2012 highlights in translational 'omics

Genomic approaches to human disease have exploded during 2012, and the number of diseases for which the genes are being identified by exome sequencing are too numerous to list and too exciting to highlight any one study over another. Of particular interest is the ability of genomic analysis to reveal complex patterns of inheritance. The thrombocytopenia absent radius (TAR) syndrome was previously associated with either de novo or inherited deletion of 1q21.1; however, evidence suggested that variation at an additional locus was necessary for disease expression. Exome sequencing revealed that low-frequency regulatory single-nucleotide polymorphisms for RBM8A (which maps to the 1q21.1 region and encodes a component of the exon-junction complex), in combination with a 1q21.1 deletion, are necessary and sufficient to cause TAR syndrome [1]. Exome sequencing also revealed that a form of fascioscapulohumeral muscular dystrophy (FSHD2) results from digenic inheritance of an allele of the D4Z4 microsatellite array on chromosome 4, which is permissive for the expression of the embedded DUX4 gene, and single-nucleotide variation (SNV) at the SMCHD1 locus (encoding structural maintenance of chromosomes flexible hinge domain containing 1) [2]. Thus, an SNV or point mutation allele in SMCHD1 on chromosome 18 acts as an epigenetic, epistatic modifier of the D4Z4 allele and acts as a genetic determinant underlying the FSHD2 disease trait [3].2012 may perhaps be remembered as the year of de novo mutation (DNM). Three different approaches applied genomic sequencing to directly measure intergenerational DNM rates [4-6]. DNMs were experimentally measured to occur at about half the previously estimated rate of about 2.5 × 10-8. Furthermore, these studies confirm and quantify a long-held observation of a paternal effect on DNM rates [7]. The DNM rate for SNV in the paternal germline is about four times greater than that in the maternal germline; it increases linearly by about two DNMs p