Theoretical aspects of applying sib-pair linkage tests to livestock species

The Haseman-Elston (HE) sib-pair linkage test in its original form is computationally simple but suffers from low power. With the advent of highly polymorphic markers, the exclusive use of fully informative matings (ie matings where the number of genes identical by descent for any sib pair can be inferred without error) for the HE test becomes feasible. This article examines the influence of highly polymorphic marker systems (5 alleles), large family sizes (6 full-sibs) and hierarchical breeding structures (mating ratio of 25) on the power of the HE test by means of simulation studies. Simulations are performed under the assumption that the costs of marker genotyping are a limiting factor for marker-QTL linkage studies. Consequently, the total number of individuals (parents and offspring) typed is fixed at 5 000 in each of the situations compared. The results show that the power of the HE test is considerably increased when both highly polymorphic markers and large full-sib families are available. For example, for a locus explaining 8% of the phenotypic variance the power of the test increases from 14 to 74% if the locus has 5 alleles instead of 2 and sibship size is 6 instead of 2. Hierarchical breeding structures tend to further increase the power of the test, for the example given from 74 to 79%.Dans sa forme originelle, le test de liaison génétique de Haseman-Elston (HE), basé sur les couples de germains, est simple à calculer, mais statistiquement peu puissant. Avec des marqueurs hautement polymorphes, l’utilisation exclusive d’accouplements totalement informatifs (ie des accouplements permettant d’établir avec certitude le nombre de gènes d’origine identique pour n’importe quel couple de germains) peut être envisagée. Cet article examine, à l’aide de simulations, l’effet d’un système génétique hautement polymorphe (5 allèles également fréquents), d’une grande taille de fratrie (6 germains) et d’une structure d’élevage polygynique (25 femelles accouplées à chaque mâle) sur la puissance du test HE. Les simulations sont faites en supposant que le coût des typages génétiques est le facteur limitant des études de liaisons entre gènes marqueurs et locus de caractères quantitatifs. En conséquence, le nombre total d’individus typés (parents et descendants) est fixé à 5 000 dans chacune des situations comparées. Les résultats montrent que la puissance du test HE est considérablement accrue quand on dispose à la fois de marqueurs hautement polymorphes et de grandes fratries. Ainsi, pour un locus expliquant 8% de la variance phénotypique du caractère, la puissance du test au seuil de 5% est de 0,74 au lieu de 0, 14 quand on passe de 2 à 5 allèles au locus marqueur et de 2 à 6 frères par fratrie. Les structures d’élevage-polygyniques tendent à accroître encore la puissance du test, qui, dans l’exemple ci-dessus, passe de 0,74 à 0,79 avec une structure de 25 fratries issues du même père, par rapport à des couples de parents indépendants

Use of sib-pair linkage methods for the estimation of the genetic variance at a quantitative trait locus

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Increased plasma viscosity as a reason for inappropriate erythropoietin formation.

The aim of this study was to examine whether altered plasma viscosity could contribute to the inappropriately low production rate of erythropoietin (EPO) observed in patients suffering from hypergammaglobulinemias associated with multiple myeloma or Waldenström's disease. We found that the EPO formation in response to anemia in these patients was inversely related to plasma viscosity. A similar inverse relationship between plasma viscosity and EPO production was seen in rats in which EPO formation had been stimulated by exchange transfusion and the plasma viscosity of which was thereby altered by using exchange solutions of different composition to alter plasma viscosity and thus whole blood viscosity independently from hematocrit. Raising the gammaglobulin concentration to approximately 40 mg/ml plasma in the rats almost totally blunted the rise in serum EPO levels despite a fall of the hematocrit to 20%. Determination of renal EPO mRNA levels by RNase protection revealed that the reductions in serum EPO levels at higher plasma viscosities were paralleled by reductions in renal EPO mRNA levels. Taken together, our findings suggest that plasma viscosity may be a significant inhibitory modulator of anemia-induced EPO formation. The increased plasma viscosity in patients with hypergammaglobulinemias may therefore contribute to the inappropriate EPO production, which is a major reason for the anemia developing in these patients