Richard Durbin

Bio: Richard Durbin is an academic researcher from University of Cambridge. The author has contributed to research in topics: Genome & Population. The author has an hindex of 125, co-authored 319 publications receiving 207192 citations. Previous affiliations of Richard Durbin include Wellcome Trust Sanger Institute & University of Manchester.

No evidence for maintenance of a sympatric Heliconius species barrier by chromosomal inversions.

Abstract: Mechanisms that suppress recombination are known to help maintain species barriers by preventing the breakup of coadapted gene combinations. The sympatric butterfly species Heliconius melpomene and Heliconius cydno are separated by many strong barriers, but the species still hybridize infrequently in the wild, and around 40% of the genome is influenced by introgression. We tested the hypothesis that genetic barriers between the species are maintained by inversions or other mechanisms that reduce between-species recombination rate. We constructed fine-scale recombination maps for Panamanian populations of both species and their hybrids to directly measure recombination rate within and between species, and generated long sequence reads to detect inversions. We find no evidence for a systematic reduction in recombination rates in F1 hybrids, and also no evidence for inversions longer than 50 kb that might be involved in generating or maintaining species barriers. This suggests that mechanisms leading to global or local reduction in recombination do not play a significant role in the maintenance of species barriers between H. melpomene and H. cydno.

Ancestral Hybridization Facilitated Species Diversification in the Lake Malawi Cichlid Fish Adaptive Radiation.

Abstract: The adaptive radiation of cichlid fishes in East African Lake Malawi encompasses over 500 species that are believed to have evolved within the last 800,000 years from a common founder population. It has been proposed that hybridization between ancestral lineages can provide the genetic raw material to fuel such exceptionally high diversification rates, and evidence for this has recently been presented for the Lake Victoria region cichlid superflock. Here, we report that Lake Malawi cichlid genomes also show evidence of hybridization between two lineages that split 3-4 Ma, today represented by Lake Victoria cichlids and the riverine Astatotilapia sp. "ruaha blue." The two ancestries in Malawi cichlid genomes are present in large blocks of several kilobases, but there is little variation in this pattern between Malawi cichlid species, suggesting that the large-scale mosaic structure of the genomes was largely established prior to the radiation. Nevertheless, tens of thousands of polymorphic variants apparently derived from the hybridization are interspersed in the genomes. These loci show a striking excess of differentiation across ecological subgroups in the Lake Malawi cichlid assemblage, and parental alleles sort differentially into benthic and pelagic Malawi cichlid lineages, consistent with strong differential selection on these loci during species divergence. Furthermore, these loci are enriched for genes involved in immune response and vision, including opsin genes previously identified as important for speciation. Our results reinforce the role of ancestral hybridization in explosive diversification by demonstrating its significance in one of the largest recent vertebrate adaptive radiations.

Bounds on the learning capacity of some multi-layer networks

Abstract: We obtain bounds for the capacity of some multi-layer networks of linear threshold units. In the case of a network having n inputs, a single layer of h hidden units and an output layer of s units, where all the weights in the network are variable and s?h?n, the capacity m satisfies 2n?m?nt logt, where t=1=h/s. We consider in more detail the case where there is a single output that is a fixed boolean function of the hidden units. In this case our upper bound is of order nh logh but the argument which provided the lower bound of 2n no longer applies. However, by explicit computation in low dimensional cases we show that the capacity exceeds 2n but is substantially less than the upper bound. Finally, we describe a learning algorithm for multi-layer networks with a single output unit. This greatly outperforms back propagation at the task of learning random vectors and provides further empirical evidence that the lower bound of 2n can be exceeded.

Efficiently inferring the demographic history of many populations with allele count data.

Abstract: The sample frequency spectrum (SFS), or histogram of allele counts, is an important summary statistic in evolutionary biology, and is often used to infer the history of population size changes, mig...

Bi-allelic Truncating Mutations in TANGO2 Cause Infancy-Onset Recurrent Metabolic Crises with Encephalocardiomyopathy

Abstract: Molecular diagnosis of mitochondrial disorders is challenging because of extreme clinical and genetic heterogeneity. By exome sequencing, we identified three different bi-allelic truncating mutations in TANGO2 in three unrelated individuals with infancy-onset episodic metabolic crises characterized by encephalopathy, hypoglycemia, rhabdomyolysis, arrhythmias, and laboratory findings suggestive of a defect in mitochondrial fatty acid oxidation. Over the course of the disease, all individuals developed global brain atrophy with cognitive impairment and pyramidal signs. TANGO2 (transport and Golgi organization 2) encodes a protein with a putative function in redistribution of Golgi membranes into the endoplasmic reticulum in Drosophila and a mitochondrial localization has been confirmed in mice. Investigation of palmitate-dependent respiration in mutant fibroblasts showed evidence of a functional defect in mitochondrial β-oxidation. Our results establish TANGO2 deficiency as a clinically recognizable cause of pediatric disease with multi-organ involvement.

Gapped BLAST and PSI-BLAST: a new generation of protein database search programs.

Abstract: The BLAST programs are widely used tools for searching protein and DNA databases for sequence similarities. For protein comparisons, a variety of definitional, algorithmic and statistical refinements described here permits the execution time of the BLAST programs to be decreased substantially while enhancing their sensitivity to weak similarities. A new criterion for triggering the extension of word hits, combined with a new heuristic for generating gapped alignments, yields a gapped BLAST program that runs at approximately three times the speed of the original. In addition, a method is introduced for automatically combining statistically significant alignments produced by BLAST into a position-specific score matrix, and searching the database using this matrix. The resulting Position-Specific Iterated BLAST (PSIBLAST) program runs at approximately the same speed per iteration as gapped BLAST, but in many cases is much more sensitive to weak but biologically relevant sequence similarities. PSI-BLAST is used to uncover several new and interesting members of the BRCT superfamily.

The Sequence Alignment/Map format and SAMtools

Abstract: Summary: The Sequence Alignment/Map (SAM) format is a generic alignment format for storing read alignments against reference sequences, supporting short and long reads (up to 128 Mbp) produced by different sequencing platforms. It is flexible in style, compact in size, efficient in random access and is the format in which alignments from the 1000 Genomes Project are released. SAMtools implements various utilities for post-processing alignments in the SAM format, such as indexing, variant caller and alignment viewer, and thus provides universal tools for processing read alignments. Availability: http://samtools.sourceforge.net Contact: [email protected]

Fast and accurate short read alignment with Burrows–Wheeler transform

Abstract: Motivation: The enormous amount of short reads generated by the new DNA sequencing technologies call for the development of fast and accurate read alignment programs. A first generation of hash table-based methods has been developed, including MAQ, which is accurate, feature rich and fast enough to align short reads from a single individual. However, MAQ does not support gapped alignment for single-end reads, which makes it unsuitable for alignment of longer reads where indels may occur frequently. The speed of MAQ is also a concern when the alignment is scaled up to the resequencing of hundreds of individuals. Results: We implemented Burrows-Wheeler Alignment tool (BWA), a new read alignment package that is based on backward search with Burrows–Wheeler Transform (BWT), to efficiently align short sequencing reads against a large reference sequence such as the human genome, allowing mismatches and gaps. BWA supports both base space reads, e.g. from Illumina sequencing machines, and color space reads from AB SOLiD machines. Evaluations on both simulated and real data suggest that BWA is ~10–20× faster than MAQ, while achieving similar accuracy. In addition, BWA outputs alignment in the new standard SAM (Sequence Alignment/Map) format. Variant calling and other downstream analyses after the alignment can be achieved with the open source SAMtools software package. Availability: http://maq.sourceforge.net Contact: [email protected]

Fiji: an open-source platform for biological-image analysis

Abstract: Fiji is a distribution of the popular open-source software ImageJ focused on biological-image analysis. Fiji uses modern software engineering practices to combine powerful software libraries with a broad range of scripting languages to enable rapid prototyping of image-processing algorithms. Fiji facilitates the transformation of new algorithms into ImageJ plugins that can be shared with end users through an integrated update system. We propose Fiji as a platform for productive collaboration between computer science and biology research communities.

Trimmomatic: a flexible trimmer for Illumina sequence data

Abstract: Motivation: Although many next-generation sequencing (NGS) read preprocessing tools already existed, we could not find any tool or combination of tools that met our requirements in terms of flexibility, correct handling of paired-end data and high performance. We have developed Trimmomatic as a more flexible and efficient preprocessing tool, which could correctly handle paired-end data. Results: The value of NGS read preprocessing is demonstrated for both reference-based and reference-free tasks. Trimmomatic is shown to produce output that is at least competitive with, and in many cases superior to, that produced by other tools, in all scenarios tested. Availability and implementation: Trimmomatic is licensed under GPL V3. It is cross-platform (Java 1.5+ required) and available at http://www.usadellab.org/cms/index.php?page=trimmomatic Contact: ed.nehcaa-htwr.1oib@ledasu Supplementary information: Supplementary data are available at Bioinformatics online.