On the allelic spectrum of human disease

Reich, David E; Lander, Eric S

doi:10.1016/s0168-9525(01)02410-6

Cited by 1,185Genetic Associations and EpidemiologyGenomics and Rare DiseasesEvolution and Genetic Dynamics

On the allelic spectrum of human disease

Reich, David E, Lander, Eric S·2001·Trends in Genetics

DOI 10.1016/s0168-9525(01)02410-6

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Abstract

Human disease genes show enormous variation in their allelic spectra; that is, in the number and population frequency of the disease-predisposing alleles at the loci. For some genes, there are a few predominant disease alleles. For others, there is a wide range of disease alleles, each relatively rare. The allelic spectrum is important: disease genes with only a few deleterious alleles can be more readily identified and are more amenable to clinical testing. Here, we weave together strands from the human mutation and population genetics literature to provide a framework for understanding and predicting the allelic spectra of disease genes. The theory does a reasonable job for diseases where the genetic etiology is well understood. It also has bearing on the Common Disease/Common Variants (CD/CV) hypothesis, predicting that at loci where the total frequency of disease alleles is not too small, disease loci will have relatively simple spectra.

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The existence of disease-promoting variants reflects a balance between mutation creating new susceptibility variants and selection preventing them from drifting into the population.
“The existence of disease-promoting variants reflects the balance between mutation creating new susceptibility variants, and selection preventing them from drifting into the population2,28.”
From Rare and common variants: twenty arguments (2012) · cites this paper as [2]
The common disease-common variant hypothesis has been refuted by the missing heritability problem.
“When GWAS began the field was dominated by the simple common disease-common variant (CD-CV) hypothesis1–4 has been refuted in light of the so-called ‘missing heritability problem’”
From Rare and common variants: twenty arguments (2012) · cites this paper as [2]
All diseases have significant heritability, and purifying selection has been unable to purge the population of disease-promoting variants.
“the consistent observation is that all diseases have significant heritability, and hence purifying selection has been unable to purge the population of disease-promoting variants2.”
From Rare and common variants: twenty arguments (2012) · cites this paper as [2]
Mildly deleterious alleles can rise to moderate frequency, particularly in populations that have undergone recent expansion.
“Mildly deleterious alleles can rise to moderate frequency, particularly in populations that have undergone recent expansion (34).”
From Genetic Mapping in Human Disease (2008) · cites this paper as [34]

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Authors: Reich, D. E., & Lander, E. S.
Affiliations: Massachusetts Institute of Technology (US)
Corresponding author: Reich, David E
Lander, Eric S
ORCID: Reich, David E
Lander, Eric S
Venue: Trends in Genetics
Publisher: Elsevier BV
Published: 2001-09
Volume: 17
Issue: 9
Pages: 502-510
ISSN: 0168-9525 (ISSN-L)
DOI: 10.1016/s0168-9525(01)02410-6
OpenAlex: W2110343195
Cited by: 1,185
References: 57
Citations by year: 2026: 4 · 2025: 11 · 2024: 11 · 2023: 21 · 2022: 14 · 2021: 19 · 2020: 22 · 2019: 40 · 2018: 29 · 2017: 34 · 2016: 52 · 2015: 38 · 2014: 51 · 2013: 73 · 2012: 79
FWCI: 5.20
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Trends in Genetics (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
Keywords: disease susceptibility, allele frequency, human mutations, population genetics, genetic etiology, clinical genetic testing, disease gene identification
MeSH terms: Alleles, Chromosome Mapping, Gene Frequency, Genes, Recessive, Humans, Genetic Linkage, Models, Genetic, Mutation, Predictive Value of Tests, Selection, Genetic, Genetic Variation, X Chromosome, Genetic Predisposition to Disease

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