Mixed model-based eQTL analysis reveals lncRNAs associated with regulation of genes involved in sex determination and spermatogenesis: The key to understanding human gender imbalance

Abstract

Background: An imbalance in the prenatal sex ratio in humans may be due to several factors affecting sperm physiology, including genetic features. In this study, we conducted a transcriptome-wide analysis of expression quantitative trait loci (eQTLs) to identify target genes associated with previously described QTLs associated with gender imbalance. Methods: A mixed model explaining polygenic effects by genomic covariance among individuals was used to identify the eQTLs using gene expression and genotype data from 462 European/African individuals. Results: Eight eGenes were associated with four QTLs (P < 4.00 x 10-5), with strong associations found (P < 4.00 x 10-8) between rs2485007 and eGenes ANKRD26P3 (P = 3.40 x 10-9) and LINC00421 (P = 1.35 x 109). ANKRD26P3 and LINC00421 are both lncRNAs associated with the control of testis-dominant genes PELP1, TAF15, NANOG, TEX14, TCF3, ZNF433, ZNF555, TEX37, FATE1, TCP11, and CYLC2 and Y-linked genes SRY and ZFY, as well as several genes with roles in spermatogenesis (ODF1, SPATC1, SPATA3, SPATA31E1, SPERT, SPATA16, MOSPD1, SPATA24, and SPO11) and sex determination (SOX family genes). Conclusions: The above eGenes contribute directly or indirectly to gene regulation for sex determination and spermatogenesis, thereby serving as important functional clues for gender-biased selection.