School of Agriculture, Food and Ecosystem Sciences - Research Publications
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ItemNo Preview AvailableBootstrapping of gene-expression data improves and controls the false discovery rate of differentially expressed genes(E D P SCIENCES, 2004)The ordinary-, penalized-, and bootstrap t-test, least squares and best linear unbiased prediction were compared for their false discovery rates (FDR), i.e. the fraction of falsely discovered genes, which was empirically estimated in a duplicate of the data set. The bootstrap-t-test yielded up to 80% lower FDRs than the alternative statistics, and its FDR was always as good as or better than any of the alternatives. Generally, the predicted FDR from the bootstrapped P-values agreed well with their empirical estimates, except when the number of mRNA samples is smaller than 16. In a cancer data set, the bootstrap-t-test discovered 200 differentially regulated genes at a FDR of 2.6%, and in a knock-out gene expression experiment 10 genes were discovered at a FDR of 3.2%. It is argued that, in the case of microarray data, control of the FDR takes sufficient account of the multiple testing, whilst being less stringent than Bonferoni-type multiple testing corrections. Extensions of the bootstrap simulations to more complicated test-statistics are discussed.
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ItemNo Preview AvailableMapping multiple QTL using linkage disequilibrium and linkage analysis information and multitrait data(BMC, 2004)A multi-locus QTL mapping method is presented, which combines linkage and linkage disequilibrium (LD) information and uses multitrait data. The method assumed a putative QTL at the midpoint of each marker bracket. Whether the putative QTL had an effect or not was sampled using Markov chain Monte Carlo (MCMC) methods. The method was tested in dairy cattle data on chromosome 14 where the DGAT1 gene was known to be segregating. The DGAT1 gene was mapped to a region of 0.04 cM, and the effects of the gene were accurately estimated. The fitting of multiple QTL gave a much sharper indication of the QTL position than a single QTL model using multitrait data, probably because the multi-locus QTL mapping reduced the carry over effect of the large DGAT1 gene to adjacent putative QTL positions. This suggests that the method could detect secondary QTL that would, in single point analyses, remain hidden under the broad peak of the dominant QTL. However, no indications for a second QTL affecting dairy traits were found on chromosome 14.
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ItemNo Preview AvailableA practical approach for minimising inbreeding and maximising genetic gain in dairy cattle(BMC, 2007)A method that predicts the genetic composition and inbreeding (F) of the future dairy cow population using information on the current cow population, semen use and progeny test bulls is described. This is combined with information on genetic merit of bulls to compare bull selection methods that minimise F and maximise breeding value for profit (called APR in Australia). The genetic composition of the future cow population of Australian Holstein-Friesian (HF) and Jersey up to 6 years into the future was predicted. F in Australian HF and Jersey breeds is likely to increase by about 0.002 and 0.003 per year between 2002 and 2008, respectively. A comparison of bull selection methods showed that a method that selects the best bull from all available bulls for each current or future cow, based on its calf's APR minus F depression, is better than bull selection methods based on APR alone, APR adjusted for mean F of prospective progeny after random mating and mean APR adjusted for the relationship between the selected bulls. This method reduced F of prospective progeny by about a third to a half compared to the other methods when bulls are mated to current and future cows that will be available 5 to 6 years from now. The method also reduced the relationship between the bulls selected to nearly the same extent as the method that is aimed at maximising genetic gain adjusted for the relationship between bulls. The method achieves this because cows with different pedigree exist in the population and the method selects relatively unrelated bulls to mate to these different cows. Selecting the best bull for each current or future cow so that the calf's genetic merit minus F depression is maximised can slow the rate of increase in F in the population.
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ItemNo Preview AvailableGenes influencing milk production traits predominantly affect one of four biological pathways(EDP SCIENCES S A, 2008)In this study we introduce a method that accounts for false positive and false negative results in attempting to estimate the true proportion of quantitative trait loci that affect two different traits. This method was applied to data from a genome scan that was used to detect QTL for three independent milk production traits, Australian Selection Index (ASI), protein percentage (P%) and fat percentage corrected for protein percentage (F% - P%). These four different scenarios are attributed to four biological pathways: QTL that (1) increase or decrease total mammary gland production (affecting ASI only); (2) increase or decrease lactose synthesis resulting in the volume of milk being changed but without a change in protein or fat yield (affecting P% only); (3) increase or decrease protein synthesis while milk volume remains relatively constant (affecting ASI and P% in the same direction); (4) increase or decrease fat synthesis while the volume of milk remains relatively constant (affecting F% - P% only). The results indicate that of the positions that detected a gene, most affected one trait and not the others, though a small proportion (2.8%) affected ASI and P% in the same direction.
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ItemNo Preview AvailableTesting the neutral theory of molecular evolution using genomic data: a comparison of the human and bovine transcriptome(EDP SCIENCES S A, 2006)Despite growing evidence of rapid evolution in protein coding genes, the contribution of positive selection to intra- and interspecific differences in protein coding regions of the genome is unclear. We attempted to see if genes coding for secreted proteins and genes with narrow expression, specifically those preferentially expressed in the mammary gland, have diverged at a faster rate between domestic cattle (Bos taurus) and humans (Homo sapiens) than other genes and whether positive selection is responsible. Using a large data set, we identified groups of genes based on secretion and expression patterns and compared them for the rate of nonsynonymous (dN) and synonymous (dS) substitutions per site and the number of radical (Dr) and conservative (Dc) amino acid substitutions. We found evidence of rapid evolution in genes with narrow expression, especially for those expressed in the liver and mammary gland and for genes coding for secreted proteins. We compared common human polymorphism data with human-cattle divergence and found that genes with high evolutionary rates in human-cattle divergence also had a large number of common human polymorphisms. This argues against positive selection causing rapid divergence in these groups of genes. In most cases dN/dS ratios were lower in human-cattle divergence than in common human polymorphism presumably due to differences in the effectiveness of purifying selection between long-term divergence and short-term polymorphism.
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ItemNo Preview AvailableThe distribution of the effects of genes affecting quantitative traits in livestock(E D P SCIENCES, 2001)Meta-analysis of information from quantitative trait loci (QTL) mapping experiments was used to derive distributions of the effects of genes affecting quantitative traits. The two limitations of such information, that QTL effects as reported include experimental error, and that mapping experiments can only detect QTL above a certain size, were accounted for. Data from pig and dairy mapping experiments were used. Gamma distributions of QTL effects were fitted with maximum likelihood. The derived distributions were moderately leptokurtic, consistent with many genes of small effect and few of large effect. Seventeen percent and 35% of the leading QTL explained 90% of the genetic variance for the dairy and pig distributions respectively. The number of segregating genes affecting a quantitative trait in dairy populations was predicted assuming genes affecting a quantitative trait were neutral with respect to fitness. Between 50 and 100 genes were predicted, depending on the effective population size assumed. As data for the analysis included no QTL of small effect, the ability to estimate the number of QTL of small effect must inevitably be weak. It may be that there are more QTL of small effect than predicted by our gamma distributions. Nevertheless, the distributions have important implications for QTL mapping experiments and Marker Assisted Selection (MAS). Powerful mapping experiments, able to detect QTL of 0.1sigma(p), will be required to detect enough QTL to explain 90% the genetic variance for a quantitative trait.
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ItemNo Preview AvailablePrediction of identity by descent probabilities from marker-haplotypes(BIOMED CENTRAL LTD, 2001)The prediction of identity by descent (IBD) probabilities is essential for all methods that map quantitative trait loci (QTL). The IBD probabilities may be predicted from marker genotypes and/or pedigree information. Here, a method is presented that predicts IBD probabilities at a given chromosomal location given data on a haplotype of markers spanning that position. The method is based on a simplification of the coalescence process, and assumes that the number of generations since the base population and effective population size is known, although effective size may be estimated from the data. The probability that two gametes are IBD at a particular locus increases as the number of markers surrounding the locus with identical alleles increases. This effect is more pronounced when effective population size is high. Hence as effective population size increases, the IBD probabilities become more sensitive to the marker data which should favour finer scale mapping of the QTL. The IBD probability prediction method was developed for the situation where the pedigree of the animals was unknown (i.e. all information came from the marker genotypes), and the situation where, say T, generations of unknown pedigree are followed by some generations where pedigree and marker genotypes are known.
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ItemA Validated Genome Wide Association Study to Breed Cattle Adapted to an Environment Altered by Climate Change(PUBLIC LIBRARY SCIENCE, 2009-08-18)Continued production of food in areas predicted to be most affected by climate change, such as dairy farming regions of Australia, will be a major challenge in coming decades. Along with rising temperatures and water shortages, scarcity of inputs such as high energy feeds is predicted. With the motivation of selecting cattle adapted to these changing environments, we conducted a genome wide association study to detect DNA markers (single nucleotide polymorphisms) associated with the sensitivity of milk production to environmental conditions. To do this we combined historical milk production and weather records with dense marker genotypes on dairy sires with many daughters milking across a wide range of production environments in Australia. Markers associated with sensitivity of milk production to feeding level and sensitivity of milk production to temperature humidity index on chromosome nine and twenty nine respectively were validated in two independent populations, one a different breed of cattle. As the extent of linkage disequilibrium across cattle breeds is limited, the underlying causative mutations have been mapped to a small genomic interval containing two promising candidate genes. The validated marker panels we have reported here will aid selection for high milk production under anticipated climate change scenarios, for example selection of sires whose daughters will be most productive at low levels of feeding.
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ItemAn examination of positive selection and changing effective population size in Angus and Holstein cattle populations (Bos taurus) using a high density SNP genotyping platform and the contribution of ancient polymorphism to genomic diversity in Domestic cattle(BIOMED CENTRAL LTD, 2009-04-24)BACKGROUND: Identifying recent positive selection signatures in domesticated animals could provide information on genome response to strong directional selection from domestication and artificial selection. With the completion of the cattle genome, private companies are now providing large numbers of polymorphic markers for probing variation in domestic cattle (Bos taurus). We analysed over 7,500 polymorphic single nucleotide polymorphisms (SNP) in beef (Angus) and dairy (Holstein) cattle and outgroup species Bison, Yak and Banteng in an indirect test of inbreeding and positive selection in Domestic cattle. RESULTS: Outgroup species: Bison, Yak and Banteng, were genotyped with high levels of success (90%) and used to determine ancestral and derived allele states in domestic cattle. Frequency spectrums of the derived alleles in Angus and Holstein were examined using Fay and Wu's H test. Significant divergences from the predicted frequency spectrums expected under neutrality were identified. This appeared to be the result of combined influences of positive selection, inbreeding and ascertainment bias for moderately frequent SNP. Approximately 10% of all polymorphisms identified as segregating in B. taurus were also segregating in Bison, Yak or Banteng; highlighting a large number of polymorphisms that are ancient in origin. CONCLUSION: These results suggest that a large effective population size (N(e)) of approximately 90,000 or more existed in B. taurus since they shared a common ancestor with Bison, Yak and Banteng ~1-2 million years ago (MYA). More recently N(e) decreased sharply probably associated with domestication. This may partially explain the paradox of high levels of polymorphism in Domestic cattle and the relatively small recent N(e) in this species. The period of inbreeding caused Fay and Wu's H statistic to depart from its expectation under neutrality mimicking the effect of selection. However, there was also evidence for selection, because high frequency derived alleles tended to cluster near each other on the genome.
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ItemMolecular evolution of the Bovini tribe (Bovidae, Bovinae): Is there evidence of rapid evolution or reduced selective constraint in Domestic cattle?(BIOMED CENTRAL LTD, 2009-04-24)BACKGROUND: If mutation within the coding region of the genome is largely not adaptive, the ratio of nonsynonymous (dN) to synonymous substitutions (dS) per site (dN/dS) should be approximately equal among closely related species. Furthermore, dN/dS in divergence between species should be equivalent to dN/dS in polymorphisms. This hypothesis is of particular interest in closely related members of the Bovini tribe, because domestication has promoted rapid phenotypic divergence through strong artificial selection of some species while others remain undomesticated. We examined a number of genes that may be involved in milk production in Domestic cattle and a number of their wild relatives for evidence that domestication had affected molecular evolution. Elevated rates of dN/dS were further queried to determine if they were the result of positive selection, low effective population size (N(e)) or reduced selective constraint. RESULTS: We have found that the domestication process has contributed to higher dN/dS ratios in cattle, especially in the lineages leading to the Domestic cow (Bos taurus) and Mithan (Bos frontalis) and within some breeds of Domestic cow. However, the high rates of dN/dS polymorphism within B. taurus when compared to species divergence suggest that positive selection has not elevated evolutionary rates in these genes. Likewise, the low rate of dN/dS in Bison, which has undergone a recent population bottleneck, indicates a reduction in population size alone is not responsible for these observations. CONCLUSION: The effect of selection depends on effective population size and the selection coefficient (N(e)s). Typically under domestication both selection pressure for traits important in fitness in the wild and Ne are reduced. Therefore, reduced selective constraint could be responsible for the observed elevated evolutionary ratios in domesticated species, especially in B. taurus and B. frontalis, which have the highest dN/dS in the Bovini. This may have important implications for tests of selection such as the McDonald-Kreitman test. Surprisingly we have also detected a significant difference in the supposed neutral substitution rate between synonymous and noncoding sites in the Bovine genome, with a 30% higher rate of substitution at synonymous sites. This is due, at least in part, to an excess of the highly mutable CpG dinucleotides at synonymous sites, which will have implications for time of divergence estimates from molecular data.