Physical mapping of the cystic fibrosis region by pulsed-field gel electrophoresis

Drumm, Mitchell L.; Smith, Cassandra L.; Dean, Michael; Cole, Jeffery L.; Iannuzzi, Michael C.; Collins, Francis S.

doi:10.1016/0888-7543(88)90024-9

Cited by 41 publications

(10 citation statements)

References 37 publications

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“…CF is a recessive disorder, caused by mutations in CFTR, a 230,000-base long gene on chromosome 7q31.2. Deletion of codon 508 (phenylalanine), first identified in 1988 [18], is found in 66% of the cases. However, there are more than 1000 other deleterious mutations, a great majority of which are very rare variants.…”

Section: Discussionmentioning

confidence: 99%

How Many Genetic Variants Remain to Be Discovered?

2009

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A great majority of genetic markers discovered in recent genome-wide association studies have small effect sizes, and they explain only a small fraction of the genetic contribution to the diseases. How many more variants can we expect to discover and what study sizes are needed? We derive the connection between the cumulative risk of the SNP variants to the latent genetic risk model and heritability of the disease. We determine the sample size required for case-control studies in order to achieve a certain expected number of discoveries in a collection of most significant SNPs. Assuming similar allele frequencies and effect sizes of the currently validated SNPs, complex phenotypes such as type-2 diabetes would need approximately 800 variants to explain its 40% heritability. Much smaller numbers of variants are needed if we assume rare-variants but higher penetrance models. We estimate that up to 50,000 cases and an equal number of controls are needed to discover 800 common low-penetrant variants among the top 5000 SNPs. Under common and rare low-penetrance models, the very large studies required to discover the numerous variants are probably at the limit of practical feasibility. Under rare-variant with medium- to high-penetrance models (odds-ratios between 1.6 and 4.0), studies comparable in size to many existing studies are adequate provided the genotyping technology can interrogate more and rarer variants.

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Section: Discussionmentioning

confidence: 99%

How Many Genetic Variants Remain to Be Discovered?

2009

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“…Several long-range restriction maps of human genomic regions have been constructed using PFGE methods. These include maps of up to 10 Mb at the Duchenne Muscular Dystrophy locus (18)(19)(20), about 3 Mb at the HLA complex (21 ,22), two recent maps in the CF region covenng 3-5 Mb (23,24), and shorter regions at other loci (25)(26)(27)(28). Using seven of the markers mentioned above and eight restriction endonucleases that cut human DNA infrequently, we have used PFGE techniques to construct a restriction map spanning over 12 Mb of DNA at the CF locus.…”

Section: Introductionmentioning

confidence: 99%

A 12 megabase restriction map at the cystic fibrosis locus

Fulton

Bowcock

Smith³

et al. 1989

Nucl Acids Res

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We have constructed a physical map of the chromosomal region containing the cystic fibrosis locus using seven DNA markers and pulsed-field gel electrophoresis methods. The map includes cleavage sites for 8 rare-cutting restriction enzymes and spans over 12 megabases (Mb) of DNA, with one unlinked probe covering an additional 5 Mb. To our knowledge, this is the largest segment of human DNA which has been restriction-mapped to date. We can identify thirteen putative HTF islands spaced at intervals of 0.3-3.2 Mb. The region between loci D7S8 and MET, where the CF gene lies, includes 1.4-1.9 Mb of DNA.

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“…The demonstration of linkage of the CF mutation to protein and DNA markers in 1985 led to the assignment of the CF locus to chromosome 7@1 [21,42,58,60,61]. The Met oncogene locus and the anonymous DNA marker J3.11, which are about 1500 kilobases apart, were identified as the probable borders of the CF gene-containing region [2,20,49].…”

Section: Cf: the Gene And Its Genetic Markersmentioning

confidence: 99%

The cystic fibrosis defect approached from different angles — new perspectives on the gene, the chloride channel, diagnosis and therapy

et al. 1990

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Abstract. The search for the basic defect in cystic fibrosis (CF) has reached a decisive stage since the recent identification of the responsible gene. Electrophysiological and biochemical research had defined the CF defect as a dysregulation of epithelial chloride channels. The putative protein product of the now identified gene shares properties with other known transport proteins, but it is not necessarily itself a chloride channel protein. Elucidation of the primary cellular defect will certainly have important aetiological and hopefully therapeutic implications. The identification of the major gene mutation already has significant consequences for genetic counselling and prenatal diagnosis. Heterozygote detection at the population level awaits identification of the probably heterogenous mutations on about 30% of the CF chromosomes. At present, about 50% of CF patients are homozygous for the recently identified major CF mutation.

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Physical mapping of the cystic fibrosis region by pulsed-field gel electrophoresis

Cited by 41 publications

References 37 publications

How Many Genetic Variants Remain to Be Discovered?

How Many Genetic Variants Remain to Be Discovered?

A 12 megabase restriction map at the cystic fibrosis locus

The cystic fibrosis defect approached from different angles — new perspectives on the gene, the chloride channel, diagnosis and therapy

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