Genetic association of variations in the kappa-casein and beta-lactoglobulin genes with milk traits in girolando cattle.

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The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Desempenho produtivo de vacas Girolando estimado pelo modelo de Wood ajustado por metodologia bayesiana.

Utilizou-se o modelo de Wood analisado por metodologia bayesiana, para estimar os componentes da curva de lactação de diferentes grupos genéticos, de primeira (OP1) e segunda (OP2) ordem de parto: 1/4 Holandês - 3/4 Gir; 1/2 Holandês -  1/2 Gir; 3/4 Holandês - 1/4 Gir; 5/8 Holandês - 3/8 Gir e 7/8 Holandês - 1/8 Gir. Os dados de produção de leite até 305 dias de lactação pertencem ao Arquivo Zootécnico do Centro Nacional de Pesquisa em Gado de Leite da Empresa Brasileira de Pesquisa Agropecuária (EMBRAPA/CNPGL). Após a estimação dos parâmetros do modelo, foram calculadas produção no pico (PP), tempo para atingir o pico (TP), persistência na lactação (PER) e duração da lactação para cada grupo genético. Animais de OP1 apresentaram menores produções por todas as fases da lactação, além de demorarem mais tempo para alcançar o pico de produção. Animais de OP2 apresentaram maior produção total de leite. A produção total de leite dos animais 7/8H-1/8G de OP1 foi semelhante a dos animais 3/4H-1/4G e 1/2H-1/2G. Para a OP2, os animais mais produtivos foram os 7/8H-1/8G, seguidos dos 3/4H-1/4G e 1/2H-1/2G. Produção intermediaria foi verificada nos animais 5/8H-3/8G e inferiores nos animais 1/4H-3/4G para ambas as ordens de parto. Não foi observada diferença significativa para duração da lactação entre os grupos genéticos estudados. Animais de OP1 são mais persistentes que animais de OP2, porém, estes são mais produtivos. Os grupos genéticos estudados se mostram persistentes quanto à duração da lactação. A metodologia bayesiana no ajuste do modelo de Wood permite estimativas acuradas das características da curva de lactação dos animais e na estimação de produção total de leite, duração da lactação e persistência

Genetic fitness in Huntington's disease and spinocerebellar ataxia 1: A population genetics model for CAG repeat expansions

An analysis of genetic fitness was performed in Huntington's Disease (HD) and Spinocerebellar Ataxia 1 (SCA1) families. Two partially overlapping samples were used: clinically defined HD and SCA1 patients from families ascertained in definite geographical areas, and molecularly typed carriers of HD and SCA1 mutations (CAG trinucleotide expansions). In both cases, a control group of normal relatives was used. HD and SCA1 patients born before 1915-20 had more children than normal controls. Carriers of HD and SCA1 mutations, all in the low/medium expansion range (37-49 and 47-54 CAG repeats respectively), had a higher number of children than controls up to more recent times (1935-1950). The reproduction of heterozygotes for large expansions could be analysed only in subjects born after 1950 and provided indirect evidence of a lower than normal number of children. The above results fit a model based on a differential fitness according to the degree of expansion. Such a model predicts that 1) up to relatively recently the frequency of alleles in the low/medium range has been maintained or even increased by the increased fitness of their carriers, as well as by new mutations, and 2) the frequency of large expansions, part of which are lost at each generation, is maintained through further expansions of alleles in the low/medium expansion range. The implications of such a model on linkage disequilibrium and the possible spread of these diseases in future generations are discussed

Use of olive recombinant 13-Hydroperoxide Lyase in the biocatalytic process of production of green note compounds

International audienc

Use of biocatalytic processes for the production of value-added compounds

International audienc