Epidemiology, evolutionary origin, and malaria-induced positive selection effects of G6PD-deficient alleles in Chinese populations

Abstract

Background: Although glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common inherited disorder in the Chinese population, there is scarce evidence regarding the epidemiology, evolutionary origin, and malaria-induced positive selection effects of G6PD-deficient alleles in various Chinese ethnic populations.

Methods: We performed a large population-based screening (n = 15,690) to examine the impact of selection on human nucleotide diversity and to infer the evolutionary history of the most common deficiency alleles in Chinese populations.

Results: The frequencies of G6PD deficiency ranged from 0% to 11.6% in 12 Chinese ethnic populations. A frequency map based on geographic information showed that G6PD deficiency was highly correlated with historical malaria prevalence in China and was affected by altitude and latitude. The five most frequently occurring G6PD gene variants were NM_001042351.3:c.1376G>T, NM_001042351.3:c.1388G>A, NM_001042351.3:c.95A>G, NM_001042351.3:c.1311T>C, and NM_001042351.3:c.1024C>T, which were distributed with ethnic features. A pathogenic but rarely reported variant site (NM_001042351.3:c.448G>A) was identified in this study. Bioinformatic analysis revealed a strong and recent positive selection targeting the NM_001042351.3:c.1376G>T allele that originated in the past 3125 to 3750 years and another selection targeting the NM_001042351.3:c.1388G>A allele that originated in the past 5000 to 6000 years. Additionally, both alleles originated from a single ancestor.

Conclusion: These results indicate that malaria has had a major impact on the Chinese genome since the introduction of rice agriculture.

Keywords: Chinese population; evolutionary origin; glucose-6-phosphate dehydrogenase (G6PD); malaria; natural selection.

FIGURE 1

Epidemiology of G6PD deficiency, spatial distribution of historical malaria, and relationship with geographical coordinates in China. (a) The frequency and mutation spectrum of G6PD deficiency in 12 Chinese populations in the current study and the relationship with the spatial distribution of historical malaria endemicity in China. Different colors on the map of China represent the different epidemic degrees of malaria. Different colors on each pie represent the different SNPs of G6PD; (b) shows the relationship between the occurrence frequency of G6PD deficiency and latitude, longitude, and altitude

FIGURE 2

LD structure constructed from 33 marker‐inferred haplotypes in the Zhuang population. (a) The red, orange, and blue rectangles indicate the positions of the G6PD Canton allele (rs72554664), G6PD Kaiping allele (rs72554665) and G6PD Gaohe allele (rs137852340) alleles, respectively. The value in the square is the |D′| between the pair of loci. Darker red squares indicate higher values of |D′| with statistical significance (LOD >2). Blue squares indicate high values of |D′| but with no statistically significant LD. White squares indicate low values of |D′| and LOD simultaneously. The black triangle indicates the LD block based on the four gamete rule method; (b) Pairwise |D′| between the G6PD Canton allele (rs72554664) and 32 other Tag SNPs; (C) Pairwise |D′| between the G6PD Kaiping allele (rs72554665) and 32 other Tag SNPs; (d) Pairwise |D′| between the G6PD Gaohe allele (rs137852340) and 32 other Tag SNPs

FIGURE 3

Results of evolutionary analysis. (a) REHH plot of the core region covering the G6PD Canton (rs72554664) and G6PD Kaiping (rs72554665) in the Zhuang population. The values are plotted against the genetic distance from the selected core region. The plot of core haplotype containing G6PD Canton or G6PD Kaiping is indicated by the solid purple line and solid green line, respectively. (b) Phylogenetic network of haplotypes of one Tag SNP (rs1050757), G6PD Canton and Kaiping. (c) Evaluation of the ages of the G6PD Canton by linear regression of ‐ln(EHH) and 2r. The X‐axis represents the 2 × r, where r is the genetic distance between the core and a given marker; the Y‐axis represents the –lnEHH of that marker. We could obtain the vector of (r, EHH) for each marker and make a plot. Each diamond corresponds to an SNP. (d) Evaluation of the ages of the G6PD Kaiping by linear regression of ‐ln(EHH) and 2r. The X‐axis represents the 2 × r, where r is the genetic distance between the core and a given marker; the Y‐axis represents the –lnEHH of that marker. We could obtain the vector of (r, EHH) for each marker and make a plot. Each diamond corresponds to an SNP

FIGURE 4

Heatmap of G6PD‐deficient allele frequency distributions for Chinese and Southeast Asian populations. Blue indicates the lowest allele frequency, and red indicates the highest G6PD‐deficient allele frequency