What Have Studies of Genomic Disorders Taught Us About Our Genome?

Abstract

The elucidation of genomic disorders began with molecular technologies that enabled detection of genomic changes which were (a) smaller than those resolved by traditional cytogenetics (less than 5 Mb) and (b) larger than what could be determined by conventional gel electrophoresis. Methods such as pulsed field gel electrophoresis (PFGE) and fluorescent in situ hybridization (FISH) could resolve such changes but were limited to locus-specific studies. The study of genomic disorders has rapidly advanced with the development of array-based techniques. These enabled examination of the entire human genome at a higher level of resolution, thus allowing elucidation of the basis of many new disorders, mechanisms that result in genomic changes that can result in copy number variation (CNV), and most importantly, a deeper understanding of the characteristics, features, and plasticity of our genome. In this chapter, we focus on the structural and architectural features of the genome, which can potentially result in genomic instability, delineate how mechanisms, such as NAHR, NHEJ, and FoSTeS/MMBIR lead to disease-causing rearrangements, and briefly describe the relationship between the leading methods presently used in studying genomic disorders. We end with a discussion on our new understanding about our genome including: the contribution of new mutation CNV to disease, the abundance of mosaicism, the extent of subtelomeric rearrangements, the frequency of de novo rearrangements associated with sporadic birth defects, the occurrence of balanced and unbalanced translocations, the increasing discovery of insertional translocations, the exploration of complex rearrangements and exonic CNVs. In the postgenomic era, our understanding of the genome has advanced very rapidly as the level of technical resolution has become higher. This leads to a greater understanding of the effects of rearrangements present both in healthy subjects and individuals with clinically relevant phenotypes.

Clinical and molecular studies in four patients with SRY-positive 46,XX testicular disorders of sex development: implications for variable sex development and genomic rearrangements

“…Such genomic structure at the fusion point is characteristic of non-homologous end joining that can lead to various genomic rearrangements including translocations. 8 It is likely, therefore, that Xp;Yp translocations are caused by several mechanisms for genomic rearrangements, although Xp;Yp translocations resulting from replication-based mechanisms such as fork stalling and template switching and microhomology-mediated break-induced replication remain to be identified at present. 8 In addition to 46,XX-TDSD, case 2 had branchial arch syndrome.…”

“…8 It is likely, therefore, that Xp;Yp translocations are caused by several mechanisms for genomic rearrangements, although Xp;Yp translocations resulting from replication-based mechanisms such as fork stalling and template switching and microhomology-mediated break-induced replication remain to be identified at present. 8 In addition to 46,XX-TDSD, case 2 had branchial arch syndrome. Thus, case 2 would have a branchial arch syndrome-related genetic aberration that could not be identified by the whole genome array CGH.…”

“…8 In particular, previous studies have revealed the recurrent NAHR events between X-Y homologous sequences around PRKX and PRKY, especially at the 'hot spot A' on the 5 0 sequence and the 'hot spot B' on the C-terminal coding sequence, in a subgroup of males with a common B3.5 Mb paracentric Yp inversion mediated by Y-specific long inverted repeats. 9 Since PRKX and PRKY are aligned in the same direction during paternal meiosis in such Yp inversion-positive males, this would have permitted the occurrence of NAHR around PRKX and PRKY.…”

Decoding NF1 Intragenic Copy-Number Variations

“…[1][2][3][4][5][6] These rearrangements are mediated by mutational mechanisms that are not completely understood. Currently, several mechanisms have been proposed, including non-allelic homologous recombination (NAHR), non-homologous end joining (NHEJ), fork stalling and template switching (FoSTeS), and microhomology-mediated break-induced replication (MMBIR).…”

Palindrome-Mediated and Replication-Dependent Pathogenic Structural Rearrangements within theNF1Gene

“…Genomic rearrangements represent a class of DNA variations (deletion, duplication, insertion, inversion, translocation) ranging in size from hundreds to millions of bp and cause both Mendelian and complex disorders (reviewed by [Chen et al, 2010;Girirajan et al, 2011;Gonzaga-Jauregui et al, 2012;Liu et al, 2012;Simmons et al, 2012]). Genomic rearrangements originally were thought to be randomly distributed among the human genome.…”