T21-specific variants: Expression level of Chromosome 21 genes is lower than expected. (A) Potential transcriptome signature of T21-specific selection: T21 fetuses with decreased expression level of Chromosome 21 genes are expected to have an advantage during embryogenesis. (B) Less than 1.5-fold increase in the expression level of highly constrained Chromosome 21 genes. Relative increase in the expression level of 233 Chromosome 21 genes in their trisomic (3N) state does not significantly differ from 1.5. However, for a subset of 23 highly functionally constrained genes, the increase in the expression level is lower than the expected 1.5. (*) P-value < 0.05. (C) A scheme defining loss of expression (LOE) and gain of expression (GOE) cis-eQTLs (upper) and our extrapolation of the effects of cis-eQTLs to the triploid case (dark gray box plots on lower panel). (D) Regulatory variants can compensate the overexpression of Chromosome 21 genes. The dotted line represents our expectation if the excess/deficit of genotypes is independent of the direction of expression changes (GOE or LOE). However, in the T21 live-born cohort, we observed an excess of homozygotes for the loss of expression derived alleles (LOE DDD) and a deficit of homozygotes for the gain of expression derived alleles (GOE DDD). (*) P-value < 0.05.