Large-effect Quantitative Trait Loci Research Articles

Detection, number and effects of QTLs for a complex character

Summary — Factors influencing the detection of quantitative trait loci (QTLs) via molecular markers are discussed in the case of recombinant inbred lines. The importance of the residual genetic variance present is emphasized and an expression for the minimum detectable effect is presented, which only depends on the design (trait heritability and number of lines studied); for relatively realistic situations, this minimum effect may be as high as 20 to 30% of the genetic SD. Therefore only QTLs with relatively large effects, and that are sufficiently closely linked to the marker, are likely to be detected. Increasing the genetic distance between parents can increase the probability of finding crosses in which significant (ie large-effect) QTLs are found, at the expense of decreasing the probability of detecting existing small-effect QTLs. Epistasis can diminish QTL detectability. Its possible importance has been discussed, and appears to be difficult to demonstrate. It has been shown that for a complex character, detected QTLs can at most only constitute a small subset of the existing QTLs. Furthermore, the occurrence of numerous small-effect QTLs regularly distributed over a chromosomal fraction in a directional manner has been shown to lead to the artefactual detection of a QTL by a centrally located marker.

Molecular events comprising activation of the alternative complement pathway

The acute and permanent effects of a single damaging noise exposure were compared in CBA/J, C57BL/6 (B6), and closely related strains of mice. Two hours of broadband noise (4–45 kHz) at 110 dB SPL led to temporary reduction in the endocochlear potential (EP) of CBA/J and CBA/CaJ (CBA) mice and acute cellular changes in cochlear stria vascularis and spiral ligament. For the same exposure, B6 mice showed no EP reduction and little of the pathology seen in CBA. Eight weeks after exposure, all mice showed a normal EP, but only CBA mice showed injury and cell loss in cochlear lateral wall, despite the fact that B6 sustained larger permanent threshold shifts. Examination of noise injury in B6 congenics carrying alternate alleles of genes encoding otocadherin (Cdh23), agouti protein, and tyrosinase (albinism) indicated that none of these loci can account for the strain differences observed. Examination of CBA×B6 F1 mice and N2 backcross mice to B6 further indicated that susceptibility to noise-related EP reduction and associated cell pathology are inherited in an autosomal dominant manner, and are established by one or a few large effect quantitative trait loci. Findings support a common genetic basis for an entire constellation of noise-related cochlear pathologies in cochlear lateral wall and spiral limbus. Even within species, cellular targets of acute and permanent cochlear noise injury may vary with genetic makeup.