Genome-wide deserts for copy number variation in vertebrates

Takashi Makino et al., Genome-wide deserts for copy number variation in vertebrates, Nature Communications 2013, doi:10.1038/ncomms3283

Most copy number variations are neutral, but some are deleterious and associated with various human diseases. Copy number variations are distributed non-randomly in vertebrate genomes, and it was recently reported that ohnologs, which are duplicated genes derived from whole genome duplication, are refractory to copy number variations.

Here we show that non-ohnologs neighboring ohnologs are unlikely to have copy number variations, resulting in ohnolog-rich regions in vertebrate genomes being copy number variation deserts. Our results suggest that the genomic location of ohnologs is a determining factor in the retention of copy number variations and that the dosage-balaced ohnologs are likely to cause the deleterious effect of copy number variations in these regions.

CNSs are not randomly distributed in eukaryotic genome, in particular they tend to be located copse to telomeres and centromeres.

Whole genome duplication (WGD) occurred early in the vertebrate lineage. Duplicated genes derived from WGD (ohnologs) are refractory to CNVs and small-scale duplication (SSD), probably due to dosage balance constraints.

Changes in the relative amounts of dosage-balanced genes (DBGs) is deleterious, and the expectation is that duplication of these genes will not be tolerated except when the duplication is itself balanced. WGD duplicates all genes simultaneously and therefore does not perturb relative dosages.

We find non-ohnologs neighboring ohnologs are unlikely to display CNVs, and observe CNV deserts in ohnolog-righ regions (ORRs). Similarly probable dosage-sensitive singletons that are unduplicated in all vertebrate lineages also repress CNVs of their immediate neighbours.

About 40% (8,240/20,907) of human genes (4,321 ohnologs and 3,919 non-ohnologs) were in ORRs.

The dosage-sensitive singletons within ORRs are likely to be genes that returned to single-copy status from ohnologs after WGD. These results indicate that non-ohnologs within ORRs may also be dosage-sensitive genes. Previously reported candidate genes for diseases associated with pathogenic CNVs are frequently ohnologs.

Olfactory receptors are important for detecting signals from the environment. Detecting thousands of different chemicals in the environment is essential for many organisms, and about 4% of vertebrate genes encode proteins related to smell.


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