Impact of QTL properties on the accuracy of multi-breed genomic prediction

Background

Although simulation studies show that combining multiple breeds in one reference population increases accuracy of genomic prediction, this is not always confirmed in empirical studies. This discrepancy might be due to the assumptions on quantitative trait loci (QTL) properties applied in simulation studies, including number of QTL, spectrum of QTL allele frequencies across breeds, and distribution of allele substitution effects. We investigated the effects of QTL properties and of including a random across- and within-breed animal effect in a genomic best linear unbiased prediction (GBLUP) model on accuracy of multi-breed genomic prediction using genotypes of Holstein-Friesian and Jersey cows.

Methods

Genotypes of three classes of variants obtained from whole-genome sequence data, with moderately low, very low or extremely low average minor allele frequencies (MAF), were imputed in 3000 Holstein-Friesian and 3000 Jersey cows that had real high-density genotypes. Phenotypes of traits controlled by QTL with different properties were simulated by sampling 100 or 1000 QTL from one class of variants and their allele substitution effects either randomly from a gamma distribution, or computed such that each QTL explained the same variance, i.e. rare alleles had a large effect. Genomic breeding values for 1000 selection candidates per breed were estimated using GBLUP modelsincluding a random across- and a within-breed animal effect.

Results

For all three classes of QTL allele frequency spectra, accuracies of genomic prediction were not affected by the addition of 2000 individuals of the other breed to a reference population of the same breed as the selection candidates. Accuracies of both single- and multi-breed genomic prediction decreased as MAF of QTL decreased, especially when rare alleles had a large effect. Accuracies of genomic prediction were similar for the models with and without a random within-breed animal effect, probably because of insufficient power to separate across- and within-breed animal effects.

Conclusions

Accuracy of both single- and multi-breed genomic prediction depends on the properties of the QTL that underlie the trait. As QTL MAF decreased, accuracy decreased, especially when rare alleles had a large effect. This demonstrates that QTL properties are key parameters that determine the accuracy of genomic prediction.

Electronic supplementary material

The online version of this article (doi:10.1186/s12711-015-0124-6) contains supplementary material, which is available to authorized users.     

Phylogeography and conservation of the bull shark (Carcharhinus leucas) inferred from mitochondrial and microsatellite DNA

The bull shark (Carcharhinus leucas) is a widely distributed, large coastal shark species known to travel long distances. These characteristics, coupled with the species?? long life span and late age of maturity, would lead one to predict significant global genetic exchange among bull shark populations. By contrast, data show localized depletion in some areas of large coastal shark fisheries, indicating some geographic isolation may exist. We examined genetic variation in the control region of mitochondrial DNA and at five nuclear microsatellite loci in bull sharks sampled from the western Atlantic to investigate the degree of population subdivision. The average per sample haplotype and nucleotide diversity in the mtDNA (0.51 ± 0.26 and 0.12% ± 0.12, respectively) and expected heterozygosity (0.84) in the microsatellite loci contrast sharply in having lower and higher values (respectively) relative to many other shark species. Significant structure exists between the Brazilian and all northern populations at the mtDNA control region (pairwise ??_ST > 0.8, P < 0.001), but not at the nuclear microsatellite loci. Adjacent northern populations show weak to no genetic differentiation for both markers. These results are congruent with restricted maternal gene flow between populations caused by female site fidelity to nursery areas. We estimate the current effective population size to be around 160,000 and 221,000 individuals for the southern and northern Atlantic populations, respectively. The philopatric habits and the relatively low levels of mtDNA genetic diversity observed in bull sharks must be considered in the conservation of this species. Our results indicate that effective bull shark management strategies will require local, regional, and international attention and cooperation.     

The essential fatty acid status in phenylketonuria patients under treatment

Phenylketonuric patients are on a special diet that lacks certain essential fatty acids. This study evaluates the essential fatty acid status of a group of phenylketonuric patients in the Netherlands undergoing dietary treatment. To this end, the essential fatty acid status of nine phenylketonuria patients was studied. On the basis of age and gender, two control subjects were selected for each patient. The essential fatty acid composition of duplicate food portions and the essential fatty acid status of plasma and erythrocytes were analyzed. Phenylketonuria subjects had a different essential fatty acid profile from their peers, especially concerning the n-3 fatty acids. N-6 and n-3 fatty long-chain polyenes were hardly consumed by phenylketonuria subjects, in contrast to the control subjects. Linoleic acid, on the other hand, was consumed in significantly higher amounts by phenylketonuria subjects and made up about 40% of their daily fat consumption. The essential fatty acid consumption pattern of the phenylketonuria subjects is mirrored by the essential fatty acid concentrations in blood. The essential fatty acid status of the phenylketonuric diet should be improved in order to prevent deficiency in n-3 fatty acids.     

Lipoteichoic acid is an important microbe-associated molecular pattern of Lactobacillus rhamnosus GG

Background

Receptors with a single transmembrane (TM) domain are essential for the signal transduction across the cell membrane. NMR spectroscopy is a powerful tool to study structure of the single TM domain. The expression and purification of a TM domain in Escherichia coli (E.coli) is challenging due to its small molecular weight. Although ketosteroid isomerase (KSI) is a commonly used affinity tag for expression and purification of short peptides, KSI tag needs to be removed with the toxic reagent cyanogen bromide (CNBr).

Result

The purification of the TM domain of p75 neurotrophin receptor using a KSI tag with the introduction of a thrombin cleavage site is described herein. The recombinant fusion protein was refolded into micelles and was cleaved with thrombin. Studies showed that purified protein could be used for structural study using NMR spectroscopy.

Conclusions

These results provide another strategy for obtaining a single TM domain for structural studies without using toxic chemical digestion or acid to remove the fusion tag. The purified TM domain of p75 neurotrophin receptor will be useful for structural studies.     

Clinical features and predictors for disease natural progression in adults with Pompe disease: a nationwide prospective observational study

Background

Due partly to physicians’ unawareness, many adults with Pompe disease are diagnosed with great delay. Besides, it is not well known which factors influence the rate of disease progression, and thus disease outcome. We delineated the specific clinical features of Pompe disease in adults, and mapped out the distribution and severity of muscle weakness, and the sequence of involvement of the individual muscle groups. Furthermore, we defined the natural disease course and identified prognostic factors for disease progression.

Methods

We conducted a single-center, prospective, observational study. Muscle strength (manual muscle testing, and hand-held dynamometry), muscle function (quick motor function test), and pulmonary function (forced vital capacity in sitting and supine positions) were assessed every 3–6 months and analyzed using repeated-measures ANOVA.

Results

Between October 2004 and August 2009, 94 patients aged between 25 and 75 years were included in the study. Although skeletal muscle weakness was typically distributed in a limb-girdle pattern, many patients had unfamiliar features such as ptosis (23%), bulbar weakness (28%), and scapular winging (33%). During follow-up (average 1.6 years, range 0.5-4.2 years), skeletal muscle strength deteriorated significantly (mean declines of ?1.3% point/year for manual muscle testing and of ?2.6% points/year for hand-held dynamometry; both p<0.001). Longer disease duration (>15 years) and pulmonary involvement (forced vital capacity in sitting position <80%) at study entry predicted faster decline. On average, forced vital capacity in supine position deteriorated by 1.3% points per year (p=0.02). Decline in pulmonary function was consistent across subgroups. Ten percent of patients declined unexpectedly fast.

Conclusions

Recognizing patterns of common and less familiar characteristics in adults with Pompe disease facilitates timely diagnosis. Longer disease duration and reduced pulmonary function stand out as predictors of rapid disease progression, and aid in deciding whether to initiate enzyme replacement therapy, or when.

     

Spatiotemporal clustering of cell death in the avian forebrain proliferative zone

The extent to which programmed cell death is the fate of proliferative, rather than post-mitotic, cells remains controversial, but a preponderance of evidence suggests that at least some cells within the brain's proliferative zone die during mammalian brain development. One major unresolved question is the extent to which cell death in the proliferative zone is spatiotemporally patterned. In order to answer this question we used the terminal dUTP nick end labeling (TUNEL) method to stain apoptotic cells in the forebrain of chicken embryos at relatively early stages of brain development (Hamburger-Hamilton stages 19-32). Our principal finding is that most of the TUNEL-positive cells within the brain's proliferative zone are concentrated into distinct clusters, whose location varies with developmental stage. At stage 19, many TUNEL+ cells are found within the basal synencephalon, just below where the forebrain's first neurons are located. At stages 24-26, numerous TUNEL+ cells are located within the preoptic area and along the optic stalk. After stage 26, TUNEL labeling is prominent in two telencephalic areas: the thin dorsomedial telencephalon and the thickest portions of the telencephalon's lateral walls (i.e. the dorsal ventricular ridge). Collectively, the observed pattern of TUNEL staining suggests that cell death in the proliferative zone plays a substantial role in shaping the forebrain. In addition, cell death in the proliferative zone may be related to cell cycle exit.     

Age and growth of the endemic Xingu River stingray Potamotrygon leopoldi validated using fluorescent dyes

Between 2003 and 2005, vertebrae of 151 Xingu River Potamotrygon leopoldi (Potamotrygonidae) (75 males and 76 females) were analysed to derive a growth curve for this species. The disc width (W _D) was significantly different between sexes, with females measuring 149–700 mm W _D and males 109–500 mm W _D. The average percentage error for vertebrae readings of the whole sample was 2·7%. The marginal increment ratio (R _MI) showed an increasing trend with the highest value in November, decreasing from December on. The majority of vertebrae displaying R _MI zero, occurred in September, but the annual periodicity of ring deposition throughout the year was not conclusive. Tetracycline (TCN) injected specimens were held in captivity for 13 months and displayed a fluorescent mark in vertebrae confirming a yearly periodicity of band pair formation with the translucent ring deposited in September–October. The Akaike information criterion (AIC) showed that, among the seven models considered, the best fit was obtained for the von Bertalanffy modified with W ₀ (where W ₀ = W _D at birth) for both sexes. Growth parameters for females were: W ₀ = 149 mm; W _∞ = 763·06 mm; k = 0·12 year^{– 1}, whereas for males: W ₀ = 109 mm; W _∞ = 536·4 and k = 0·22 year^?1. Maximal ages were 7·2 years in males and 14·3 years in females. The species shows sexual dimorphism expressed in the growth pattern, size at maturity, longevity and asymptotic sizes. Concern for sustainability is raised due to the construction of the Belo Monte Hydroelectric Power Plant (2015 and 2016) in the State of Pará causing changes to the habitat of this species, which is endemic to the Xingu River and two of its tributaries.     

Algorithm of OMA for large-scale orthology inference

Background  

OMA is a project that aims to identify orthologs within publicly available, complete genomes. With 657 genomes analyzed to date, OMA is one of the largest projects of its kind.