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The extent of linkage disequilibrium caused by selection on G6PD in humans.

ABSTRACT: The gene coding for glucose-6-phosphate dehydrogenase (G6PD) is subject to positive selection by malaria in some human populations. The G6PD A- allele, which is common in sub-Saharan Africa, is associated with deficient enzyme activity and protection from severe malaria. To delimit the impact of selection on patterns of linkage disequilibrium (LD) and nucleotide diversity, we resequenced 5.1 kb at G6PD and approximately 2-3 kb at each of eight loci in a 2.5-Mb region roughly centered on G6PD in a diverse sub-Saharan African panel of 51 unrelated men (including 20 G6PD A-, 11 G6PD A+, and 20 G6PD B chromosomes). The signature of selection is evident in the absence of genetic variation at G6PD and at three neighboring loci within 0.9 Mb from G6PD among all individuals bearing G6PD A- alleles. A genomic region of approximately 1.6 Mb around G6PD was characterized by long-range LD associated with the A- alleles. These patterns of nucleotide variability and LD suggest that G6PD A- is younger than previous age estimates and has increased in frequency in sub-Saharan Africa due to strong selection (0.1 < s < 0.2). These results also show that selection can lead to nonrandom associations among SNPs over great physical and genetic distances, even in African populations.

SUBMITTER: Saunders MA

PROVIDER: S-EPMC1456824 | biostudies-literature | 2005 Nov

REPOSITORIES: biostudies-literature

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The extent of linkage disequilibrium caused by selection on G6PD in humans.

Saunders Matthew A MA Slatkin Montgomery M Garner Chad C Hammer Michael F MF Nachman Michael W MW

Genetics 20050714 3

The gene coding for glucose-6-phosphate dehydrogenase (G6PD) is subject to positive selection by malaria in some human populations. The G6PD A- allele, which is common in sub-Saharan Africa, is associated with deficient enzyme activity and protection from severe malaria. To delimit the impact of selection on patterns of linkage disequilibrium (LD) and nucleotide diversity, we resequenced 5.1 kb at G6PD and approximately 2-3 kb at each of eight loci in a 2.5-Mb region roughly centered on G6PD in ...[more]

PMID: 16020776

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Project description:BackgroundPrevious studies on linkage disequilibrium have investigated second order linkage disequilibrium in animal and plant populations. The objective of this paper was to investigate the genome-wide levels of third order linkage disequilibrium in a composite line founded by admixture of four Iberian pig strains. A model for the generation of third order linkage disequilibrium by population admixture is proposed. A computer Expectation-Maximization algorithm is developed and applied to the estimation of third order linkage disequilibrium at inter- and intra-chromosomal level using 26,347 SNPs typed in 306 sows. The relationship of third order linkage disequilibrium with physical distance was investigated over 35 million triplets in SSC12. Basic and normalized estimates of inter and intra-chromosomal third order linkage disequilibrium are reported.ResultsGenome-wide analyses revealed that third order linkage disequilibrium is rather common among linked loci in this Iberian pig line. It is shown that population admixture of multiple populations may explain the observed levels of third order linkage disequilibrium although it could be generated by genetic drift. Third order linkage disequilibrium decreases rapidly up to 4 Mb and then declines slowly. The short distances between consecutive markers explain the maintenance of the observed third order linkage disequilibria levels when using a model incorporating the break-up of disequilibrium by recombination. Genome-wide testing also revealed that only 3.6% of the normalized estimates were different from 1, - 1, 0, or from a not well-defined situation in which there is only one possible value for the third order linkage disequilibrium parameter, given allele frequencies and pairwise linkage disequilibria parameters.ConclusionsThird order linkage disequilibrium is common among linked markers in the analyzed pig line and may have been generated by population admixture of multiple populations or by genetic drift. As with second order linkage disequilibrium, the absolute value of the third order linkage disequilibrium decreases with physical distance. Normalization of third order linkage disequilibrium should be avoided for closely linked bi-allelic loci.

Dataset Information

The extent of linkage disequilibrium caused by selection on G6PD in humans.

Publications

The extent of linkage disequilibrium caused by selection on G6PD in humans.

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