Although mutations — the fundamental process by which genomic variation is acquired — are necessary to the evolution and success of a species, they are also the origin of all genetic disease. Hence, defining the mechanisms that control their occurrence is crucial to our basic understanding of genome biology, disease mechanisms and, ultimately, evolution.
Reciprocal copy number variation (CNV), or duplication or deletion, of the 16p11.2 region of chromosome 16 causes a multi-system genomic disorder. While there has been a concerted research effort to characterize the clinical symptoms of this disorder, we still do not understand the mechanisms driving many of the phenotypes observed. Michael Talkowski and his colleagues aim to investigate the tissue-specific transcriptional consequences of deletion and duplication of the genes within the 16p11.2 microdeletion or duplication segment in mouse models harboring deletion or duplication of the syntenic genomic segment 7qf3.
Autism is diagnosed in boys four times more frequently than in girls. Recent genetic research suggests that this difference is due to the fact that girls are protected from autism risk factors rather than boys being subjected to additional risk factors. The nature of this ‘female protective effect’ remains unknown.
Brian J. O’Roak’s team at Oregon Health and Science University in Portland has been exploring genetic mutations that are difficult to identify using conventional means, and what role these mutations might play in neurodevelopmental disorders. In a previous study, O’Roak and his colleagues sequenced the protein-coding regions of the genome, or ‘exomes,’ in more than 200 families that have a single child affected with autism.
Biological networks provide a natural framework for integrating the diverse genetic variations associated with complex and multifactorial disorders. The main challenge in the analysis of rare genetic variations, such as de novo single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) — duplications or deletions of stretches of DNA — is precisely their rarity. With currently available sample sizes, a vast majority of the observed genetic events are either unique or show only limited recurrency.
Evan Eichler and his colleagues at the University of Washington aim to perform the systematic discovery of single nucleotide variations (SNVs), insertions and deletions in DNA (indels) and structural variations within 160 genomes from 40 families in the Simons Simplex Collection (SSC).
Comprehensive studies of the human genome using high-speed DNA sequencing have identified new genes whose mutations appear to contribute to autism. One class of autism genes consists of regulators of the way that cells, including neurons in the brain, compact their DNA so that it can fit into the nucleus of the cell, while also being available for the selective production of proteins required for brain function. These genes, called chromatin regulators, appear to be among the most frequently mutated genes in individuals with autism. It seems that chromatin regulators control the production of proteins necessary for the development of neural circuits, and perhaps transmission of electrical impulses in the brain.
Individuals with autism frequently display accelerated brain growth during infancy and a larger brain size that is also associated with increased symptom severity. Given the widely documented heritability suggesting that autism is predominantly a genetic condition, and the well-established link between autism and abnormally accelerated brain-growth patterns, genes involved in brain growth are excellent candidates for better understanding autism.
Autism genetics has made demonstrable progress in the past few years with the recognition of the role of de novo, or spontaneous, copy number variants (CNVs), loss-of-function point mutations and common inherited DNA variants. Although landmark studies have proved the important role of genetics, the common and robust finding is twofold: Hundreds of genes contribute to autism pathogenesis, but owing to limitations of statistical power and sample size, only a tiny fraction of them can be conclusively identified.
The goal of Evan Eichler’s project is to define high-impact genes and mutations associated with sporadic autism. Using molecular inversion probe (MIP) technology, Eichler and his colleagues plan to resequence the protein-coding sequence of 200 autism candidate genes in 8,588 participants who have autism or intellectual disabilities, from eight diagnostic centers worldwide.