Ethnically biased microsatellites contribute to differential gene expression and glutathione metabolism in Africans and Europeans

Abstract

Approximately three percent of the human genome is occupied by microsatellites: a type of short tandem repeat (STR). Microsatellites have well established effects on (a) the genetic structure of diverse human populations and (b) expression of nearby genes. These lines of inquiry have uncovered 3,984 ethnically biased microsatellite loci (EBML) and 28,375 expression STRs (eSTRs), respectively. We hypothesize that a combination of EBML, eSTRs, and gene expression data (RNA-seq) can be used to show that microsatellites contribute to differential gene expression and phenotype in human populations. In fact, our previous study demonstrated a degree of mutual overlap between EBML and eSTRs but fell short of quantifying effects on gene expression. The present work aims to narrow the gap. First, we identify 313 overlapping EBML/eSTRs and recapitulate their mutual overlap. The 313 EBML/eSTRs are then characterized across ethnicity and tissue type. We use RNA-seq data to pursue validation of 49 regions that affect whole blood gene expression; 32 out of 54 affected genes are differentially expressed in Africans and Europeans. We quantify the relative contribution of these 32 genes to differential expression; fold change tends to be less than other differentially expressed genes. Repeat length correlates with expression for 15 of the 32 genes; two are conspicuously involved in glutathione metabolism. Finally, we repurpose a mathematical model of glutathione metabolism to investigate how a single polymorphic microsatellite affects phenotype. We conclude with a testable prediction that microsatellite polymorphisms affect GPX7 expression and oxidative stress in Africans and Europeans.

Mutation and selection processes regulating short tandem repeats give rise to genetic and phenotypic diversity across species

“…Further, a genomic survey on STRs in human populations (Kinney et al, 2019 ) identified eSTRs whose frequencies significantly differ between ethnicities. The same group also found 15 eSTRs whose repeat length correlates with gene expression (Kinney et al, 2021 ).…”

webTWAS: a resource for disease candidate susceptibility genes identified by transcriptome-wide association study

“…Population information is mapped to the five super-populations (AFR, AMR, EAS, EUR and SAS) from the 1000 Genomes Project (1KGP) ( 39 ). The GTEx reference panel used by webTWAS consists mainly of individuals of European ancestry ( 40 , 41 ), and is not suitable for imputing GReX in non-European individuals due to variations in gene expression between different populations. We therefore only include GWAS statistics from the European super-population (EUR) in the current version of webTWAS.…”

Polymorphisms of the GCLC Gene Are Novel Genetic Markers for Susceptibility to Psoriasis Associated with Alcohol Abuse and Cigarette Smoking

“…Following this approach, nevertheless, it should be taken into account that SNPs might be characterized by weak or moderate phenotypic effects that cannot be reproduced in independent populations given their genetic heterogeneity in minor allele frequencies and linkage disequilibrium between the loci [ 85 , 86 ]. Importantly, some studies have recently reported genetic differences in glutathione metabolism between races or ethnicities [ 47 , 87 ].…”