Abstract
Differences in gene regulation have been suggested to play essential roles in the evolution of phenotypic changes. Although DNA changes in cis-regulatory elements affect only the regulation of its corresponding gene, variations in gene regulatory factors (trans) can have a broader effect, because the expression of many target genes might be affected. Aiming to better understand how natural selection may have shaped the diversity of gene regulatory factors in human, we assembled a catalog of all proteins involved in controlling gene expression. We found that at least five DNA-binding transcription factor classes are enriched among genes located in candidate regions for selection, suggesting that they might be relevant for understanding regulatory mechanisms involved in human local adaptation. The class of KRAB-ZNFs, zinc-finger (ZNF) genes with a Krüppel-associated box, stands out by first, having the most genes located on candidate regions for positive selection. Second, displaying most nonsynonymous single nucleotide polymorphisms (SNPs) with high genetic differentiation between populations within these regions. Third, having 27 KRAB-ZNF gene clusters with high extended haplotype homozygosity. Our further characterization of nonsynonymous SNPs in ZNF genes located within candidate regions for selection, suggests regulatory modifications that might influence the expression of target genes at population level. Our detailed investigation of three candidate regions revealed possible explanations for how SNPs may influence the prevalence of schizophrenia, eye development, and fertility in humans, among other phenotypes. The genetic variation we characterized here may be responsible for subtle to rough regulatory changes that could be important for understanding human adaptation.
Highlights
The molecular basis of phenotypic divergence between species and populations is still far from being fully understood
We evaluated if Gene regulatory factors (GRFs) are enriched among the top 5% of all human protein-coding genes for each one of the three statistical tests for detecting positive selection (CLR, XP-composite likelihood ratio (CLR), and XP-extended haplotype homozygosity (EHH)), and genetic differentiation (FST) in any of three human populations (CEU, Chinese in Bejing (CHB), and Yoruba in Ibadan (YRI))
About 53% of the GRFs located in candidate regions for selection for YRI seem to be population specific, the greater overlap detected between CEU and CHB suggests that genetic variation in the majority of the GRFs for CEU and CHB has resulted from evolutionary processes that followed the migration Out of Africa
Summary
The molecular basis of phenotypic divergence between species and populations is still far from being fully understood. Within short evolutionary time scales, changes in gene expression play crucial roles in the diversification of phenotypical traits (Bornberg-Bauer et al 2010; Nowick et al 2011; Albert and Kruglyak 2015). Gene regulatory factors (GRFs) include proteins that bind directly to DNA (Wingender et al 2015), cofactors that bind to transcription factors (TFs) bound to DNA, and histone modifying enzymes (Li et al 2015). Another type of regulatory molecules, noncoding RNAs, plays a role in gene regulation (Zhu et al 2013). Variations in the expression levels, timing, and tissue-specificity coupled with sequence and structural changes in GRFs are important components of the genotype–phenotype map (Emerson and Li 2010)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
