Frequency and complexity of de novo structural mutation in autism

Abstract

Genetic studies of autism spectrum disorder (ASD) have established that de novo duplications and deletions contribute to risk. However, ascertainment of structural variants (SVs) has been restricted by the coarse resolution of current approaches. By applying a custom pipeline for SV discovery, genotyping, and de novo assembly to genome sequencing of 235 subjects (71 affected individuals, 26 healthy siblings, and their parents), we compiled an atlas of 29,719 SV loci (5,213/genome), comprising 11 different classes. We found a high diversity of de novo mutations, the majority of which were undetectable by previous methods. In addition, we observed complex mutation clusters where combinations of de novo SVs, nucleotide substitutions, and indels occurred as a single event. We estimate a high rate of structural mutation in humans (20%) and propose that genetic risk for ASD is attributable to an elevated frequency of gene-disrupting de novo SVs, but not an elevated rate of genome rearrangement.

TIAM2S as a novel regulator for serotonin level enhances brain plasticity and locomotion behavior

“…Previously, a genome‐wide association study of human TIAM2 demonstrated that one single‐nucleotide polymorphism variant in the intron region (rs9384245; chr6 155201820 T→C) is associated with the risk of the development of attention deficit hyperactivity disorder, a prevalent neurodevelopmental disorder marked by an ongoing pattern of inattention and/or hyperactivity‐impulsivity symptoms. In addition, genomic structural variants of human TIAM2 at intron 1 (chr6 155438256) or intron 4 (chr6 155463366) with Alu mobile‐element insertions is associated with autism spectrum disorders, which are neurodevelopmental disorders with typical impairment in communication, aberrant social interaction, and restrictive patterns of behaviors. Furthermore, the expression profile of TIAM2 is the highest correlated with TSHZ3 (a zinc‐finger transcription factor), the dysfunction of which contributes to nervous system pathologies of autism spectrum disorders, in the developing neocortex .…”

Origins and long-term patterns of copy-number variation in rhesus macaques

“…We used published CNVs from a sample of 235 humans (Brandler et al 2016) to study the similarities and differences between primate species. We find that the proportions of segregating deletions and duplications are not significantly different between the two species ( Figure 1B; χ 2 = 3.77, d.f.…”

“…We took every effort to eliminate methodological bias between the macaque CNV calls and the human CNV data set. In their paper, Brandler et al (2016) use several different CNV calling and genotyping methods. We have restricted our comparisons to CNVs called with the same methods we employed for the macaque data, namely CNVs called with Lumpy (Layer et al 2014) and genotyped with SVtyper (Chiang et al 2015).…”

“…This is likely due to a combination of errors accruing from both ongoing spermatogenesis and unrepaired DNA damage. However, no such paternal age effect has been found among de novo deletions and duplications (also known as copy-number variants, or CNVs) in humans (MacArthur et al 2014;Kloosterman et al 2015;Brandler et al 2016;Girard et al 2016), though the origin of CNVs have been studied less often than single nucleotide mutations (Sebat et al 2007;Itsara et al 2010;Schrider et al 2013;MacArthur et al 2014;Kloosterman et al 2015;Brandler et al 2016;Girard et al 2016;Werling et al 2018).…”

“…Duplications in genic regions have been found to outnumber deletions in many lineages when comparing closely related species (Fortna et al 2004;Dumas et al 2007;Sudmant et al 2013), possibly indicating differential effects of natural selection on gene duplications versus deletions. However, recent wholegenome studies in humans point to a different pattern in non-genic regions, with deletions far outnumbering duplications (Brandler et al 2016). In order to determine whether such patterns are specific to humans, or are representative of the joint effects of mutational input and selection on the long-term survival of duplications and deletions, we require fine-scale studies in additional species.…”