Measures of variation at DNA repeat loci under a general stepwise mutation model

Area of Science:

• Population Genetics
• Molecular Evolution
• Bioinformatics

Background:

• Polymorphisms in tandem repeat loci arise from mutations that can alter allele sizes by multiple repeat units.
• These mutational changes may occur with unequal probabilities (asymmetric), making simple models potentially inadequate.

Purpose of the Study:

• To evaluate the expectation and variance of within-population variance in allele size distribution and expected homozygosity.
• To develop a general stepwise mutation model accommodating arbitrary and asymmetric mutational transitions.

Main Methods:

• Coalescence approach applied to a general stepwise mutation model.
• Analysis of expectation and variance of within-population variance and expected homozygosity.
• Comparison with existing models for symmetric one-step, two-step, and multi-step geometric mutations.

Main Results:

• In finite populations at steady state, the expectation of within-population variance is proportional to N*nu (effective population size times mutation rate).
• The stochastic variance of allele sizes is a quadratic function of N*nu and does not decay with sample size.
• Analysis of CEPH pedigree data shows trends compatible with the theory, though second-order variance may be underestimated.

Conclusions:

• The general stepwise mutation model provides a more accurate framework for studying population dynamics at tandem repeat loci.
• Deviations in empirical data may suggest non-equilibrium population structures or sampling biases.
• The model's predictions offer a baseline for interpreting genetic variation at microsatellite loci.