Gene expression microarrays are an innovative technology with enormous promise to help geneticists explore and understand the genome. Although the potential of this technology has been clearly demonstrated, many important and interesting statistical questions persist. We relate certain features of microarrays to other kinds of experimental data and argue that classical statistical techniques are appropriate and useful. We advocate greater attention to experimental design issues and a more prominent role for the ideas of statistical inference in microarray studies.

Dense maps of short-tandem-repeat polymorphisms (STRPs) have allowed genome-wide searches for genes involved in a great variety of diseases with genetic influences, including common complex diseases. Generally for this purpose, marker sets with a 10 cM spacing are genotyped in hundreds of individuals. We have performed power simulations to estimate the maximum possible inter-marker distance that still allows for sufficient power. In this paper we further report on modifications of previously published protocols, resulting in a powerful screening set containing 229 STRPs with an average spacing of 18·3 cM. A complete genome scan using our protocol requires only 80 multiplex PCR reactions which are all carried out using one set of conditions and which do not contain overlapping marker allele sizes. The multiplex PCR reactions are grouped by sets of chromosomes, which enables on-line statistical analysis of a set of chromosomes, as sets of chromosomes are being genotyped. A genome scan following this modified protocol can be performed using a maximum amount of 2·5 μg of genomic DNA per individual, isolated from either blood or from mouth swabs.

The impact of the hobo transposable element in global reorganization of the Drosophila melanogaster genome has been investigated in transgenic lines generated by injection of hobo elements into the Hikone strain, which lacked them. In the present extensive survey, the chromosomal distribution of hobo insertion sites in the line 28 was found to be homogeneous and similar for all chromosomal arms, except 3L, when compared with other transgenic lines. However, some original features were observed in this line at the genetic and chromosomal levels. Several hotspots of insertion sites were observed on the X, second and third chromosomes. Five sites with a high frequency of hobo insertions were present on the 3L arm in most individuals tested, suggesting the action of selection for hobo element in some sites. The presence of doublets or triplet was also observed, implying that hobo inserts can show local jumps or insertions in preferred regions. This local transposition occurred independently in 11 specific genomic regions in many individuals and generations. The dynamics of this phenomenon were analysed across generations. These results support the use of the hobo system as an important tool in fundamental and applied Drosophila genetics.

The efficient design of association mapping studies relies on a knowledge of the rate of decay of linkage disequilibrium with distance. This rate depends on the population recombination rate, C. An estimate of C for humans is usually obtained from a comparison of physical and genetic maps, assuming an effective population size of approximately 104. We demonstrate that under both a constant population size model and a model of long-term exponential growth, there is evidence for more recombination in polymorphism data than is expected from this estimate. An important contribution of gene conversion to meiotic recombination helps to explain our observation, but does not appear to be sufficient. The occurrence of multiple hits at CpG sites and the presence of population structure are not explanations.

Formulae for the effective population sizes of autosomal, X-linked, Y-linked and maternally transmitted loci in age-structured populations are developed. The approximations used here predict both asymptotic rates of increase in probabilities of identity, and equilibrium levels of neutral nucleotide site diversity under the infinite-sites model. The applications of the results to the interpretation of data on DNA sequence variation in Drosophila, plant, and human populations are discussed. It is concluded that sex differences in demographic parameters such as adult mortality rates generally have small effects on the relative effective population sizes of loci with different modes of inheritance, whereas differences between the sexes in variance in reproductive success can have major effects, either increasing or reducing the effective population size for X-linked loci relative to autosomal or Y-linked loci. These effects need to be accounted for when trying to understand data on patterns of sequence variation for genes with different transmission modes.

The effects of a single population bottleneck of differing severity on heritability and additive genetic variance was investigated experimentally using a butterfly. An outbred laboratory stock was used to found replicate lines with one pair, three pairs and 10 pairs of adults, as well as control lines with approximately 75 effective pairs. Heritability and additive genetic variance of eight wing pattern characters and wing size were estimated using parent–offspring covariances in the base population and in all daughter lines. Individual morphological characters and principal components of the nine characters showed a consistent pattern of treatment effects in which average heritability and additive genetic variance was lower in one pair and three pair lines than in 10 pair and control lines. Observed losses in heritability and additive genetic variance were significantly greater than predicted by the neutral additive model when calculated with coefficients of inbreeding estimated from demographic parameters alone. However, use of molecular markers revealed substantially more inbreeding, generated by increased variance in family size and background selection. Conservative interpretation of a statistical analysis incorporating this previously undetected inbreeding led to the conclusion that the response to inbreeding of the morphological traits studied showed no significant departure from the neutral additive model. This result is consistent with the evidence for minimal directional dominance for these traits. In contrast, egg hatching rate in the same experimental lines showed strong inbreeding depression, increased phenotypic variance and rapid response to selection, highly indicative of an increase in additive genetic variance due to dominance variance conversion.

Whole-genome scans have identified Dmo1 as a major quantitative trait locus (QTL) for obesity and dyslipidaemia in the Otsuka Long Evans Tokushima Fatty (OLETF) rat. We have produced congenic rats for the Dmo1 locus, using marker-assisted speed congenic protocols, enforced by selective removal of other QTL regions (QTL-marker-assisted counterselection), to efficiently transfer chromosomal segments from non-diabetic Fischer 344 (F344) rats into the OLETF background. In the third generation of congenic animals, we observed a substantial therapeutic effect of the Dmo1 locus on lipid metabolism, obesity control and plasma glucose homeostasis. We conclude that single-allele correction of an impaired genetic pathway can generate a substantial therapeutic effect, despite the complex polygenic nature of type II diabetic syndromes.

A major obstacle to the positional cloning of quantitative trait loci (QTLs) lies in resolving genetic factors whose allelic effects are blurred by environmental and background genetic variation. We investigate a fine-mapping approach that combines the use of an interval-specific congenic strain with progeny testing of recombinants for markers flanking a QTL. We apply the approach to map a murine QTL with an approximately 20% effect on growth rate by progeny testing 39 recombinants in a 12 cM region of the X chromosome. We use a likelihood analysis in an attempt to maximize the information on QTL map location and effect. The major X-linked effect is mapped to an approximately 2 cM region flanked by markers about 5 cM apart, outside which LOD support for the QTL drops extremely steeply by about 80. Nearly unambiguous assignment of the QTL genotypic state is obtained for each recombinant. The resolution of individual recombinants in the region is therefore sufficiently high to facilitate the positional cloning of the locus, although progress has been hampered because the genomic region containing the QTL shows an exceptionally low level of polymorphism in comparison with recent studies.

Interval mapping by simple regression is a powerful method for the detection of quantitative trait loci (QTLs) in line crosses such as F2 populations. Due to the ease of computation of the regression approach, relatively complex models with multiple fixed effects, interactions between QTLs or between QTLs and fixed effects can easily be accommodated. However, polygenic effects, which are not targeted in QTL analysis, cannot be treated as random effects in a least squares analysis. In a cross between true inbred lines this is of no consequence, as the polygenic effect contributes just to the residual variance. In a cross between outbred lines, however, if a trait has high polygenic heritability, the additive polygenic effect has a large influence on variation in the population. Here we extend the fixed model for the regression interval mapping method to a mixed model using an animal model. This makes it possible to use not only the observations from progeny (e.g. F2), but also those from the parents (F1) to evaluate QTLs and polygenic effects. We show how the animal model using parental observations can be applied to an outbred cross and so increase the power and accuracy of QTL analysis. Three estimation methods, i.e. regression and an animal model either with or without parental observations, are applied to simulated data. The animal model using parental observations is shown to have advantages in estimating QTL position and additive genotypic value, especially when the polygenic heritability is large and the number of progeny per parent is small.