Abstract
Recent advances in the field of human molecular genetics have resulted in an exponential increase in the number of disease genes isolated and characterized. The identification of these disease genes has been the result of the development of specific strategies coupled with powerful and new technologies. Pivotal to these new technologies was the discovery and refinement of the polymerase chain reaction (PCR), and its application to linkage studies, mutation screening, and clone isolation. Mendelian Inheritance in Man lists all the known inherited human disorders and the defective genes associated with them, and to date there are 6000 traits listed (1) Most of the genes identified are those responsible for single-gene disorders. The more common and complex “disease-genes” to identify are those that act in combination to cause disease. These multigene diseases are called polygenic or multifactorial. In view of the advances made in the study of single-gene disorders, there is justifiable optimism that new methods in statistical analysis and laboratory methodologies will be developed to tackle this new challenge. An important stage in any cloning strategy is the generation of candidate clones. This stage is the end-point of one of four optional strategies:
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Positional cloning (PC), based on knowing nothing except subchromosomal location of the disease gene.
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Cloning based on an aspect of deduced or known function (CFK), dependent on the gene product being known or a functional assay being available.
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Cloning based on suggested animal homologues (CAH) or gene family similarities and independent of subchromosomal location.
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Cloning based on database searches (CDS) and known chromosomal location of the disease (“positional candidate”). The positional candidate approach, is becoming increasingly important as more human genes are being mapped to specific chromosomal locations.
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References
McKusick, V. A., Francomano, C. A., Antonorakis, S. E. (1992) Mendelian Inheritance in Man, The John Hopkins University Press, Baltimore.
HYP Consortium, Francis, F., Hennig, S., et al. (1995) A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. Nat. Genet. 11,130–136.
Rowe, P. S. N., Goulding, J. N., Francis, F., et al. (1996) The gene for X-linked hypophosphataemic rickets maps to a 200–300 kb region in Xp22.1, and is located on a single YAC containing a putative vitamin D response element (VDRE). Hum. Genet. 97, 345–352.
Rowe, P. S. (1997) The PEX gene, its role in X-linked rickets, osteomalacia, and bone mineral metabolism. Exp. Nephrol. 5, 355–363.
Rowe, P. S. N (1994) Molecular biology of hypophosphataemic rickets and oncogenic osteomalacia. Hum. Genet. 94 (5), 457–467.
Econs, M. J. and Francis, F. (1997) Positional cloning of the PEX gene, new insights into the pathophysiology of X-linked hypophosphatemic rickets. 1997 Am. J. Physiol. 273, F489 — F498.
Francis, F., Strom, T. M., Hennig, S., et al. (1997) Genomic organisation of the human PEX gene mutated in X-linked dominant hypophosphataemic rickets. Genet. Res. 7 (6), 573–585.
Rowe, P. S. N., Oudet, C., Francis, F., et al. (1997) Distribution of mutations in the PEX gene in families with X-linked hypophosphataemic rickets (HYP). Hum. Mol. Genet. 6, 539–549.
Anonymous (1994) Population variation of common cystic fibrosis mutations. The Cystic Fibrosis Genetic Analysis Consortium. Hum. Mutat. 4, 167–177.
Wagner, K., Greil, I., Schneditz, P., et al. (1994) A cystic fibrosis patient with delta F508, G542X and a deletion at the D7S8 locus. Hum. Mutat. 3, 327–329.
Anonymous (1996) To affinitychrw(133) and beyond! [editorial, comment]. Nat. Genet. 14, 367–370.
Keen, J., Lester, D., Inglehearn, C., et al. (1991) Rapid detection of single base mismatches as heteroduplexes on hydrolink gels. Trends Genet. 7, 5.
Sheffield, V. C., Beck, J. S., Kwitek, A. S., et al. 1993 The sensitivity of single-strand conformation polymorphism analysis for the detection of single base substitutions. Genomics 16, 325–332.
Beck, L., Soumounou, Y., Martel, J., et al. (1997) Pex/PEX tissue distribution and evidence for a deletion in the 3’ region of the Pex gene in X–linked hypophosphatemic mice. J. Clin. Invest. 99, 1200–1209.
Du, L., Desbarats, M., Viel, J., et al. (1996) cDNA cloning of the murine PEX gene implicated in X-linked hypophosphataemia and evidence for expression in bone. Genomics 36, 22–28.
Guo, R. and Quarles, L. D. (1997) Cloning and sequencing of human PEX from a bone cDNA library, evidence for its developmental stage–specific regulation in osteoblasts (In Process Citation). J. Bone Miner. Res. 12, 1009–1017.
Sarkar, G., Yoon, H. S., and Sommer, S. S. (1992) Dideoxy fingerprinting (ddE), a rapid and efficient screen for the presence of mutations. Genomics 13, 441–443.
Youil, R., Kemper, B. W., and Cotton, R. G. (1995) Screening for mutations by enzyme mismatch cleavage with T4 endonuclease VII. Proc. Natl. Acad. Sci. USA 92, 87–91.
Youil, R., Kemper, B., and Cotton, R. G. (1996) Detection of 81 of 81 known mouse beta-globin promoter mutations with T4 endonuclease VII—the EMC method. Genomics 32, 431–435.
Babon, J. J., Youil, R., and Cotton, R. G. (1995) Improved strategy for mutation detection—a modification to the enzyme mismatch cleavage method. Nucleic Acids Res. 23, 5082–5084.
Myers, R. M., Larin, Z., and Maniatis, T. (1985) Detection of single base substitutions by ribonuclease cleavage at mismatches in RNA,DNA duplexes. Science 230, 1242–1246.
Cariello, N. F. and Skopek, T. R. (1993) Mutational analysis using denaturing gradient gel electrophoresis and PCR. Mutat. Res. 288, 103–112.
van der Luijt, R., Khan, P. M., Vasen, H., et al. (1994) Rapid detection of translation-terminating mutations at the adenomatous polyposis coli (APC) gene by direct protein truncation test. Genomics 20, 1–4.
Fu, Y. H., Kuhl, D. P., Pizzuti, A., et al. (1991) Variation of the CGG repeat at the fragile X site results in genetic instability, resolution of the Sherman paradox. Cell 67, 1047–1058.
Schalling, M., Hudson, T. J., Buetow, K. H., et al. (1993) Direct detection of novel expanded trinucleotide repeats in the human genome. Nat. Genet. 4, 135–139.
Fodor, S. P., Rava, R. P., Huang, X. C., et al. (1993) Multiplexed biochemical assays with biological chips. Nature 364, 555–556.
Lipshutz, R. J., Morris, D., Chee, M., et al. (1995) Using oligonucleotide probe arrays to access genetic diversity.BioTechniques 19 442–447
Hacia, J. G., Brody, L. C., Chee, M. S., et al. (1996) Detection of heterozygous mutations in BRCA1 using high density oligonucleotide arrays and two—colour fluorescence analysis. Nat. Genet. 14, 441–447.
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Rowe, P.S.N. (2000). Finding Mutations in Disease Genes. In: Econs, M.J. (eds) The Genetics of Osteoporosis and Metabolic Bone Disease. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-033-9_22
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DOI: https://doi.org/10.1007/978-1-59259-033-9_22
Publisher Name: Humana Press, Totowa, NJ
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