Haplotype differences for copy number variants in the 22q11.23 region among human populations: a pigmentation-based model for selective pressure

Abstract

Two gene clusters are tightly linked in a narrow region of chromosome 22q11.23: the macrophage migration inhibitory factor (MIF) gene family and the glutathione S-transferase theta class. Within 120 kb in this region, two 30-kb deletions reach high frequencies in human populations. This gives rise to four haplotypic arrangements, which modulate the number of genes in both families. The variable patterns of linkage disequilibrium (LD) between these copy number variants (CNVs) in diverse human populations remain poorly understood. We analyzed 2469 individuals belonging to 27 human populations with different ethnic origins. Then we correlated the genetic variability of 22q11.23 CNVs with environmental variables. We confirmed an increasing strength of LD from Africa to Asia and to Europe. Further, we highlighted strongly significant correlations between the frequency of one of the haplotypes and pigmentation-related variables: skin color (R(2)=0.675, P<0.001), distance from the equator (R(2)=0.454, P<0.001), UVA radiation (R(2)=0.439, P<0.001), and UVB radiation (R(2)=0.313, P=0.002). The fact that all MIF-related genes are retained on this haplotype and the evidences gleaned from experimental systems seem to agree with the role of MIF-related genes in melanogenesis. As such, we propose a model that explains the geographic and ethnic distribution of 22q11.23 CNVs among human populations, assuming that MIF-related gene dosage could be associated with adaptation to low UV radiation.

Figure 1

Multidimensional scaling based on F_ST distances. African populations are represented by triangles, Americans by stars, Central Asians by diamonds, East Asians by squares, and Europeans by circles.

Figure 2

Correlation analyses between the frequency of haplotype A*1_B*1 and pigmentation-related variables. African populations are represented by triangles, Americans by stars, Central Asians by diamonds, East Asians by squares, and Europeans by circles. (a) Correlation between the frequency of A*1_B*1 and skin color classes as proposed by Biasutti. (b) Correlation between the frequency of A*1_B*1 and distance from the equator. (c, d) Correlations between the frequency of A*1_B*1 and UVA and UVB radiation classes, respectively, as defined by Jablonsky and Chaplin. AFE: African-Ecuadorians; BAM: BAmileke; ORO: Oromo; AMA: Amhara; COL: Colorados; CAY: Cayapas; KM: Kanthy&Mansi; CHK: Chukchee; ITA: Italians; PER: Perm Russians. For the definition of the others acronyms, see Material and Methods.

Figure 3

Alignment of the proteins encoded by the four members of the MIF gene family residing in 22q11.23. The alignment was obtained with BLAST using the following sequences: MIF: P14174 – human MIF; DDT: P30046 – human DOPD; DDTL: A6NHG4 – human DDTL; and LOC391322: 2013031826IQRD3TSY. The amino-acid sequence of LOC391322 (2013031826IQRD3TSY) was downloaded from the UCSC database. Asterisks represent sequence similarity, colons indicate conservation between groups of strongly similar properties, and periods highlighted conservation between groups of weakly similar properties.

Figure 4

Heatmap of expression analysis of MIF-related genes obtained from the Gene Expression Atlas database. In each cell, the number of studies is reported. Overexpression is represented by light grey, and the underexpression is represented by dark grey. Cells split with light and dark grey represent experimental conditions with conflicting data.