Biomedical subjects

David Swarbreck

Publications and source records attributed to David Swarbreck.

6 recordsLinked to original sources

PubMed2025

Whole Genome Sequencing Reveals How Plasticity and Genetic Differentiation Underlie Sympatric Morphs of Arctic Charr.

Salmonids have a remarkable ability to form sympatric morphs after postglacial colonisation of freshwater lakes. These morphs often differ in morphology, feeding and spawning behaviour. Here, we explored the genetic basis of morph differentiation in Arctic charr (n = 283) by first establishing a high-quality reference genome and then using this in whole genome sequencing of distinct morphs present in two Norwegian and two Icelandic lakes. The four lakes represent the spectrum of genetic differentiation between morphs from one lake with no genetic differentiation between morphs, implying phenotypic plasticity, to two lakes with locus-specific genetic differentiation, implying incomplete reproductive isolation, and one lake with strong genome-wide divergence consistent with complete reproductive isolation. As many as 12 putative inversions ranging from 0.45 to 3.25 Mbp in size segregated among the four morphs present in one lake, Thingvallavatn, and these contributed significantly to the genetic differentiation among morphs. None of the putative inversions were found in any of the other lakes, but there were cases of partial haplotype sharing in similar morph contrasts in other lakes. Our findings are consistent with a highly polygenic basis of morph differentiation with population-specific selection on alleles linked to the development of similar morph phenotypes. The results support a model where morph differentiation is first established through phenotypic plasticity, leading to niche expansion and separation. This may be followed by gradual development of reproductive isolation, locus-specific differentiation and eventually complete reproductive isolation and genome-wide divergence.

Whole Genome Sequencing↗

PubMed2006

GENCODE: producing a reference annotation for ENCODE.

BACKGROUND: The GENCODE consortium was formed to identify and map all protein-coding genes within the ENCODE regions. This was achieved by a combination of initial manual annotation by the HAVANA team, experimental validation by the GENCODE consortium and a refinement of the annotation based on these experimental results. RESULTS: The GENCODE gene features are divided into eight different categories of which only the first two (known and novel coding sequence) are confidently predicted to be protein-coding genes. 5' rapid amplification of cDNA ends (RACE) and RT-PCR were used to experimentally verify the initial annotation. Of the 420 coding loci tested, 229 RACE products have been sequenced. They supported 5' extensions of 30 loci and new splice variants in 50 loci. In addition, 46 loci without evidence for a coding sequence were validated, consisting of 31 novel and 15 putative transcripts. We assessed the comprehensiveness of the GENCODE annotation by attempting to validate all the predicted exon boundaries outside the GENCODE annotation. Out of 1,215 tested in a subset of the ENCODE regions, 14 novel exon pairs were validated, only two of them in intergenic regions. CONCLUSION: In total, 487 loci, of which 434 are coding, have been annotated as part of the GENCODE reference set available from the UCSC browser. Comparison of GENCODE annotation with RefSeq and ENSEMBL show only 40% of GENCODE exons are contained within the two sets, which is a reflection of the high number of alternative splice forms with unique exons annotated. Over 50% of coding loci have been experimentally verified by 5' RACE for EGASP and the GENCODE collaboration is continuing to refine its annotation of 1% human genome with the aid of experimental validation.

Chromosome Mapping↗

PubMed2006

DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage.

Chromosome 17 is unusual among the human chromosomes in many respects. It is the largest human autosome with orthology to only a single mouse chromosome, mapping entirely to the distal half of mouse chromosome 11. Chromosome 17 is rich in protein-coding genes, having the second highest gene density in the genome. It is also enriched in segmental duplications, ranking third in density among the autosomes. Here we report a finished sequence for human chromosome 17, as well as a structural comparison with the finished sequence for mouse chromosome 11, the first finished mouse chromosome. Comparison of the orthologous regions reveals striking differences. In contrast to the typical pattern seen in mammalian evolution, the human sequence has undergone extensive intrachromosomal rearrangement, whereas the mouse sequence has been remarkably stable. Moreover, although the human sequence has a high density of segmental duplication, the mouse sequence has a very low density. Notably, these segmental duplications correspond closely to the sites of structural rearrangement, demonstrating a link between duplication and rearrangement. Examination of the main classes of duplicated segments provides insight into the dynamics underlying expansion of chromosome-specific, low-copy repeats in the human genome.

Animals↗

PubMed2006

Genomic anatomy of the Tyrp1 (brown) deletion complex.

Chromosome deletions in the mouse have proven invaluable in the dissection of gene function. The brown deletion complex comprises >28 independent genome rearrangements, which have been used to identify several functional loci on chromosome 4 required for normal embryonic and postnatal development. We have constructed a 172-bacterial artificial chromosome contig that spans this 22-megabase (Mb) interval and have produced a contiguous, finished, and manually annotated sequence from these clones. The deletion complex is strikingly gene-poor, containing only 52 protein-coding genes (of which only 39 are supported by human homologues) and has several further notable genomic features, including several segments of >1 Mb, apparently devoid of a coding sequence. We have used sequence polymorphisms to finely map the deletion breakpoints and identify strong candidate genes for the known phenotypes that map to this region, including three lethal loci (l4Rn1, l4Rn2, and l4Rn3) and the fitness mutant brown-associated fitness (baf). We have also characterized misexpression of the basonuclin homologue, Bnc2, associated with the inversion-mediated coat color mutant white-based brown (B(w)). This study provides a molecular insight into the basis of several characterized mouse mutants, which will allow further dissection of this region by targeted or chemical mutagenesis.

Animals↗

PubMed2004

General condition biomarkers in relation to contaminant burden in European flounder (Platichthys flesus).

In respect to the differences found for vitellogenin (VTG) expression in male and immature flounder, general biological aspects and a set of chemical residues in the liver were compared between flounder from the Mersey and Dee estuaries (UK). Except for alpha-HCH, all pollutant chemicals analysed in flounder liver differed highly significantly between Mersey and Dee fish. Overall, the higher liver contaminant concentrations were found in VTG-induced Mersey flounder. The biomarkers studied were not found to indicate significant differences between Mersey and Dee fish. However, when all of the minor differences are taken into consideration, it appears that the slightly lower growth rates after age 2 in Mersey flounder, lower gonadosomatic index in both mature male and female animals, less precise seasonal patterns of condition factor (CF), hepatosomatic index and gonadosomatic index, and lower CF in immature Mersey fish may well be signs of a contaminant-affected Mersey population.

Age Factors↗

PubMed2003

Isolation and characterisation of two multidrug resistance associated protein genes from maize.

Two genes encoding ATP-binding cassette (ABC) transporters were isolated from the crop plant Zea mays (maize). The clones, designated ZmMRP1 and ZmMRP2, were highly homologous to members of the multidrug resistance associated protein (MRP) subfamily. Genomic Southern analysis and characterisation of bacterial artificial chromosome (BAC) clones demonstrated that both genes are present in two copies in maize, which are located in proximity to each other, suggesting the occurrence of duplication events. The full-length genomic and cDNA sequences of ZmMRP1 and 2 were obtained, permitting analysis of the intron/exon structures and protein domains. Intron positions and phasing were conserved between ZmMRP1 and 2 and their closest Arabidopsis homologues. Both clones contained two copies each of the membrane spanning domains and nucleotide-binding folds diagnostic of the ABC superfamily, and ZmMRP1 contained an additional N-terminal membrane-spanning domain (MSD0) that is typical of MRP transporters but which is lacking in the most closely related Arabidopsis and rice MRPs. In contrast, ZmMRP2 and its closest rice but not Arabidopsis homologues lacked MSD0, suggesting the repeated loss of this domain in MRP family evolution. ZmMRP1 and 2 were expressed in all tissues examined but displayed distinct expression profiles in response to herbicide safeners and pro-oxidants. ZmMRP1 was induced by aminotriazole and to a lesser extent by menadione, whereas ZmMRP2 was expressed at a lower constitutive level and did not exhibit strong induction by any of the compounds tested. The characterisation of these clones represents an important step in the experimental analysis of the MRP subfamily in a monocotyledonous crop plant.

Amino Acid Sequence↗