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Paucimorphic alleles versus polymorphic alleles and rare mutations in disease causation: Theory, observation and detection

Paucimorphic alleles versus polymorphic alleles and rare mutations in disease causation: Theory, observation and detection
Paucimorphic alleles versus polymorphic alleles and rare mutations in disease causation: Theory, observation and detection
Definitions of polymorphism in a gene include occurrence of a rarer allele of at least 1% frequency; or occurrence of the commonest allele at less than 95% frequency. Many alleles of single nucleotide polymorphisms (SNPs) in genes occur at much higher frequency (up to 50%). Many common diseases have a substantial genetic component. The prevailing hypothesis for the molecular basis of common diseases is that it involves the combinatoric action of common polymorphic alleles of minor effect (common disease / common variant, CD / CV hypothesis). The ready development of genome-wide databases of high frequency SNPs is enabling the testing of this hypothesis. A contrasting approach has been the study of very highly selected cases and families by linkage and mutation detection techniques to identify rare mutations of large effect on a gene, often private to a single family (rare disease / rare variant, RD / RV hypothesis. These approaches have formed the mainstay of disease gene discovery, the latter having been feasible for a decade, the former just now becoming feasible. However, an intermediate possibility exists. Sequence changes at an intermediate frequency (herewith, “paucimorphisms”, arbitrarily 0.0005<q<0.05) may exist and may have a moderate effect. A number of different loci may predispose to the same disease, although only one paucimorphic allele of one particular gene will be found in any one individual. Exploring the “paucimorphisms hypothesis” will require mutation detection applied both at the level of large numbers of relatively unselected cases and at the population level. In this review we consider the foundations of this hypothesis, relevant available technologies and possible future approaches to systematically explore this hypothesis.
paucimorphic aleles, polymorphic alleles, rarer allele, single nucleotide polymorphisms
1389-2029
431-438
Day, I.N.M.
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Alharbi, K.K.
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Smith, M.
558e1c6b-5c57-444a-9508-509c50128f91
Aldahmesh, M.A.
92d5a487-a2ee-46d9-9630-499ab0cb17d2
Chen, X.H.
fe7ddffb-99db-4473-8d70-c9ecc07f2b16
Lotery, A.J.
5ecc2d2d-d0b4-468f-ad2c-df7156f8e514
Pante-De-Sousa, G.
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Hou, G.W.
6d1b5709-9d53-43cd-b6b5-7e96d440606f
Ye, S.
73027825-861c-4bca-8ce6-67a325fa2d2c
Eccles, D.
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Cross, N.C.P.
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Fox, K.R.
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Rodriguez, S.
b047a823-28c8-4043-8d4f-dc6b23f52e4e
Day, I.N.M.
1a55713e-ee42-4f9c-9867-955202528f17
Alharbi, K.K.
8a762c78-c1df-4708-b6b6-ca4e52a76f53
Smith, M.
558e1c6b-5c57-444a-9508-509c50128f91
Aldahmesh, M.A.
92d5a487-a2ee-46d9-9630-499ab0cb17d2
Chen, X.H.
fe7ddffb-99db-4473-8d70-c9ecc07f2b16
Lotery, A.J.
5ecc2d2d-d0b4-468f-ad2c-df7156f8e514
Pante-De-Sousa, G.
fc2d2c5a-7050-48de-8ced-3e9d307e332a
Hou, G.W.
6d1b5709-9d53-43cd-b6b5-7e96d440606f
Ye, S.
73027825-861c-4bca-8ce6-67a325fa2d2c
Eccles, D.
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23
Cross, N.C.P.
f87650da-b908-4a34-b31b-d62c5f186fe4
Fox, K.R.
9da5debc-4e45-473e-ab8c-550d1104659f
Rodriguez, S.
b047a823-28c8-4043-8d4f-dc6b23f52e4e

Day, I.N.M., Alharbi, K.K., Smith, M., Aldahmesh, M.A., Chen, X.H., Lotery, A.J., Pante-De-Sousa, G., Hou, G.W., Ye, S., Eccles, D., Cross, N.C.P., Fox, K.R. and Rodriguez, S. (2004) Paucimorphic alleles versus polymorphic alleles and rare mutations in disease causation: Theory, observation and detection. Current Genomics, 5 (5), 431-438.

Record type: Article

Abstract

Definitions of polymorphism in a gene include occurrence of a rarer allele of at least 1% frequency; or occurrence of the commonest allele at less than 95% frequency. Many alleles of single nucleotide polymorphisms (SNPs) in genes occur at much higher frequency (up to 50%). Many common diseases have a substantial genetic component. The prevailing hypothesis for the molecular basis of common diseases is that it involves the combinatoric action of common polymorphic alleles of minor effect (common disease / common variant, CD / CV hypothesis). The ready development of genome-wide databases of high frequency SNPs is enabling the testing of this hypothesis. A contrasting approach has been the study of very highly selected cases and families by linkage and mutation detection techniques to identify rare mutations of large effect on a gene, often private to a single family (rare disease / rare variant, RD / RV hypothesis. These approaches have formed the mainstay of disease gene discovery, the latter having been feasible for a decade, the former just now becoming feasible. However, an intermediate possibility exists. Sequence changes at an intermediate frequency (herewith, “paucimorphisms”, arbitrarily 0.0005<q<0.05) may exist and may have a moderate effect. A number of different loci may predispose to the same disease, although only one paucimorphic allele of one particular gene will be found in any one individual. Exploring the “paucimorphisms hypothesis” will require mutation detection applied both at the level of large numbers of relatively unselected cases and at the population level. In this review we consider the foundations of this hypothesis, relevant available technologies and possible future approaches to systematically explore this hypothesis.

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More information

Published date: 1 July 2004
Keywords: paucimorphic aleles, polymorphic alleles, rarer allele, single nucleotide polymorphisms

Identifiers

Local EPrints ID: 56821
URI: http://eprints.soton.ac.uk/id/eprint/56821
ISSN: 1389-2029
PURE UUID: 699047f1-2b0d-44be-940f-47115ca594f1
ORCID for A.J. Lotery: ORCID iD orcid.org/0000-0001-5541-4305
ORCID for D. Eccles: ORCID iD orcid.org/0000-0002-9935-3169
ORCID for N.C.P. Cross: ORCID iD orcid.org/0000-0001-5481-2555
ORCID for K.R. Fox: ORCID iD orcid.org/0000-0002-2925-7315

Catalogue record

Date deposited: 06 Aug 2008
Last modified: 19 Feb 2021 02:32

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Contributors

Author: I.N.M. Day
Author: K.K. Alharbi
Author: M. Smith
Author: M.A. Aldahmesh
Author: X.H. Chen
Author: A.J. Lotery ORCID iD
Author: G. Pante-De-Sousa
Author: G.W. Hou
Author: S. Ye
Author: D. Eccles ORCID iD
Author: N.C.P. Cross ORCID iD
Author: K.R. Fox ORCID iD
Author: S. Rodriguez

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