mCNVs: YET TO BE DISCOVERED
Several hundreds of human genomic traits (and maybe even more) show CNVs (Copy Number Variations) within a very large range of alleles. Such CNVs are also called multi-allelic CNVs (mCNVs).
Non-Allelic Homologous Recombination (NAHR)
mCNVs can evolve with mechanism of non-allelic homologous recombination (NAHR) at a much higher mutational rate than SNPs (Single Nucletoide Polymorphisms). Because of NAHR events, mCNVs may show a particularly complex structure, which cannot be explained by simple deletions/duplications events alone. mCNVs are currently poorly understood and, at several loci, their alleles haven’t been fully characterized. This is mainly due to technical difficulties, like, for instance, the ones encountered in detecting and defining multiplications of more than 4 copies.
For example, in the highly variable region of 8p23.1 (short arm of the chromosome 8), a cluster of at least three genes (DEFB4, DEFB103 and DEFB104) is found within a DNA segment of 240 Kb which can be highly polymorphic in its copy number. Most individuals of the general population show from 2 to 7 copies, but up to 12 copies have been observed in healthy individuals (up to 8 copies can lie just on one chromosome). Another hypervariable site is on chromosome 17q21.31. A 1.5 Mb inversion and at least 9 other forms of structural variations have been found in this region, where genes may have several different number of copies and different locations.
Attempts to find mCNVs
In the aim to identify the most common CNVs with an extension of 5Kb or more, Handsaker et al (2015) have analyzed 849 human genomes from 14 different populations. They have identified 1356 mCNVs. Of these, 121 showed 4 or more copies and 45 showed 5 copies or more. Human mCNVs may be more than what expected thus far and, although being a minority of all CNVs, they represent the 88% of the variation in genic dosage among individuals.
For references go to the main page of this chapter: