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Biomedical subjects

Thomas Mailund

Publications and source records attributed to Thomas Mailund.

11 recordsLinked to original sources

Identifying loci under positive selection in complex population histories.

Detailed modeling of a species' history is of prime importance for understanding how natural selection operates over time. Most methods designed to detect positive selection along sequenced genomes, however, use simplified representations of past histories as null models of genetic drift. Here, we present the first method that can detect signatures of strong local adaptation across the genome using arbitrarily complex admixture graphs, which are typically used to describe the history of past divergence and admixture events among any number of populations. The method-called graph-aware retrieval of selective sweeps (GRoSS)-has good power to detect loci in the genome with strong evidence for past selective sweeps and can also identify which branch of the graph was most affected by the sweep. As evidence of its utility, we apply the method to bovine, codfish, and human population genomic data containing panels of multiple populations related in complex ways. We find new candidate genes for important adaptive functions, including immunity and metabolism in understudied human populations, as well as muscle mass, milk production, and tameness in specific bovine breeds. We are also able to pinpoint the emergence of large regions of differentiation owing to inversions in the history of Atlantic codfish.

Animals↗

Whole genome association mapping by incompatibilities and local perfect phylogenies.

BACKGROUND: With current technology, vast amounts of data can be cheaply and efficiently produced in association studies, and to prevent data analysis to become the bottleneck of studies, fast and efficient analysis methods that scale to such data set sizes must be developed. RESULTS: We present a fast method for accurate localisation of disease causing variants in high density case-control association mapping experiments with large numbers of cases and controls. The method searches for significant clustering of case chromosomes in the "perfect" phylogenetic tree defined by the largest region around each marker that is compatible with a single phylogenetic tree. This perfect phylogenetic tree is treated as a decision tree for determining disease status, and scored by its accuracy as a decision tree. The rationale for this is that the perfect phylogeny near a disease affecting mutation should provide more information about the affected/unaffected classification than random trees. If regions of compatibility contain few markers, due to e.g. large marker spacing, the algorithm can allow the inclusion of incompatibility markers in order to enlarge the regions prior to estimating their phylogeny. Haplotype data and phased genotype data can be analysed. The power and efficiency of the method is investigated on 1) simulated genotype data under different models of disease determination 2) artificial data sets created from the HapMap ressource, and 3) data sets used for testing of other methods in order to compare with these. Our method has the same accuracy as single marker association (SMA) in the simplest case of a single disease causing mutation and a constant recombination rate. However, when it comes to more complex scenarios of mutation heterogeneity and more complex haplotype structure such as found in the HapMap data our method outperforms SMA as well as other fast, data mining approaches such as HapMiner and Haplotype Pattern Mining (HPM) despite being significantly faster. For unphased genotype data, an initial step of estimating the phase only slightly decreases the power of the method. The method was also found to accurately localise the known susceptibility variants in an empirical data set--the DeltaF508 mutation for cystic fibrosis--where the susceptibility variant is already known--and to find significant signals for association between the CYP2D6 gene and poor drug metabolism, although for this dataset the highest association score is about 60 kb from the CYP2D6 gene. CONCLUSION: Our method has been implemented in the Blossoc (BLOck aSSOCiation) software. Using Blossoc, genome wide chip-based surveys of 3 million SNPs in 1000 cases and 1000 controls can be analysed in less than two CPU hours.

Chromosome Mapping↗

Fast calculation of the quartet distance between trees of arbitrary degrees.

BACKGROUND: A number of algorithms have been developed for calculating the quartet distance between two evolutionary trees on the same set of species. The quartet distance is the number of quartets - sub-trees induced by four leaves - that differs between the trees. Mostly, these algorithms are restricted to work on binary trees, but recently we have developed algorithms that work on trees of arbitrary degree. RESULTS: We present a fast algorithm for computing the quartet distance between trees of arbitrary degree. Given input trees T and T', the algorithm runs in time O(n + /V/./V'/ min{id, id'}) and space O(n + /V/./V'/), where n is the number of leaves in the two trees, V and V are the non-leaf nodes in T and T', respectively, and id and id' are the maximal number of non-leaf nodes adjacent to a non-leaf node in T and T', respectively. The fastest algorithms previously published for arbitrary degree trees run in O(n3) (independent of the degree of the tree) and O(/V/./V'/.id.id'), respectively. We experimentally compare the algorithm with existing algorithms for computing the quartet distance for general trees. CONCLUSION: We present a new algorithm for computing the quartet distance between two trees of arbitrary degree. The new algorithm improves the asymptotic running time for computing the quartet distance, compared to previous methods, and experimental results indicate that the new method also performs significantly better in practice.

Journal Article↗

The effective size of the Icelandic population and the prospects for LD mapping: inference from unphased microsatellite markers.

Characterizing the extent of linkage disequilibrium (LD) in the genome is a pre-requisite for association mapping studies. Patterns of LD also contain information about the past demography of populations. In this study, we focus on the Icelandic population where LD was investigated in 12 regions of approximately 15 cM using regularly spaced microsatellite loci displaying high heterozygosity. A total of 1753 individuals were genotyped for 179 markers. LD was estimated using a composite disequilibrium measure based on unphased data. LD decreases with distance in all 12 regions and more LD than expected by chance can be detected over approximately 4 cM in our sample. Differences in the patterns of decrease of LD with distance among genomic regions were mostly due to two regions exhibiting, respectively, higher and lower proportions of pairs in LD than average within the first 4 cM. We pooled data from all regions, except these two and summarized patterns of LD by computing the proportion of pairs of loci exhibiting significant LD (at the 5% level) as a function of distance. We compared observed patterns of LD with simulated data sets obtained under scenarios with varying demography and intensity of recombination. We show that unphased data allow to make inferences on scaled recombination rates from patterns of LD. Patterns of LD in Iceland suggest a genome-wide scaled recombination rate of rho* = 200 (130-330) per cM (or an effective size of roughly 5000), in the low range of estimates recently reported in three populations from the HapMap project.

Biological Evolution↗

GeneRecon--a coalescent based tool for fine-scale association mapping.

UNLABELLED: GeneRecon is a tool for fine-scale association mapping using a coalescence model. GeneRecon takes as input case-control data from phased or unphased SNP and microsatellite genotypes. The posterior distribution of disease locus position is obtained by Metropolis-Hastings sampling in the state space of genealogies. Input format, search strategy and the sampled statistics can be configured through the Guile Scheme programming language embedded in GeneRecon, making GeneRecon highly configurable. AVAILABILITY: The source code for GeneRecon, written in C++ and Scheme, is available under the GNU General Public License (GPL) at http://www.birc.au.dk/~mailund/GeneRecon CONTACT: mailund@birc.au.dk.

Algorithms↗

Recrafting the neighbor-joining method.

BACKGROUND: The neighbor-joining method by Saitou and Nei is a widely used method for constructing phylogenetic trees. The formulation of the method gives rise to a canonical Theta(n3) algorithm upon which all existing implementations are based. RESULTS: In this paper we present techniques for speeding up the canonical neighbor-joining method. Our algorithms construct the same phylogenetic trees as the canonical neighbor-joining method. The best-case running time of our algorithms are O(n2) but the worst-case remains O(n3). We empirically evaluate the performance of our algoritms on distance matrices obtained from the Pfam collection of alignments. The experiments indicate that the running time of our algorithms evolve as Theta(n2) on the examined instance collection. We also compare the running time with that of the QuickTree tool, a widely used efficient implementation of the canonical neighbor-joining method. CONCLUSION: The experiments show that our algorithms also yield a significant speed-up, already for medium sized instances.

Algorithms↗

CoaSim: a flexible environment for simulating genetic data under coalescent models.

BACKGROUND: Coalescent simulations are playing a large role in interpreting large scale intra-specific sequence or polymorphism surveys and for planning and evaluating association studies. Coalescent simulations of data sets under different models can be compared to the actual data to test the importance of different evolutionary factors and thus get insight into these. RESULTS: We have created the CoaSim application as a flexible environment for Monte Carlo simulation of various types of genetic data under equilibrium and non-equilibrium coalescent processes for a variety of applications. Interaction with the tool is through the Guile version of the Scheme scripting language. Scheme scripts for many standard and advanced applications are provided and these can easily be modified by the user for a much wider range of applications. A graphical user interface with less functionality and flexibility is also included. It is primarily intended as an exploratory and educational tool CONCLUSION: CoaSim is a powerful tool because of its flexibility and ease of use. This is illustrated through very varied uses of the application, e.g. evaluation of association mapping methods, parametric bootstrapping, and design and choice of markers for specific questions.

Case-Control Studies↗

Pigs in sequence space: a 0.66X coverage pig genome survey based on shotgun sequencing.

BACKGROUND: Comparative whole genome analysis of Mammalia can benefit from the addition of more species. The pig is an obvious choice due to its economic and medical importance as well as its evolutionary position in the artiodactyls. RESULTS: We have generated approximately 3.84 million shotgun sequences (0.66X coverage) from the pig genome. The data are hereby released (NCBI Trace repository with center name "SDJVP", and project name "Sino-Danish Pig Genome Project") together with an initial evolutionary analysis. The non-repetitive fraction of the sequences was aligned to the UCSC human-mouse alignment and the resulting three-species alignments were annotated using the human genome annotation. Ultra-conserved elements and miRNAs were identified. The results show that for each of these types of orthologous data, pig is much closer to human than mouse is. Purifying selection has been more efficient in pig compared to human, but not as efficient as in mouse, and pig seems to have an isochore structure most similar to the structure in human. CONCLUSION: The addition of the pig to the set of species sequenced at low coverage adds to the understanding of selective pressures that have acted on the human genome by bisecting the evolutionary branch between human and mouse with the mouse branch being approximately 3 times as long as the human branch. Additionally, the joint alignment of the shot-gun sequences to the human-mouse alignment offers the investigator a rapid way to defining specific regions for analysis and resequencing.

Animals↗

RBT--a tool for building refined Buneman trees.

SUMMARY: We have developed a tool implementing an efficient algorithm for refined Buneman tree reconstruction. The algorithm--which has the same complexity as the neighbour-joining method and the (plain) Buneman tree construction--enables refined Buneman tree reconstruction on large taxa sets. AVAILABILITY: The source code for RBT, written in Java, is available under the GNU Public License (GPL) at http://www.birc.dk/Software/RBT CONTACT: besen@daimi.au.dk.

Algorithms↗

QuickJoin--fast neighbour-joining tree reconstruction.

We have built a tool for fast construction of very large phylogenetic trees. The tool uses heuristics for speeding up the neighbour-joining algorithm-while still constructing the same tree as the original neighbour-joining algorithm-making it possible to construct trees for 8000 species in <10 min on a single desktop PC. In comparison, the same task takes more than 30 min using the QuickTree neighbour-joining implementation.

Algorithms↗

QDist--quartet distance between evolutionary trees.

SUMMARY: QDist is a program for computing the quartet distance between two unrooted trees, i.e. the number of quartet topology differences between the trees, where a quartet topology is the topological subtree induced by four species. The program is based on an algorithm with running time O(n log2 n), which makes it practical to compare large trees. Available under GNU license. AVAILABILITY: http://www.birc.dk/Software/QDist

Algorithms↗