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EASTBIO Haplotype evaluation of key regions of the ovine genome involved in variation in response to infection and vaccination using long read single molecule sequencing technologies

  • Full or part time

    Dr K Ballingall
  • Application Deadline
    Sunday, January 05, 2020
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Royal (Dick) School of Veterinary Studies / The Roslin Institute

Immunologically significant regions of the ovine genome including the major histocompatibility complex (MHC), leukocyte receptor complex (LRC) and the natural killer cell receptor complex (NKC) remain poorly characterised. Each of these genomic regions include multiple genes that are important in regulating the nature and specificity of innate and adaptive arms of the immune system (1). The MHC, LRC and NKC are some of the most gene dense regions of the vertebrate genome. They are structurally complex, due to rapid changes in haplotype structure, gene duplication, exon shuffling and present extreme levels of allelic diversity at many loci. Current theory suggests that the maintenance of high levels of haplotype diversity are maintained within populations by positive selection driven by rapidly evolving pathogen diversity (2). As such in the latest ovine genome assemblies of these regions are poorly assembled and annotated and despite their importance they are poorly covered in the latest high density SNP chips. Attempts at sequencing these regions have used heterozygous animals and short read sequencing technologies with poor resolution. Therefore, high quality reference sequence of these regions of the ovine genome derived from a single haplotype is required to allow targeted comparative analysis and to support studies of immune variation in livestock populations.

Previous European funding has supported construction of a BAC library using DNA from an MHC homozygous Scottish Blackface sheep, purpose bred through sire daughter mating. Many of the classical and non-classical MHC class I and II gene transcripts have been identified from this haplotype and have formed reference sequences for allelic nomenclature within the IPD-MHC database (3). The BAC library held at MRI is arrayed across 390, 384 well plates. The student will generate DNA pools providing resource templates to be screened using primers covering targeted loci across the MHC, LRC and NKC haplotypes. In collaboration with the Roslin Institute, selected BAC clones will be sequenced using a combination of short read and the latest long read single molecule sequencing technologies. Training will be provided in molecular genetics and bioinformatics associated with next generation sequence data analysis through the MRI, Rosin Institutes and University of Edinburgh networks which will enable the student to generate high quality reference sequences of ovine MHC, LRC and NKC haplotypes. Comparative analyses of haplotypes and selected gene clusters such as the MHC class I or MHC class II with orthologous regions from other haplotypes and species will provide information on intra and inter species haplotype diversity and its functional significance in relation to variations in immune responses to infection and vaccination in livestock populations.

Eligibility:
All candidates should have or expect to have a minimum of an appropriate upper 2nd class degree. To qualify for full funding students must be UK or EU citizens who have been resident in the UK for 3 years prior to commencement.

Funding Notes

Applications:
Completed application form along with your supporting documents should be sent to our PGR student team at

References:
Please send the reference request form to two referees. Completed forms for University of Edinburgh, Royal (Dick) School of Veterinary Studies and the Roslin Institute project should be returned to by the closing date: 5th January 2020.

It is your responsibility to ensure that references are provided by the specified deadline.
Download application and reference forms via:
View Website

References

1. Parham P, Guethlein LA (2018) Genetics of Natural Killer Cells in Human Health, Disease, and Survival. Annual Review of Immunology 36:519-548
2. Spurgin LG, Richardson DS (2010) How pathogens drive genetic diversity: MHC, mechanisms and misunderstandings. Proc R Soc London B Biol Sci 277:979-988
3. Ballingall KT et al. (2019) Allelic nomenclature for the duplicated MHC class II DQ genes in sheep (2019). Immunogenetics, 71:347-351

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