Epistasis and the genetics of disease resistance (360G-Wellcome-096063_Z_11_Z)

£250,000

I have shown that two epistatic interactions (a cancellation of malaria protection when alpha thalassaemia and sickle cell are coinherited, and an alleviation of blood disorder when alpha and beta thalassaeamia are coinherited) could explain aspects of the distribution of the malaria protective haemoglobinopathies: particularly the rarity of sickle cell in the Mediterranean region (Penman et al, 2010). The goals of the first part of this proposal are to (i) use mathematical models to determine w hether epistasis could account for the east/West divide between sickle cell and HbE; (ii) analyse a detailed population genetic dataset from Kenya to look for new epistatic interactions between malaria protective genes, and (iii) conduct in vitro studies to determine whether erythrocytes carrying both alpha and beta thalassaemia offer malaria protection. Two crucial sets of human immune system genes: the HLAs and the KIRs display striking genomic organisation. For the second part of this p roposal, my goal is to investigate whether epistatic interactions could help maintain HLA and KIR haplotypes. I will build mathematical models that capture the interplay between HLA loci, KIR loci and pathogen selection, and test the models predictions against HLA and KIR sequence data in online databases.

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Grant Details

Amount Awarded 250000
Applicant Surname Penman
Approval Committee Sir Henry Wellcome Postdoctoral Fellowships Interview Committee
Award Date 2011-05-23T00:00:00+00:00
Financial Year 2010/11
Grant Programme: Title Sir Henry Wellcome Postdoctoral Fellowship
Internal ID 096063/Z/11/Z
Lead Applicant Dr Bridget Penman
Partnership Value 250000
Planned Dates: End Date 2016-01-31T00:00:00+00:00
Planned Dates: Start Date 2011-08-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region South East
Sponsor(s) Prof Paul Harvey