Gene conversion and different population histories may explain the contrast between polymorphism and linkage disequilibrium levels

Abstract

To characterize linkage disequilibrium (LD) levels in human populations, we have analyzed 10 independent noncoding segments in three population samples from the major ethnic groups--that is, Africans, Asians, and Europeans. Descriptive statistics show that LD decays much faster in the African samples than in the non-African ones. With the assumption of an equilibrium model, we estimated the population crossing-over parameter (4N(e)r(bp), where N(e) is the effective population size and r(bp) is the crossing-over rate per generation between adjacent base pairs) in the presence of gene conversion. In the African sample, LD and polymorphism levels lead to similar estimates of effective population size, as expected under an equilibrium model. Conversely, in both non-African samples, LD levels suggest a smaller effective population size than that implied by polymorphism levels. This observation is paralleled by significant departures from an equilibrium model in the spectrum of allele frequencies of the non-African samples. Besides ruling out the possibility that non-African populations are at equilibrium, these results suggest different demographic history (temporal and spatial) of these groups. Interestingly, the African sample fits the expectations of an equilibrium model based on polymorphism and divergence levels and on frequency spectrum. For this sample, the estimated ratio of gene conversion to crossing-over rates is 7.3 for a mean tract length of 500 bp, suggesting that gene conversion may be more frequent than previously thought. These findings imply that disease-association studies will require a much denser map of polymorphic sites in African than in non-African populations.

Figure 1

Decay of pairwise linkage disequilibrium with distance. Symbols in red indicate r² values, and symbols in blue indicate |D′| values. The dots indicate the observed values for each pair of polymorphic sites. The solid triangles and circles indicate, respectively, the average values of |D′| and r² within and between 1-kb segments. The solid lines indicate the decay of LD expected under a model of crossing-over and gene conversion for L = 500 bp and f = 8. The dashed lines indicate the decay of LD expected under a model of crossing-over only. For each population sample, the expected LD decay was calculated based on the corresponding estimates of ρ from table 4.

Figure 2

Pairwise composite likelihood surface for the African sample. The heavy contour line indicates an approximate 95% confidence region based on simulations (see Material and Methods section). The other contour lines are at arbitrary intervals to depict the shape of the surface. The dot indicates the maximum at f=7.3 and r=.00089.