Evidence for Positive Selection on a Number of MicroRNA Regulatory Interactions during Recent Human Evolution

MicroRNA (miRNA)–mediated gene regulation is of critical functional importance in animals and is thought to be largely constrained during evolution. However, little is known regarding evolutionary changes of the miRNA network and their role in human evolution. Here we show that a number of miRNA binding sites display high levels of population differentiation in humans and thus are likely targets of local adaptation. In a subset we demonstrate that allelic differences modulate miRNA regulation in mammalian cells, including an interaction between miR-155 and TYRP1, an important melanosomal enzyme associated with human pigmentary differences. We identify alternate alleles of TYRP1 that induce or disrupt miR-155 regulation and demonstrate that these alleles are selected with different modes among human populations, causing a strong negative correlation between the frequency of miR-155 regulation of TYRP1 in human populations and their latitude of residence. We propose that local adaptation of microRNA regulation acts as a rheostat to optimize TYRP1 expression in response to differential UV radiation. Our findings illustrate the evolutionary plasticity of the microRNA regulatory network in recent human evolution

rs683 modulates endogenous <i>TYRP1</i> targeting by miR-155 in SK-MEL-19 cells.

<p>(A) Genotyping the rs683 locus in SK-MEL-19 cells. The region around rs683 was amplified from SK-MEL-19 genomic DNA and sequenced. Sequence traces (shown) revealed rs683 heterozygosity at the <i>TYRP1</i> locus, as indicated. (B) Ectopic miR-155 expression reduces <i>TYRP1</i> protein levels. <i>TYRP1</i> levels in the skin-derived melanoma cell line, SK-Mel-19 were analyzed by performing immunoblotting on cell lysates from miR-CTL transfected or cells transfected with increasing amounts of miR-155 as indicated. Densitometric quantitation of <i>TYRP1</i> levels is indicated as protein levels relative to the mock transfectants. (C) miR-155 reduces <i>TYRP1</i> mRNA levels in SK-Mel19. SK-MEL19 cells were mock transfected or transfected with the indicated miR-CTL or miR-155. mRNA was extracted and <i>TYRP1</i> levels assessed by qPCR. Results are plotted relative to miR-CTL-treated cells. Bars are the mean ± standard deviation of triplicate experiments. The differences in expression between miR-155 transfected cells and either mock or miR-CTL are statistically significant (P<0.01, Students <i>t</i> test). (D) Targeting of the derived allele by miR-155. SK-Mel-19 cells were transfected with increasing amounts of miR-155 as indicated. mRNA was then extracted and expression of the ancestral (blue) versus the derived allele (red) assessed by allele-specific TaqMan SNP qPCR. Results are plotted as the expression level of each <i>TYRP1</i> allele relative to controls (log2 transformed). Note that the transcripts carrying the derived allele were suppressed by miR-155 greater that 2-fold, whereas transcripts carrying the ancestral allele were only modestly affected.</p

The 17‐gene stemness score associates with relapse risk and long‐term outcomes following allogeneic haematopoietic cell transplantation in acute myeloid leukaemia

Abstract A 17‐gene stemness (LSC17) score determines risk in acute myeloid leukaemia patients treated with standard chemotherapy regimens. The present study further analysed the impact of the LSC17 score at diagnosis on outcomes following allogeneic haematopoietic cell transplantation (HCT). Out of 452 patients with available LSC17 score, 123 patients received allogeneic HCT. Transplant outcomes, including overall (OS), leukaemia‐free survival (LFS), relapse incidence (RI) and non‐relapse mortality (NRM), were compared according to the LSC17 scored group. The patients with a low LSC17 score had higher OS (56.2%) and LFS (54.4%) at 2 years compared to patients with high LSC17 score (47.2%, p = 0.0237 for OS and 46.0%, p = 0.0181 for LFS). The low LSC17 score group also had a lower relapse rate at 2 years (12.7%) compared to 25.3% in the high LSC17 score group (p = 0.017), but no difference in NRM (p = 0.674). Worse outcomes in the high LSC17 score group for OS, LFS and relapse were consistently observed across all stratified sub‐groups. The use of more intensive conditioning did not improve outcomes for either group. In contrast, chronic graft‐versus‐host‐disease was associated with more favourable outcomes in both groups. The 17‐gene stemness score is highly prognostic for survival and relapse risk following allogeneic HCT