Fig 1.
Types of CNVs in the different datasets.
(A) CNVs can overlap entire genes or fractions of genes. CNVs overlapping with exons of a gene (exonic CNVs) and CNVs found within introns (intronic CNVs). (B-D) Number of whole gene, exonic and intronic CNV events, showing the different proportions of CNV gains, losses and gain and loss CNVs.
Fig 2.
Changes in intron and gene size.
(A) Proportion of the reference intron that has been observed as deleted in any of the studies. (B) Proportion of the whole intronic content of a gene that has been observed as deleted. (C) Change in gene length by intronic deletions. (D) Example of gene with a substantial change in gene size with a single intronic deletion. (E) Number of different gene sizes observed in the population as a function on the number of intronic deletions detected. Genes names of the seven most extreme cases are indicated.
Fig 3.
Evolutionary age of affected genes.
Ratios of observed versus expected number of genes from each gene evolutionary age that contain deletions overlapping with exons, including partial and whole gene CNVs (A) or intronic deletions (B). Expected values were calculated with 10,000 random permutations using a global background model. Red asterisks mark the significantly enriched groups of genes. Significance: * for P<0.05, ** for P<0.005 and *** for P<0.0005. Plot (C) shows, from all the genes overlapping with deletions after aggregating the three maps, what is the proportion of genes that have all or part of their exons affected by deletions and what is the percentage of genes with intronic deletions only. The equivalent figure for each separate map is shown in S8 Fig. (D) Percentage of highly stratified variants (HSV, maximum Vst > 0.2) in each age group and by type of overlap with the gene. The absolute number of deletions is indicated above each bar.
Fig 4.
(A-E) Five types of DEL-eQTLs analysed. Thunder symbols indicate deletion breakpoints. (F) DEL-eQTL results for the five types. Number of eGenes, eTranscripts and genes with eTranscripts when comparing expression levels of individuals with a reference allele and an allele with a specific deletion versus individuals with two reference alleles. P-values obtained after performing Student’s t-tests were FDR-corrected (FDR = 5%). The number of expected eGenes, eTranscripts or genes with eTranscripts was calculated after randomizations of the individuals carrying or not the deletion, and P-values were calculated by comparing the observed versus the 10000 random values. Significance: * for P<0.05, ** for P<0.005 and *** for P<0.0005. (G) Examples of intronic deletions in a gene associated to expression changes of another gene that interacts in 3D. Black boxes represent exons and the light blue box the PCHiC fragment in contact with the differentially expressed gene. The position of the deletion is marked with dashed red lines. Gene expression of the eGenes is represented using PEER-RPKM values.
Fig 5.
Impact of CNVs on genes and their evolution.
(A) Percentage of genes of each group of evolutionary ages that is associated to an eCNV, for each type of eCNV. (B) RVIS percentile of the eGenes, by type of eCNV. Genes with the lowest percentile are among the most intolerant of human genes. (C) Evolutionarily ancient and young genes accumulate different kinds of structural variants. While young genes are enriched in coding deletions (which alter gene dosage or disrupt the protein, sometimes affecting gene expression), ancient genes have highly conserved coding sequence but an enrichment of deletions within their introns. As we have shown, these changes in introns can be associated with changes in gene expression, showing that although the protein is highly conserved, the expression of it can change from an individual to another due to changes in regulation.