How does a new mutation spread through a population?

In human reproduction, the child receives one copy of each gene from the mother (in the egg), and another copy from the father (in the sperm). Each chromosome in each egg or sperm is created by recombining genes from the grandparents. For example, genes A, B, and C in the egg might come from the materal grandmother, while genes D, E, and F might come from the maternal grandfather. Genes that are found close together on the chromosome tend to be inherited together. Thus, a new mutation arising in a population tends to be linked with neighboring genes for many generations. This phenomenon is called linkage disequilibrium.

Based on linkage disequilibrium, we show that the 1226G Gaucher disease mutation probably originated less than 1000 generations ago. Its recent origin and high current allele frequency provide strong evidence for heterozygote selection.

Heterozygote advantage

Furthermore, we show that the linkage disequilibrium between a mutation and a nearby marker can serve as a molecular clock for the age of the mutation, but only after accounting for some of the clock's peculiar properties. For example, this "clock" can easily get stuck at zero in small populations or closely linked genes due to random loss of recombinant chromosomes. This paper's analysis of the variations in the clock speed allows us to better interpret linkage data.

An interesting corollary of this analysis is that markers extremely close to a locus of interest may stay more tightly linked to it than the expected exponential decay of linkage disequilibrium with distance. This phenomenon has been observed with markers near the ΔF508 mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

CFTR linkage disequilibrium

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Paper - © 2000 by Academic Press. Publisher's note: "This material has been published in Blood Cells, Molecules, and Diseases, August 2000, 26(4): 348-59, the only definitive repository of the content that has been certified and accepted after peer review. Copyright and all rights therein are retained by Academic Press"

Boas, F. Edward. (2000) "Linkage to Gaucher Mutations in the Ashkenazi Population: Effect of Drift on Decay of Linkage Disequilibrium and Evidence for Heterozygote Selection." Blood Cells, Molecules, and Diseases. 26(4): 348-59.

The two most common Gaucher disease mutations in the Ashkenazi population, 1226A→G and 84G→GG in the glucocerebrosidase gene, are tightly linked to a marker in the nearby pyruvate kinase gene. This paper develops a simulation of the Ashkenazi population that considers the effects of selection and drift on the mutant allele frequency and the recombinant haplotype frequency over time. Although the fraction of mutants that are linked to the original marker decays exponentially on average, this expected value is not very likely to occur. Instead, due to random loss of the recombinant haplotype, a mutation has a significant probability of retaining complete linkage disequilibrium long after its origin, so there may be large errors in estimating the age of a mutation based on linkage data. The simulations show that the 1226G mutation probably originated between 40 and 1000 generations ago (1000 to 25,000 years ago), and the 84GG mutation probably originated between 50 and 4800 generations ago (1300 to 120,000 years ago). The recent origin of the 1226G mutation and its high current allele frequency provide strong evidence for heterozygote selection. New techniques and results developed in this paper have general applicability towards analyzing linkage disequilibrium near other mutations. For example, they potentially explain the unexpected pattern of linkage disequilibrium seen around the ΔF508 mutation of the cystic fibrosis transmembrane conductance regulator gene.
Key words: Gaucher disease, linkage disequilibrium, heterozygote advantage, genetic drift, Ashkenazi, computer simulation

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