Genet. Res., Camb. (2000), 76, pp. 199–214. Printed in the United Kingdom # 2000 Cambridge University Press 199 Abstracts of papers presented at the tenth Mammalian Genetics and Deelopment Workshop (Incorporating the Promega Young Geneticists’ Meeting) held at the Institute of Child Health, Uniersity College London on 17–19Noember 1999 " # Edited by: ANDREW J. COPP AND ELIZABETH M. C. FISHER 1Institute of Child Health, Uniersity College London, 30 Guilford Street, London WC1N 1EH, UK # Neurogenetics Unit, Imperial College School of Medicine, St Mary’s Hospital, Norfolk Place, London W2 1PG, UK Sponsored by: The Genetical Society, Promega (UK) Ltd and B&K Universal Group Ltd Evidence for imprinting in type 2 diabetes: detection of Identification of a locus for primary ciliary dyskinesia parent-of-origin effects at the insulin gene on chromosome 19 " " " STEWART HUXTABLE, PHILIP SAKER, LEMA S. L. SPIDEN , M. MEEKS , A. J. WALNE ,H. # # HADDAD, ANDREW HATTERSLEY, MARK BLAU , H. MUSSAFFI-GEORGY ,H. $ % % WALKER and MARK McCARTHY SIMPSON , M. EL FEHAID , M. CHEEBAB ,M. % % Section of Endocrinology, Imperial College School of AL-DABBAGH , H. D. HAMMUM ,R.M. " " Medicine, St Mary’s Hospital, London, UK GARDINER , E. M. K. CHUNG and H. M. " MITCHISON " Variation at the insulin gene (INS) VNTR is impli- Department of Paediatrics, Royal Free and Uniersity cated in type 1 diabetes, polycystic ovarian syndrome College Medical School, Uniersity College London, # and birthweight. Case-control studies inconsistently UK; Schneider Children’s Medical Center of Israel, $ show class III VNTR association with type 2 diabetes, Petech Tika, Israel; School of Medical Sciences, but may result from population stratification. We Uniersity Sains Malaysia, Kelantan, Malaysia; % applied family-based association methods to 155 Riyadh Al Kharj Hospital Programme, Saudi Arabia parent–offspring trios, ascertained via a Europid proband with type 2 diabetes. VNTR class was Primary ciliary dyskinesia (PCD) is an autosomal inferred from the –23HphI SNP which is in tight recessive disorder with an incidence of 1:20000 linkage disequilibrium in Caucasians. Of 119 het- characterized by sinusitis, recurrent pulmonary in- erozygous parents, 65 transmitted class III and 54 fection, bronchiectasis and subfertility. Approxi- class I (P l 0n16). In 62 maternal transmissions, there mately 50% of patients also have laterality defects, was no deviation from expectation (26 vs 36, P l most commonly situs inversus (Kartegener syndrome). 0n21). Fathers, in contrast, displayed excess class III Patients have reduced or absent cilia motility, and a transmission (39 vs 18, P l 0n003). This parent-of- wide range of abnormalities in the ultrastructure of origin difference was clearly attributable to imprinting the cilia are associated with this phenotype. Six (P l 0n001, parent-of-origin LRT). The FokI SNP 3h families of Arabic origin were ascertained with a to INS distinguishes two class III haplotypes (VPH, ciliary ultrastructural defect of absent outer dynein PH) in type 1 diabetes. Only the VPH haplotype arms. The resource in total contains 37 individuals showed excess transmission to diabetic offspring (P l with 13 affected children, 4 of whom also have situs 0n02), suggesting a complete reversal of type 1 diabetes inversus. In five families the parents were first cousins, susceptibility haplotypes in type 2 diabetes. Using so a genome-wide linkage search was undertaken family-based association methods, we have demon- using homozygosity mapping. A region of excess strated that variation within the INS region influences homozygosity spanning 13 cM was identified on type 2 diabetes susceptibility. This effect is mediated chromosome 19q13.4-qter, below marker D19S418. exclusively by paternally derived VNTR alleles, Haplotype analysis is consistent with linkage in four implicating imprinted genes (e.g. IGF2) in the patho- of the families. GENEHUNTER analysis gives a genesis of type 2 diabetes. maximum multipoint lod score of 4n73 with an alpha of 0n7. This is the first definitive report of linkage for a PCD locus and work is under way to refine the critical region in order to identify potential candidate genes. Downloaded from https://www.cambridge.org/core. IP address: 170.106.40.219, on 01 Oct 2021 at 17:52:26, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0016672300004675 Abstracts of papers 200 The molecular evolution of blood coagulation Minisatellite mutation and meiotic crossing over are independent in mice COLIN DAVIDSON, EDWARD D. G. " " # TUDDENHAM and JOHN H. McVEY RUTH BARBER , YURI E. DUBROVA , , MARK $ " Haemostasis Research Group, MRC Clinical Science PLUMB and ALEC J. JEFFREYS " Centre, Imperial College School of Medicine, Department of Genetics, Uniersity of Leicester, # Hammersmith Hospital, Du Cane Road, London Leicester LE1 7RH, UK; N.I. Vailo Institute of W12 0NN, UK General Genetics, Russian Academy of Sciences, $ Moscow B-333, Russia; Medical Research Council Vertebrate blood coagulation is a delicately balanced Radiation and Genome Stability Unit, Harwell, Oxon process whose central feature is the conversion of OX11 0RD, UK fibrinogen to fibrin by the protease thrombin. The plasma coagulation factors, factor VII (FVII), factor The ability of minisatellite loci to reflect radiation- IX (FIX), factor X (FX), and prothrombin (PT) are induced structural damage in DNA makes them a zymogens of serine proteases. They are each activated useful marker for radiation exposure. However, the by limited proteolysis of one or two peptide bonds. To application of minisatellites as an indicator of en- be physiologically effective FXa and FIXa require vironmental exposure is currently limited as the assembly into complexes on phospholipid surfaces mechanisms of mutation induction at minisatellite with non-enzymatic cofactors factor Va (FVa) and loci remain unknown. A possible explanation for the factor VIIIa (FVIIIa). The modular nature of the elevated minisatellite mutation rate after exposure to enzymes and cofactors indicates that the proteins ionizing radiation is that this is a reflection of a evolved by domain duplication and exon shuffling and genome-wide increase in meiotic crossing over. To the organization and structure of the genes suggest investigate whether this hypothesis is correct, we have that vertebrate haemostasis evolved as a result of gene simultaneously analysed the frequency of minisatellite duplication events. When did these gene duplication mutation rate and crossover frequency in the offspring events occur? Do lower vertebrates have a subset of of male mice exposed either to 1 Gy of acute X-rays or blood coagulation factors? To investigate these to the anticancer drug cisplatin. The results of our questions the FVII, FX and FIX gene duplication study show that cisplatin has no effect on either events were examined in chicken, the pufferfish Fugu minisatellite mutations or crossover frequencies dur- rubripes, and lamprey Lampretra fluiatilis by database ing the most important stages of mouse sperma- mining, degenerate PCR cloning and genomic library togenesis. In contrast, whilst crossover frequencies are screening. Using this approach a genomic cosmid unaffected, both pre-meiotic and meiotic exposure to clone containing the chicken FVII and FX genes was ionizing radiation results in a dramatic increase in isolated and characterized. The chicken FVII and FX minisatellite mutation rates. The uncoupling of genes were contained on one cosmid separated by induced minisatellite instability and crossover fre- " 3n0 kb as found in mouse and man. The proximal quency as demonstrated in the radiation study suggest promoters of the human FX and FVII have been that meiotic crossing over and minisatellite mutation characterized, including the 3 kb intergenic region. in exposed mice are entirely independent processes. The tight linkage of FVII and FX genes was This may reflect the repair of double-strand DNA investigated for a functional role in coordinated gene breaks prior to meiosis, as such damage would need to regulation by comparative approach between the be present during meiotic division for an increase in chicken and human intergenic regions in an attempt legitimate crossover frequency to occur. to identify novel transcription factor binding sites. Partial cDNA clones of FVII, FX and FIX have been isolated from chicken, pufferfish and lamprey liver RNA. The occurrence of coagulation factors VII, X Genomic organization of the GART-SON-3SG locus; and IX in Agnatha (jawless vertebrates) supports the three genes in close proximity on chromosome 21 hypothesis that extensive genome duplication took place early in vertebrate evolution (2R hypothesis). It S. L. WYNN, R. A. FISHER, Q. LIU, D. WELLS, appears the coagulation cascade evolved during the C. PAGEL, I. M. KHAN, P. ZAMMITT and L. " 50 million years between the divergence of proto- BULUWELA chordates and the appearance of Agnatha and Gene Targeting Unit, Department of Neuromuscular indicates a flurry of gene duplication and exon Diseases, Imperial College School of Medicine, St shuffling during this relatively brief evolutionary Dunstan’s Road, London W6 8RP, UK period. The SON gene encodes a novel regulatory protein on human chromosome 21 within the Down syndrome Downloaded from https://www.cambridge.org/core. IP address: 170.106.40.219, on 01 Oct 2021 at 17:52:26, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0016672300004675 Abstracts of papers 201 Critical Region. We have investigated the organization homozygous mice within 24 hours of birth. To map of the SON locus in both mouse and human genomes. and subsequently clone the Loa gene, a large The mouse Son gene spans a region of approximately intraspecific backcross between the mutant mouse and 35 kb. The coding region is more than 8 kb in length the inbred strain C57BL\6 was set up. Affected N1 and has been completely sequenced. The gene is mice were backcrossed to C57BL\6 to generate over organized into 11 coding exons and 1 non-coding 1000 affected N2 animals.