DUF1220 - Links With Disease and Evolutionary Adaptation

Links With Disease and Evolutionary Adaptation

An increasingly large number of disease-associated copy number variations (CNVs) have been reported in the 1q21.1 region and these CNVs either encompass or directly flank DUF1220 domain sequences. Two independent reports have linked reciprocal 1q21.1 deletions and duplications in this region with microcephaly and macrocephaly, respectively, raising the possibility that DUF1220 copy number may be involved in influencing human brain size. More recently, Dumas et al used targeted 1q21 array CGH to follow up on this possibility and implicated DUF1220 copy number loss in 1q21-associated microcephaly. Of all 1q21 sequences tested, DUF1220 sequences were the only ones to show consistent correlation between copy number and brain size in both disease (micro/macrocephaly) and non-disease populations. In addition, in primates there is a significant correlation of DUF1220 copy number with brain size as well as with brain cortical neuron number . For the above reasons and because DUF1220 sequences at 1q21.1 have undergone a dramatic and evolutionarily rapid increase in copy number in humans, a model has been developed that proposes that 1) increasing DUF1220 domain dosage is the primary driving force behind the evolutionary expansion of the primate (and human) brain, 2) the instability of the 1q21.1 region has facilitated the rapid increase in DUF1220 copy number in humans, and 3) the evolutionary advantage of rapidly increasing DUF1220 copy number in the human genome has resulted in favoring retention of the high genomic instability of the 1q21.1 region, which, in turn, has precipitated a spectrum of recurrent human brain and developmental disorders. From this perspective, the large number of disease-associated 1q21.1 CNVs may be the price the human species paid, and continues to pay, for the adaptive benefit of having large numbers of DUF1220 copies in its genome.

These observations suggest that the 1q21.1 genome instability problems DUF1220 sequences are thought to promote may be one of the triggers of 1q21.1 duplication syndrome and 1q21.1 deletion syndrome.