Work is ongoing in the following three areas:
Disorders of genomic imprinting in humans
Genetics of recessive diseases in consanguineous families
Molecular genetics of ketohexokinase.
We have focussed considerable effort on the PMS2 DNA repair gene, which is mutated in a recessive syndrome of brain and haematological malignancies of childhood. Numerous pseudogenes make mutation analysis of PMS2 very difficult. We have further found that gene conversion involving one of these pseudogenes generates a great deal of PMS2 polymorphic variation and may be a source of cryptic genetic pathology.
We have a longstanding interest in disorders of genomic imprinting in humans. We have characterised the genetic defect in a series of families with recurrent hydatidiform mole, a disorder of imprinting in the developing oocyte. We have also defined the molecular basis for tissue-specific imprinting of the ZAC tumour suppressor gene.
Work into these and other recessive disorders has prompted the development of a new tool, AutoSNPa, that facilitates the analysis of large amounts of SNP data, allowing the rapid identification of autozygous segments.
We have collaborated with Simon Phillips’ group (Astbury Centre) in structural studies of the human ketohexokinase enzyme, and developed targetted alleles of the mouse gene to dissect the physiological roles of its alternative splice variants.
Carr IM, Flintoff KJ, Taylor GR, Markham AF, Bonthron DT. Interactive visual analysis of SNP data for rapid autozygosity mapping in consanguineous families. Hum Mutat 27:1041-6 (2006).
Hayward BE, De Vos M, Valleley EM, Charlton RS, Taylor GR, Sheridan E, Bonthron DT. Extensive gene conversion at the PMS2 DNA mismatch repair locus. Hum Mutat 28:424-30 (2007).
Valleley EM, Cordery SF, Bonthron DT. Tissue-specific imprinting of the ZAC/PLAGL1 tumour suppressor gene results from variable utilization of monoallelic and biallelic promoters. Hum Mol Genet 16(8):972-81 (2007).