DUF1220 Dosage Is Linearly Associated with Increasing Severity of the Three Primary Symptoms of Autism

Abstract

One of the three most frequently documented copy number variations associated with autism spectrum disorder (ASD) is a 1q21.1 duplication that encompasses sequences encoding DUF1220 protein domains, the dosage of which we previously implicated in increased human brain size. Further, individuals with ASD frequently display accelerated brain growth and a larger brain size that is also associated with increased symptom severity. Given these findings, we investigated the relationship between DUF1220 copy number and ASD severity, and here show that in individuals with ASD (n = 170), the copy number (dosage) of DUF1220 subtype CON1 is highly variable, ranging from 56 to 88 copies following a Gaussian distribution. More remarkably, in individuals with ASD CON1 copy number is also linearly associated, in a dose-response manner, with increased severity of each of the three primary symptoms of ASD: social deficits (p = 0.021), communicative impairments (p = 0.030), and repetitive behaviors (p = 0.047). These data indicate that DUF1220 protein domain (CON1) dosage has an ASD-wide effect and, as such, is likely to be a key component of a major pathway underlying ASD severity. Finally, these findings, by implicating the dosage of a previously unexamined, copy number polymorphic and brain evolution-related gene coding sequence in ASD severity, provide an important new direction for further research into the genetic factors underlying ASD.

Evolution of the Human Nervous System Function, Structure, and Development

“…Among other promising candidate genes under study in the context of evolutionary neuroscience are BOLA2 and DUF1220 repeats, which are both linked to autism spectrum disorder (Davis et al, 2014; Kumar et al, 2008). BOLA2 is contained in a modern-human-specific segmental duplication in a complex region of chromosome 16, showing 2–5 copies in almost all present-day humans analyzed (Prüfer et al, 2014; Sudmant et al, 2013; Nuttle et al, 2016), which is an instance of a quick fixation after a duplication event.…”

The case for DUF1220 domain dosage as a primary contributor to anthropoid brain expansion

“…The combination of not only how many neurons are made, but also how fast they are made, may therefore explain why greater than average brain growth in early postnatal years is associated with autism, and offers a potential explanation of why DUF1220 copy number increase can be associated with both macrocephaly (Dumas et al, 2012) and autism (Davis et al, 2014). …”

Human adaptation and evolution by segmental duplication

“…Interestingly, many of these cores are enriched in rapidly evolving human–great ape gene families [16–23]. Though the function of most of these gene families has not yet been determined, biochemical investigations into a few (e.g., TBC1D3 ) have suggested an association with cell proliferation [24]; others (e.g., DUF1220 or NBPF ) have been implicated in changes of brain size [21,25,26] while some (e.g., NPIP ) show remarkable signatures of positive selection [19]. At the periphery of these core-mediated duplication blocks lie most of the human-specific segmental duplications (HSDs) [27,28].…”