On the allelic spectrum of human disease

doi:10.1016/S0168-9525(01)02410-6

Trends in Genetics

Volume 17, Issue 9, 1 September 2001, Pages 502-510

https://doi.org/10.1016/S0168-9525(01)02410-6 Get rights and content

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.

Section snippets

A simple model

We outline a simple model for making predictions about disease allele diversity.

A tale of two loci

Consider two hypothetical monogenic disorders with the same underlying mutation rate, but different overall frequency of disease alleles in the population: a rare disease with f₀ = 0.001 and a common disease with a much larger f₀ = 0.2. As noted above, the frequency of the disease class, f₀, is determined by the balance between mutation and selection. In our example, the mutation rates will be assumed to be equal at μ = 3.2 × 10⁻⁶ per generation. Hence, the frequency difference must reflect

Implications for disease mapping

The success of an association study to identify a disease-susceptibility locus depends on the detection of an increased frequency of specific disease alleles in affected individuals. This requires that the locus have a relatively simple allelic spectrum: that is, a few predominant alleles. The analysis above shows that these conditions should hold – and thus association studies should be feasible – for loci at which the total frequency f of disease alleles is above some threshold.

The threshold

Two caveats

Our simple model predicts that for disease loci with large f₀ and typical values of μ, modern allelic spectra should be simple because of a slow decay of the ancestral disease class. We now introduce two caveats due to oversimplifications of the model. The first is a mechanism that could yield a more diverse spectrum than expected. The second is an additional mechanism by which a simpler spectrum could arise.

Real diseases

How well do these insights explain the data for various monogenic disorders?

Discussion

The simple theory above aims to predict the allelic spectrum in the human population for a class of selectively equivalent alleles at a single locus, as a function of the overall frequency f₀ of the class 14, 15, 28. At equilibrium, the allelic variation should be almost independent of f₀. However, the human population is far from equilibrium, as it has been growing dramatically during the past 100 000 years. The consequences of this growth, in terms of genetic diversity, will require millions

Acknowledgements

We thank Haninah Levine for assistance with computer simulations, and Edward Byrne and Kirk Lohmueller for help in researching Table 1. We thank David Altshuler, Michele Cargill, David Goldstein and Joel Hirschhorn for comments and discussions.

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Trends in Genetics

OpinionOn the allelic spectrum of human disease

Abstract

Section snippets

A simple model

A tale of two loci

Implications for disease mapping

Two caveats

Real diseases

Discussion

Acknowledgements

Blood

Theor. Popul. Biol.

Blood Rev.

Am. J. Hum. Genet.

J. Lipid Res.

Blood Cells Mol. Dis.

Blood

Blood

Geographic distribution and regional origin of 272 cystic fibrosis mutations in European populations

Hum. Mut.

Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2

Nat. Genet.

Common BRCA1 variants and susceptibility to breast and ovarian cancer in the general population

Hum. Mol. Genet.

The new genomics: global views of biology

Science

Characterization of single-nucleotide polymorphisms in coding regions of human genes

Nat. Genet.

Population genetics – making sense out of sequence

Nat. Genet.

Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families

Science

Mutation in blood coagulation factor V associated with resistance to activated protein C

Nature

The common PPARγPro12Ala polymorphism is associated with decreased risk of type 2 diabetes

Nat. Genet.

The future of genetic studies of complex human diseases

Science

Allelic multiplicity in simple Mendelian disorders

Am. J. Hum. Genet.

A stability property of the Ewens sampling formula

J. Appl. Prob.

Allelic disequilibrium and allele frequency distribution as a function of social and demographic history

Am. J. Hum. Genet.

Population growth of human Y chromosomes: A study of Y chromosome microsatellites

Mol. Biol. Evol.

Genetic evidence for a Paleolithic human population expansion in Africa

Proc. Natl. Acad. Sci. U. S. A.

Population growth makes waves in the distribution of pairwise genetic differences

Mol. Biol. Evol.

Ionizing radiation and genetic risks IX. Estimates of the frequencies of mendelian diseases and spontaneous mutation rates in human populations: a 1998 perspective

Mut. Res.

Linkage disequilibrium in the human genome

Nature

Opinion
On the allelic spectrum of human disease