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P D Keightley

Publications and source records attributed to P D Keightley.

At least 19 recordsLinked to original sources
PubMed2002

Understanding quantitative genetic variation.

Until recently, it was impracticable to identify the genes that are responsible for variation in continuous traits, or to directly observe the effects of their different alleles. Now, the abundance of genetic markers has made it possible to identify quantitative trait loci (QTL)--the regions of a chromosome or, ideally, individual sequence variants that are responsible for trait variation. What kind of QTL do we expect to find and what can our observations of QTL tell us about how organisms evolve? The key to understanding the evolutionary significance of QTL is to understand the nature of inherited variation, not in the immediate mechanistic sense of how genes influence phenotype, but, rather, to know what evolutionary forces maintain genetic variability.

Animals↗
PubMed2001

Response to Kondrashov.

The 'mutational deterministic' hypothesis proposes that a high genomic rate of deleterious mutation (U) might maintain sexual reproduction. Our recent work casts doubt on this, as we estimate a low U for sexually reproducing species with short generation times. Following criticism by Kondrashov, here we defend our methods for estimating U and challenge the mutational deterministic hypothesis.

Animals↗
PubMed2001

High-resolution quantitative trait locus mapping for body weight in mice by recombinant progeny testing.

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.

Alleles↗
PubMed2000

Deleterious mutations and the evolution of sex.

It has been suggested that sexual reproduction is maintained because it reduces the load imposed by recurrent deleterious mutations. If rates of deleterious mutation per diploid genome per generation (U) exceed 1, and mutations interact synergistically, then sexuals can overcome their inherent twofold disadvantage. We have tested this hypothesis by estimating genomic point mutation rates for protein-coding genes in a range of animal taxa. We find a positive linear relationship between U and generation time. In species with short generation times, U is predicted to be far below 1, suggesting that sex is not maintained by its capacity to purge the genome of deleterious mutations.

Animals↗
PubMed2000

Quantitative genetics: Resolving wing shape genes.

Recent high-resolution quantitative mapping experiments aimed at elucidating the genetics of natural variation for wing shape in fruit-flies suggest that very many genes can subtly influence the trait.

Animals↗
PubMed2000

Mapping of obesity QTLs in a cross between mouse lines divergently selected on fat content.

A genome-wide quantitative trait locus (QTL) analysis was performed in a polygenic obesity mouse model resulting from a long-term selection experiment. The parental lines were outbred lines divergently selected for 53 generations for high-fat (fat, F line) or low-fat (lean, L line) percentage (fat%) that differed fivefold in fat% at 14 weeks of age. An F2 population of 436 mice was used for the QTL analysis with 71 markers distributed across the genome. The analysis revealed significant QTLs Fob1 (for F-line obesity QTL 1), Fob2, Fob3, and Fob4, on Chromosomes (Chrs) 2, 12, 15, and X, respectively. None of these QTLs map to regions of known single gene obesity mutations (Lepob, Leprdb, Cpefat, Ay, tub), though they map to regions of previously described obesity QTLs and candidate genes. The effects of Fob1, Fob3, Fob4 were additive, and that of Fob2 was dominant. Fob2 also showed a significant female-specific effect. Fob1, Fob2, Fob3, and Fob4 explained 4.9%, 19.5%, 14.4%, and 7.3% of the F2 phenotypic variance for fat%, respectively. This study identified four loci that contributed to the response to divergent selection and control a significant proportion of the difference in obesity between the F and L lines.

Animals↗
PubMed2000

Multigeneration maximum-likelihood analysis applied to mutation-accumulation experiments in Caenorhabditis elegans.

We develop a maximum-likelihood (ML) approach to estimate genomic mutation rates (U) and average homozygous mutation effects (s) from mutation-accumulation (MA) experiments in which phenotypic assays are carried out in several generations. We use simulations to compare the procedure's performance with the method of moments traditionally used to analyze MA data. Similar precision is obtained if mutation effects are small relative to the environmental standard deviation, but ML can give estimates of mutation parameters that have lower sampling variances than those obtained by the method of moments if mutations with large effects have accumulated. The inclusion of data from intermediate generations may improve the precision. We analyze life-history trait data from two Caenorhabditis elegans MA experiments. Under a model with equal mutation effects, the two experiments provide similar estimates for U of approximately 0.005 per haploid, averaged over traits. Estimates of s are more divergent and average at -0.51 and -0.13 in the two studies. Detailed analysis shows that changes of mean and variance of genetic values of MA lines in both C. elegans experiments are dominated by mutations with large effects, but the analysis does not rule out the presence of a large class of deleterious mutations with very small effects.

Animals↗
PubMed2000

Properties of ethylmethane sulfonate-induced mutations affecting life-history traits in Caenorhabditis elegans and inferences about bivariate distributions of mutation effects.

The homozygous effects of ethylmethane sulfonate (EMS)-induced mutations in Caenorhabditis elegans are compared across life-history traits. Mutagenesis has a greater effect on early than late reproductive output, since EMS-induced mutations tend to cause delayed reproduction. Mutagenesis changes the mean and variance of longevity much less than reproductive output traits. Mutations that increase total or early productivity are not detected, but the net effect of mutations is to increase and decrease late productivity to approximately equal extents. Although most mutations decrease longevity, a mutant line with increased longevity was found. A flattening of mortality curves with age is noted, particularly in EMS lines. We infer that less than one-tenth of mutations that have fitness effects in natural conditions are detected in the laboratory, and such mutations have moderately large effects ( approximately 20% of the mean). Mutational correlations for life-history traits are strong and positive. Correlations between early or late productivity and longevity are of similar magnitude. We develop a maximum-likelihood procedure to infer bivariate distributions of mutation effects. We show that strong mutation-induced genetic correlations do not necessarily imply strong directional correlations between mutational effects, since correlation is also generated by lines carrying different numbers of mutations.

Animals↗
PubMed2000

A test for epistasis among induced mutations in Caenorhabditis elegans.

Synergistic epistasis, in which deleterious mutations tend to magnify each other's effects, is a necessary component of the mutational deterministic hypothesis for the maintenance of sexual production. We tested for epistasis for life-history traits in the soil nematode Caenorhabditis elegans by inducing mutations in two genetic backgrounds: a wild-type strain and a set of genetically loaded lines that contain large numbers of independent mildly detrimental mutations. There was no significant difference between the effect of new mutations on the wild-type background and the genetically loaded background for four out of five fitness correlates. In these four cases, the maximum level of epistasis compatible with the data was very low. The fifth trait, late productivity, is not likely to be an important component of fitness. This suggests either that specific environmental conditions are required to cause epistasis or that synergistic epistasis is not a general phenomenon. We also suggest a new mechanism by which deleterious mutations may provide an advantage to sexual reproduction under low selection coefficients.

Analysis of Variance↗
PubMed1999

High frequency of cryptic deleterious mutations in Caenorhabditis elegans.

Deleterious mutations with very small phenotypic effects could be important for several evolutionary phenomena, but the extent of their contribution has been unknown. Fitness effects of induced mutations in lines of Caenorhabditis elegans were measured using a system for which the number of deleterious point mutations in the DNA can be estimated. In fitness assays, only about 4 percent of the deleterious mutations fixed in each line were detectable. The remaining 96 percent, though cryptic, are significant for mutation load and, potentially, for the evolution of sex.

Animals↗
PubMed1999

High genomic deleterious mutation rates in hominids.

It has been suggested that humans may suffer a high genomic deleterious mutation rate. Here we test this hypothesis by applying a variant of a molecular approach to estimate the deleterious mutation rate in hominids from the level of selective constraint in DNA sequences. Under conservative assumptions, we estimate that an average of 4.2 amino-acid-altering mutations per diploid per generation have occurred in the human lineage since humans separated from chimpanzees. Of these mutations, we estimate that at least 38% have been eliminated by natural selection, indicating that there have been more than 1.6 new deleterious mutations per diploid genome per generation. Thus, the deleterious mutation rate specific to protein-coding sequences alone is close to the upper limit tolerable by a species such as humans that has a low reproductive rate, indicating that the effects of deleterious mutations may have combined synergistically. Furthermore, the level of selective constraint in hominid protein-coding sequences is atypically low. A large number of slightly deleterious mutations may therefore have become fixed in hominid lineages.

Animals↗
PubMed1999

New estimates of the rates and effects of mildly deleterious mutation in Drosophila melanogaster.

The genomic rate and distribution of effects of deleterious mutations are important parameters in evolutionary theory. The most detailed information comes from the work of Mukai and Ohnishi, who allowed mutations to accumulate on Drosophila melanogaster second chromosomes, shielded from selection and recombination by being maintained heterozygous in males. Averaged over studies, the estimated rate of nonlethal viability mutations per second chromosome per generation under an equal-effects model, UBM, was 0. 12, suggesting a high genomic mutation rate. We have performed a mutation-accumulation experiment similar to those of Mukai and Ohnishi, except that three large homozygous control populations were maintained. Egg-to-adult viability of 72 nonlethal mutation-accumulation (MA) lines and the controls was assayed after 27-33 generations of mutation accumulation. The rate of decline in mean viability was significantly lower than observed by Mukai, and the rate of increase in among-line variance was significantly higher. Our UBM estimate of 0.02 is much lower than the previous estimates. Our results suggest that the rate of mutations that detectably reduce viability may not be much greater than the lethal mutation rate (0.01 in these lines), but the results also are consistent with models that include many mutations with very small effects.

Analysis of Variance↗
PubMed1999

Quantitative trait loci for growth traits in C57BL/6J x DBA/2J mice.

Quantitative trait loci (QTLs) for body weight and tail length are mapped in an F2 population of 927 C57BL/6J x DBA/2J mice. We test the concordance between the locations of the mapped QTLs with those detected by changes of marker frequency under artificial selection in a previous experiment with the same base population. The directions of effects of the QTLs are generally in agreement, and in many cases significant QTLs are found in similar map positions, but there are also discrepancies between the two experiments. There are indications of age-specific QTL effects on growth. For body weight traits, the genetic variation in the F2 appears to result from many loci with relatively small effects. For tail length at 10 weeks, however, a single QTL on Chromosome (Chr) 1 with a peak LOD score of approximately 33 contributes most of the genetic variation detected, changes the trait value by about 6%, and explains about 20% of the phenotypic variance of the trait.

Animals↗
PubMed1999

Testing the correspondence between map positions of quantitative trait loci.

There are several instances in which quantitative trait locus (QTL) mapping experiments have been independently carried out for similar traits in different laboratories. We develop a permutation test of the correspondence between the test statistics obtained from genome-wide QTL scans in two such experiments to test whether the same QTLs are segregating in the experimental pair. In simulations, we show that the permutation test has the desired properties if chromosomes are of equal length, but bias can occur if chromosomes are of unequal length, a problem connected with autocorrelation of test statistic values. We apply the test to data from three recent mouse body weight QTL mapping experiments. The results from the test are non-significant, and imply a lack of overall concordance between the QTLs that were segregating in these experiments.

Animals↗
PubMed1998

Population genetics: surviving under mutation pressure.

Concern has been voiced about the survival of endangered species, and even the long-term prospects for humans, in the face of accumulating deleterious mutations. Two experiments have investigated the mutation accumulation process in laboratory Drosophila populations, with apparently conflicting results.

Animals↗
PubMed1998

Mapping quantitative trait loci affecting sternopleural bristle number in Drosophila melanogaster using changes of marker allele frequencies in divergently selected lines.

Quantitative trait loci (QTLs) responsible for variation in sternopleural bristle number in crosses between the laboratory lines of Drosophila melanogaster OregonR and CantonS were mapped using information from allele frequency changes of two families of retrotransposon markers in divergently selected populations. QTL effects and positions were inferred by likelihood, using transition matrix iteration and Monte Carlo interval mapping. Individuals from the selected population were genotyped for markers spaced at an average distance 4.4 cM. Four QTLs of moderate effect ranging from 0.6 to 1.32 bristles accounted for most of the selection response. A permutation test of the correspondence between the mapped QTLs and the positions of bristle number candidate genes suggested that alleles at these candidate genes were no more strongly associated with selected changes in marker allele frequency than were randomly chosen positions in the genome.

Alleles↗
PubMed1998

Test of candidate gene--quantitative trait locus association applied to fatness in mice.

We test for the contribution of five strong candidate genes for obesity to quantitative variation for fatness in mice. The candidate loci are known through their major mutant phenotypes. We propose a randomization test for overall contribution of candidate genes, based on the empirical distribution of LOD scores from a quantitative trait locus (QTL) genome scan. The test is applied to data on body fat content and male gonadal fatpad weight from a QTL genome scan with an F2 population of C57BL/6J and DBA/2J inbred mice. The test is nonsignificant in this experiment for overall body fat content. QTLs detected at an experiment-wide significance level on chromosome 4, 6, 13 and 15 have effects on mean fatness of up to 19% between the homozygotes, but map to locations where there is no strong candidate gene. The test is significant for gonadal fat pad weight in males, and gives weak support for an association with the diabetes gene.

Adipose Tissue↗