Cytogenetic and Genome Research

doi: 10.1159/000097441pmid: N/A

Geurts van Kessel, Ad

doi: 10.1159/000095914pmid: N/A

Pearson, P.L.

doi: 10.1159/000095915pmid: 17124401

A widely held belief today is that genomics really only started with the DNA sequence information emanating from the genome programs for various organisms, with the human genome playing the leading role. In fact there is a discernable trail stretching for more than a 100 years from the observations of Boveri on tissue instability involving polyploidy in sea urchin embryos and human tumours to the present day. This historical review follows that trail and shows that many theoretical and technical advantages taken for granted in today’s genomics era rely heavily on earlier cytogenetic and gene mapping discoveries. Three specific examples of technical developmental paths involving in situ hybridisation, flow-sorting and DNA reassociation kinetics will be explored. In the mid-1980s the two former approaches merged to give rise to several applications of which chromosome painting and chromosome CGH are arguably the most important. The latter developed into array CGH which has now become the pre-eminent method for detecting micro-imbalances in a large number of targets. A competing emerging technology is that of genome-wide SNP typing, which itself is a product of the much earlier RFLP approach linked to DNA sequence information. Do such approaches spell the final demise of the microscope? Perhaps for narrowly defined activities this may occur, but for addressing general questions, microscopic examination will remain pre-eminent.

Zhang, J.; Feuk, L.; Duggan, G.E.; Khaja, R.; Scherer, S.W.

doi: 10.1159/000095916pmid: 17124402

The discovery of an abundance of copy number variants (CNVs; gains and losses of DNA sequences >1 kb) and other structural variants in the human genome is influencing the way research and diagnostic analyses are being designed and interpreted. As such, comprehensive databases with the most relevant information will be critical to fully understand the results and have impact in a diverse range of disciplines ranging from molecular biology to clinical genetics. Here, we describe the development of bioinformatics resources to facilitate these studies. The Database of Genomic Variants (http://projects.tcag.ca/variation/) is a comprehensive catalogue of structural variation in the human genome. The database currently contains 1,267 regions reported to contain copy number variation or inversions in apparently healthy human cases. We describe the current contents of the database and how it can serve as a resource for interpretation of array comparative genomic hybridization (array CGH) and other DNA copy imbalance data. We also present the structure of the database, which was built using a new data modeling methodology termed Cross-Referenced Tables (XRT). This is a generic and easy-to-use platform, which is strong in handling textual data and complex relationships. Web-based presentation tools have been built allowing publication of XRT data to the web immediately along with rapid sharing of files with other databases and genome browsers. We also describe a novel tool named eFISH (electronic fluorescence in situ hybridization) (http://projects.tcag.ca/efish/), a BLAST-based program that was developed to facilitate the choice of appropriate clones for FISH and CGH experiments, as well as interpretation of results in which genomic DNA probes are used in hybridization-based experiments.

Knight, S.J.L.; Regan, R.

doi: 10.1159/000095917pmid: 17124403

Learning disability (LD) is a very common, lifelong and disabling condition, affecting about 3% of the population. Despite this, it is only over the past 10–15 years that major progress has been made towards understanding the origins of LD. In particular, genetics driven advances in technology have led to the unequivocal demonstration of the importance of genome imbalance in the aetiology of idiopathic LD (ILD). In this review we provide an overview of these advances, discussing technologies such as multi-telomere FISH and array CGH that have already emerged as well as new approaches that show diagnostic potential for the future. The advances to date have highlighted new considerations such as copy number polymorphisms (CNPs) that can complicate the interpretation of genome imbalance and its relevance to ILD. More importantly though, they have provided a remarkable ∼15–20% improvement in diagnostic capability as well as facilitating genotype/phenotype correlations and providing new avenues for the identification and understanding of genes involved in neurocognitive function.

de Ravel, T.J.L.; Balikova, I.; Thienpont, B.; Hannes, F.; Maas, N.; Fryns, J.-P.; Devriendt, K.; Vermeesch, J.R.

doi: 10.1159/000095918pmid: 17124404

Molecular karyotyping has revealed that microdeletions/duplications in the human genome are a major cause of multiple congenital anomalies associated with mental retardation (MCA/MR). The identification of a de novo chromosomal imbalance in a patient with MCA/MR is usually considered causal for the phenotype while a chromosomal imbalance inherited from a phenotypically normal parent is considered as a benign variation and not related to the disorder. Around 40% of imbalances in patients with MCA/MR in this series is inherited from a healthy parent and the majority of these appear to be (extremely) rare variants. As some of these contain known disease-causing genes and have also been found to be de novo in MCA/MR patients, this challenges the general view that such familial variants are innocent and of no major phenotypic consequence. Rather, we argue, that human genomes can be tolerant of genomic copy number variations depending on the genetic and environmental background and that different mechanisms play a role in determining whether these chromosomal imbalances manifest themselves.

Feenstra, I.; Brunner, H.G.; van Ravenswaaij, C.M.A.

doi: 10.1159/000095919pmid: 17124405

High-resolution molecular cytogenetic techniques such as genomic array CGH and MLPA detect submicroscopic chromosome aberrations in patients with unexplained mental retardation. These techniques rapidly change the practice of cytogenetic testing. Additionally, these techniques may improve genotype-phenotype studies of patients with microscopically visible chromosome aberrations, such as Wolf-Hirschhorn syndrome, 18q deletion syndrome and 1p36 deletion syndrome. In order to make the most of high-resolution karyotyping, a similar accuracy of phenotyping is needed to allow researchers and clinicians to make optimal use of the recent advances. International agreements on phenotype nomenclature and the use of computerized 3D face surface models are examples of such improvements in the practice of phenotyping patients with chromosomal anomalies. The combination of high-resolution cytogenetic techniques, a comprehensive, systematic system for phenotyping and optimal data storage will facilitate advances in genotype-phenotype studies and a further deconstruction of chromosomal syndromes. As a result, critical regions or single genes can be determined to be responsible for specific features and malformations.

White, S.J.; den Dunnen, J.T.

doi: 10.1159/000095920pmid: 17124406

Recent developments have yielded new technologies that have greatly simplified the detection of deletions and duplications, i.e., copy number variants (CNVs). These technologies can be used to screen for CNVs in and around specific genomic regions, as well as genome-wide. Several genome-wide studies have demonstrated that CNV in the human genome is widespread and may include millions of nucleotides. One of the questions that emerge is which sequences, structures and/or processes are involved in their generation. Using as an example the human DMD gene, mutations in which cause Duchenne and Becker muscular dystrophy, we review the current data, determine the deletion and duplication profile across the gene and summarize the information that has been collected regarding their origin. In addition we discuss the methods most frequently used for their detection, in particular MAPH and MLPA.

Erdogan, F.; Chen, W.; Kirchhoff, M.; Kalscheuer, V.M.; Hultschig, C.; Müller, I.; Schulz, R.; Menzel, C.; Bryndorf, T.; Ropers, H.-H.; Ullmann, R.

doi: 10.1159/000095921pmid: 17124407

Krepischi-Santos, A.C.V.; Vianna-Morgante, A.M.; Jehee, F.S.; Passos-Bueno, M.R.; Knijnenburg, J.; Szuhai, K.; Sloos, W.; Mazzeu, J.F.; Kok, F.; Cheroki, C.; Otto, P.A.; Mingroni-Netto, R.C.; Varela, M.; Koiffmann, C.; Kim, C.A.; Bertola, D.R.;