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The discovery that we all carry many small, apparently benign copy number variants in our genomes was a surprise to many people, and suggests that cells are less sensitive to gene dosage (i.e. the number of copies of a gene) than originally believed. Similarly, the old paradigm of simple dominant and recessive mutations – an all or nothing approach to genetics – has also been challenged by numerous discoveries of semi-dominant relationships and mutations associated with increased susceptibility to disease.

 

A simple question therefore remains: what proportion of genes in the human genome are dosage-sensitive? An approximate answer to this question is provided by the first dosage map of a human chromosome, which has been produced by looking for disease causing mutations and copy number variations across chromosome 18 [Cody JD et al. Genet Med (2009) 11: 778-82]. Researchers mined through online resources (such as OMIM and the Database of Genomic Variants) for evidence of disease resulting from a mutation, duplication or deletion in just one copy of chromosome 18. Two hundred fifty-three genes were evaluated and categorised as to whether they showed dosage sensitivity or not. Of these, five were found to be dosage sensitive (haploinsufficient, though one only in the presence of an additional factor), and 81 were found to be dosage insensitive (haplosufficient); no information was available to determine the dosage sensitivity of the remaining 167 genes. Although there is doubtless a continuum of dosage sensitivity, this work suggests that perhaps 5-10% of human genes are dosage sensitive to such an extent that changing the copy number noticeably affects the phenotype.

 

Comment: This map is the first stage towards producing a complete understanding of the dosage-dependence of the entire human genome. In addition to providing a fascinating insight into the regulation and activity of gene products at a quantitative, molecular level, it potentially has enormous utility for interpreting clinical results from high resolution diagnostic technologies such as DNA microarrays. Moreover, because the results have been integrated into an online genomic map, this work can be applied immediately by clinicians and genetic counsellors in caring for individuals with chromosome 18 abnormalities.