DUF1220 Domain Copy Number

DUF1220 is a 65 amino acid protein domain that has undergone a striking human specific copy number expansion, resulting in the addition of over 80 new copies of the domain in humans compared to chimps. DUF1220 copy number increases as a function of a species' evolutionary proximity to humans with a trend of 28 copies being added every million years. The greatest number of copies (>270) is found in human while mice and rats have only 1 copy. DUF1220 sequences have also undergone recent positive selection and, while widely expressed, show high levels of expression in the fetal brain (Diskin et al. 2009) and in neurons (Popesco et al. 2006). The DUF1220 copy number in creases in humans involved both domain amplification and gene duplication (NBPF family), with the great majority of copies mapping to the 1q21.1 region. 1q21.1 CNVs that either flank or encompass DUF1220 domains have been implicated in a large number of diseases including microcephaly and macrocephaly (Brunetti-Pierri et al. 2008; Mefford et al. 2008), autism (Autism Genome Project Consortium 2008), schizophrenia (ISC 2008), heart disease (Mefford et al. 2008) and neuroblastoma (Diskin et al. 2009; Vandepoele et al. 2005). A model has been proposed linking the rapid increase in DUF1220 copy number with  the high number of disease-related CNVs in the 1q21.1 region (Dumas and Sikela 2009). The fact that the deletions and duplications of DUF1220-containing (or flanking) 1q21.1 sequences have been implicated in microcephaly and macrocephaly, respectively (Brunetti-Pierri et al. 2008; Mefford et al. 2008) has been used to support the view that DUF1220 copy number may be directly related to human brain size both within the human species as well as across human, primate, and mammalian evolution (Dumas and Sikela 2009). More recent worked has confirmed that DUF1220 copy number is associated with brain size pathology in pediatric populations (Dumas et al 2012).