpopulation nicht zulässig. Die Gesamtzuchtwerte der Schweizer Versuchstiere liegen innerhalb einer Standardabweichung der Mittelwerte ihrer Herkunftspopulationen. Die Tiere sind somit typische Vertreter ihrer Populationen. Unterschiede im Exterieur zwischen den importierten und den Schweizer Kühen findet man bei den Merkmalen Widerrist- und Kreuzbeinhöhe, hintere Beinlänge und Fesseln. Die importierten Tiere sind signifikant kleiner und weisen signifikant weichere Fesseln auf

Linear seesaw model with hidden SU(2)H×U(1)XSU(2)_H \times U(1)_X gauge symmetry

We propose a linear seesaw model with a hidden gauge symmetry $SU(2)_H \times U(1)_X$ where two types of standard model singlet fermions in realizing a linear seesaw mechanism are unified into $SU(2)_H$ doublet. Then we formulate scalar and gauge sector, neutrino mass matrix and lepton flavor violations. In our gauge sector, $Z$-$Z'$ mixing appears after spontaneous symmetry breaking and we investigate constraint from $\rho$-parameter. In addition we discuss $Z'$ production at the large hadron collider via $Z$-$Z'$ mixing, where $Z'$ tends to dominantly decay into heavy neutrinos.Comment: 14 pages, 2 figure

Allelic Heterogeneity at the Equine KIT Locus in Dominant White (W) Horses

White coat color has been a highly valued trait in horses for at least 2,000 years. Dominant white (W) is one of several known depigmentation phenotypes in horses. It shows considerable phenotypic variation, ranging from ∼50% depigmented areas up to a completely white coat. In the horse, the four depigmentation phenotypes roan, sabino, tobiano, and dominant white were independently mapped to a chromosomal region on ECA 3 harboring the KIT gene. KIT plays an important role in melanoblast survival during embryonic development. We determined the sequence and genomic organization of the ∼82 kb equine KIT gene. A mutation analysis of all 21 KIT exons in white Franches-Montagnes Horses revealed a nonsense mutation in exon 15 (c.2151C>G, p.Y717X). We analyzed the KIT exons in horses characterized as dominant white from other populations and found three additional candidate causative mutations. Three almost completely white Arabians carried a different nonsense mutation in exon 4 (c.706A>T, p.K236X). Six Camarillo White Horses had a missense mutation in exon 12 (c.1805C>T, p.A602V), and five white Thoroughbreds had yet another missense mutation in exon 13 (c.1960G>A, p.G654R). Our results indicate that the dominant white color in Franches-Montagnes Horses is caused by a nonsense mutation in the KIT gene and that multiple independent mutations within this gene appear to be responsible for dominant white in several other modern horse populations

Characterization of Changes in Serum Anti-Glycan Antibodies in Crohn's Disease – a Longitudinal Analysis

INTRODUCTION: Anti-glycan antibodies are a promising tool for differential diagnosis and disease stratification of patients with Crohn's disease (CD). We longitudinally assessed level and status changes of anti-glycan antibodies over time in individual CD patients as well as determinants of this phenomenon. METHODS: 859 serum samples derived from a cohort of 253 inflammatory bowel disease (IBD) patients (207 CD, 46 ulcerative colitis (UC)) were tested for the presence of anti-laminarin (Anti-L), anti-chitin (Anti-C), anti-chitobioside (ACCA), anti-laminaribioside (ALCA), anti-mannobioside (AMCA) and anti-Saccharomyces cerevisiae (gASCA) antibodies by ELISA. All patients had at least two and up to eleven serum samples taken during the disease course. RESULTS: Median follow-up time for CD was 17.4 months (Interquartile range (IQR) 8.0, 31.6 months) and for UC 10.9 months (IQR 4.9, 21.0 months). In a subgroup of CD subjects marked changes in the overall immune response (quartile sum score) and levels of individual markers were observed over time. The marker status (positive versus negative) remained widely stable. Neither clinical phenotype nor NOD2 genotype was associated with the observed fluctuations. In a longitudinal analysis neither changes in disease activity nor CD behavior led to alterations in the levels of the glycan markers. The ability of the panel to discriminate CD from UC or its association with CD phenotypes remained stable during follow-up. In the serum of UC patients neither significant level nor status changes were observed. CONCLUSIONS: While the levels of anti-glycan antibodies fluctuate in a subgroup of CD patients the antibody status is widely stable over time

Inhibitors of Foot and Mouth Disease Virus Targeting a Novel Pocket of the RNA-Dependent RNA Polymerase

Foot-and-Mouth Disease Virus (FMDV) is a picornavirus that infects cloven-hoofed animals and leads to severe losses in livestock production. In the case of an FMD outbreak, emergency vaccination requires at least 7 days to trigger an effective immune response. There are currently no approved inhibitors for the treatment or prevention of FMDV infections.Using a luciferase-based assay we screened a library of compounds and identified seven novel inhibitors of 3Dpol, the RNA-dependent RNA polymerase of FMDV. The compounds inhibited specifically 3Dpol (IC(50)s from 2-17 µM) and not other viral or bacterial polymerases. Enzyme kinetic studies on the inhibition mechanism by compounds 5D9 and 7F8 showed that they are non-competitive inhibitors with respect to NTP and nucleic acid substrates. Molecular modeling and docking studies into the 3Dpol structure revealed an inhibitor binding pocket proximal to, but distinct from the 3Dpol catalytic site. Residues surrounding this pocket are conserved among all 60 FMDV subtypes. Site directed mutagenesis of two residues located at either side of the pocket caused distinct resistance to the compounds, demonstrating that they indeed bind at this site. Several compounds inhibited viral replication with 5D9 suppressing virus production in FMDV-infected cells with EC(50) = 12 µM and EC(90) = 20 µM).We identified several non-competitive inhibitors of FMDV 3Dpol that target a novel binding pocket, which can be used for future structure-based drug design studies. Such studies can lead to the discovery of even more potent antivirals that could provide alternative or supplementary options to contain future outbreaks of FMD

Risk and symptoms of COVID-19 in health professionals according to baseline immune status and booster vaccination during the Delta and Omicron waves in Switzerland-A multicentre cohort study.

BACKGROUND Knowledge about protection conferred by previous Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and/or vaccination against emerging viral variants allows clinicians, epidemiologists, and health authorities to predict and reduce the future Coronavirus Disease 2019 (COVID-19) burden. We investigated the risk and symptoms of SARS-CoV-2 (re)infection and vaccine breakthrough infection during the Delta and Omicron waves, depending on baseline immune status and subsequent vaccinations. METHODS AND FINDINGS In this prospective, multicentre cohort performed between August 2020 and March 2022, we recruited hospital employees from ten acute/nonacute healthcare networks in Eastern/Northern Switzerland. We determined immune status in September 2021 based on serology and previous SARS-CoV-2 infections/vaccinations: Group N (no immunity); Group V (twice vaccinated, uninfected); Group I (infected, unvaccinated); Group H (hybrid: infected and ≥1 vaccination). Date and symptoms of (re)infections and subsequent (booster) vaccinations were recorded until March 2022. We compared the time to positive SARS-CoV-2 swab and number of symptoms according to immune status, viral variant (i.e., Delta-dominant before December 27, 2021; Omicron-dominant on/after this date), and subsequent vaccinations, adjusting for exposure/behavior variables. Among 2,595 participants (median follow-up 171 days), we observed 764 (29%) (re)infections, thereof 591 during the Omicron period. Compared to group N, the hazard ratio (HR) for (re)infection was 0.33 (95% confidence interval [CI] 0.22 to 0.50, p < 0.001) for V, 0.25 (95% CI 0.11 to 0.57, p = 0.001) for I, and 0.04 (95% CI 0.02 to 0.10, p < 0.001) for H in the Delta period. HRs substantially increased during the Omicron period for all groups; in multivariable analyses, only belonging to group H was associated with protection (adjusted HR [aHR] 0.52, 95% CI 0.35 to 0.77, p = 0.001); booster vaccination was associated with reduction of breakthrough infection risk in groups V (aHR 0.68, 95% CI 0.54 to 0.85, p = 0.001) and H (aHR 0.67, 95% CI 0.45 to 1.00, p = 0.048), largely observed in the early Omicron period. Group H (versus N, risk ratio (RR) 0.80, 95% CI 0.66 to 0.97, p = 0.021) and participants with booster vaccination (versus nonboosted, RR 0.79, 95% CI 0.71 to 0.88, p < 0.001) reported less symptoms during infection. Important limitations are that SARS-CoV-2 swab results were self-reported and that results on viral variants were inferred from the predominating strain circulating in the community at that time, rather than sequencing. CONCLUSIONS Our data suggest that hybrid immunity and booster vaccination are associated with a reduced risk and reduced symptom number of SARS-CoV-2 infection during Delta- and Omicron-dominant periods. For previously noninfected individuals, booster vaccination might reduce the risk of symptomatic Omicron infection, although this benefit seems to wane over time

Accumulating mutations in series of haplotypes at the KIT and MITF loci are major determinants of white markings in Franches-Montagnes horses.

Coat color and pattern variations in domestic animals are frequently inherited as simple monogenic traits, but a number are known to have a complex genetic basis. While the analysis of complex trait data remains a challenge in all species, we can use the reduced haplotypic diversity in domestic animal populations to gain insight into the genomic interactions underlying complex phenotypes. White face and leg markings are examples of complex traits in horses where little is known of the underlying genetics. In this study, Franches-Montagnes (FM) horses were scored for the occurrence of white facial and leg markings using a standardized scoring system. A genome-wide association study (GWAS) was performed for several white patterning traits in 1,077 FM horses. Seven quantitative trait loci (QTL) affecting the white marking score with p-values p≤10(-4) were identified. Three loci, MC1R and the known white spotting genes, KIT and MITF, were identified as the major loci underlying the extent of white patterning in this breed. Together, the seven loci explain 54% of the genetic variance in total white marking score, while MITF and KIT alone account for 26%. Although MITF and KIT are the major loci controlling white patterning, their influence varies according to the basic coat color of the horse and the specific body location of the white patterning. Fine mapping across the MITF and KIT loci was used to characterize haplotypes present. Phylogenetic relationships among haplotypes were calculated to assess their selective and evolutionary influences on the extent of white patterning. This novel approach shows that KIT and MITF act in an additive manner and that accumulating mutations at these loci progressively increase the extent of white markings