Integrative approaches to high-throughput data in lymphoid leukemias (on transcriptomes, the whole-genome mutational landscape, flow cytometry and gene copy-number alterations)

Within this thesis I developed a new approach for the analysis and integration of heterogeneous leukemic data sets applicable to any high-throughput analysis including basic research. All layers are stored in a semantic graph which facilitates modifications by just adding edges (relationships/attributes) and nodes (values/results) as well as calculating biological consensus and clinical correlation. The front-end is accessible through a GUI (graphical user interface) on a Java-based Semantic Web server. I used this framework to describe the genomic landscape of T-PLL (T-cell prolymphocytic leukemia), which is a rare (~0.6/million) mature T-cell malignancy with aggressive clinical course, notorious treatment resistance, and generally low overall survival. We have conducted gene expression and copy-number profiling as well as NGS (next-generation sequencing) analyses on a cohort comprising 94 T-PLL cases. TCL1A (T-cell leukemia/lymphoma 1A) overexpression and ATM (Ataxia Telangiectasia Mutated) impairment represent central hallmarks of T-PLL, predictive for patient survival, T-cell function and proper DNA damage responses. We identified new chromosomal lesions, including a gain of AGO2 (Argonaute 2, RISC Catalytic Component; 57.14% of cases), which is decisive for the chromosome 8q lesion. While we found significant enrichments of truncating mutations in ATM mut/no del (p=0.01365), as well as FAT (FAT Atypical Cadherin) domain mutations in ATM mut/del (p=0.01156), JAK3 (Janus Kinase 3) mut/ATM del cases may represent another tumor lineage. Using whole-transcriptome sequencing, we identified novel structural variants affecting chromosome 14 that lead to the expression of a TCL1A-TCR (T-cell receptor) fusion transcript and a likely degradated TCL1A protein. Two clustering approaches of normal T-cell subsets vs. leukemia gene expression profiles, as well as immunophenotyping-based agglomerative clustering and TCR repertoire reconstruction further revealed a restricted, memory-like T-cell phenotype. This is to date the most comprehensive, multi-level, integrative study on T-PLL and it led to an evolutionary disease model and a histone deacetylase-inhibiting / double strand break-inducing treatment that performs better than the current standard of chemoimmunotherapy in preclinical testing

The Peanut Genome

This book presents the current state of the art in peanut genomics, focusing particularly on the latest genomic findings, tools and strategies employed in genome sequencing, transcriptomes and analysis, availability of public and private genomic resources, and ways to maximize the use of this information in peanut breeding programs. Further, it demonstrates how advances in plant genomics can be used to improve crop breeding. The peanut or groundnut (Arachis hypogaea L. Millsp) is a globally important grain legume and oilseed crop, cultivated in over 100 countries and consumed in the form of roasted seeds, oil and confectionary in nearly every country on Earth. The peanut contributes towards achieving food and nutritional security, in addition to financial security through income generation; as such, it is also vital to the livelihood of the poor in the developing world. There have been significant advances in peanut research, especially in the last five years, including sequencing the genome of both diploid progenitors, and the availability of tremendous transcriptome resources, large-scale genomic variations that can be used as genetic markers, genetic populations (bi- and multiparent populations and germplasm sets), marker-trait associations and molecular breeding products. The immediate availability of the genome sequence for tetraploid cultivated peanuts is the most essential genomic resource for achieving a deeper understanding of peanut traits and their use in breeding programs

Entwicklung einer computerlesbaren zytogenetischen Notation zur Detektion minimal rekurrenter Aberrationen bei Patienten mit hämatologischen Neoplasien

Ergebnisse tumorzytogenetischer Analysen werden nach gültiger ISCN dokumentiert. Diese Nomenklatur ist nur sehr eingeschränkt computerlesbar. Die Metaanalyse großer Datensammlungen mit den oft komplexen Karyotypen von Tumorpatienten wird dadurch erschwert. Es wurde eine vereinfachte computerlesbare zytogenetische Notation (SCCN) und entsprechende Analyse-Programme entwickelt. Die im Karyotyp enthaltene qualitative und quantitative Metainformation wird in zwei Datenfeldern gespeichert. Die Metaanalyse der Bruchpunkte und chromosomalen Imbalancen erfolgt getrennt. Ergebnisse werden grafisch und tabellarisch dargestellt. Die SCCN und Programme wurden an einer Datensammlung von Karyotypen von 94 Patienten mit akuter lymphatischer Leukämie, t(9;22)(q34;q11) und Zusatzaberrationen getestet. Die Metaanalyse des Patientenkollektivs bestätigte die bekannten Literaturwerte

Abstracts from the 50th European Society of Human Genetics Conference: Posters

International audienc

Frameshift mutations at the C-terminus of HIST1H1E result in a specific DNA hypomethylation signature

BACKGROUND: We previously associated HIST1H1E mutations causing Rahman syndrome with a specific genome-wide methylation pattern. RESULTS: Methylome analysis from peripheral blood samples of six affected subjects led us to identify a specific hypomethylated profile. This "episignature" was enriched for genes involved in neuronal system development and function. A computational classifier yielded full sensitivity and specificity in detecting subjects with Rahman syndrome. Applying this model to a cohort of undiagnosed probands allowed us to reach diagnosis in one subject. CONCLUSIONS: We demonstrate an epigenetic signature in subjects with Rahman syndrome that can be used to reach molecular diagnosis

The mechanisms of evolutionary flexibility in earthworm genomes

Many individual organisms have latent phenotypic potentials which are never realised within their lifespans. This potential can include a huge diversity of dormant adaptations across the tree of life, such as the ability to tolerate radical changes in temperature, survive restricted nutrient availability, and resist toxins and parasites. Prior to unrealised phenotypic potentials are necessarily information potentials residing in a dormant state also. This thesis investigates the systematic interactions of facultative morphologies and atavistic adaptivity with the evolutionary systems which propagate them. Earthworms as models are for these purposes an almost archetypal form of a high-latent-potential organism. Examples abound of their thriving as peregrine species with near-global ranges

Bioinformatics

This book is divided into different research areas relevant in Bioinformatics such as biological networks, next generation sequencing, high performance computing, molecular modeling, structural bioinformatics, molecular modeling and intelligent data analysis. Each book section introduces the basic concepts and then explains its application to problems of great relevance, so both novice and expert readers can benefit from the information and research works presented here

Cereal Genomics

Cereals make an important component of daily diet of a major section of human population, so that their survival mainly depends on the cereal grain production, which should match the burgeoning human population. Due to painstaking efforts of plant breeders and geneticists, at the global level, cereal production in the past witnessed a steady growth. However, the cereal production in the past has been achieved through the use of high yielding varieties, which have a heavy demand of inputs in the form of chemical fertilizers, herbicides and insecticides/pesticides, leading to environmental degradation. In view of this, while increasing cereal production, one also needs to keep in mind that agronomic practices used for realizing high productivity do not adversely affect the environment. Improvement in cereal production in the past was also achieved through the use of alien genetic variation available in the wild relatives of these cereals, so that conservation and sustainable use of genetic resources is another important area, which is currently receiving the attention of plant breeders. The work leading to increased cereal production in the past received strong support from basic research on understanding the cereal genomes, which need to be manipulated to yield more from low inputs without any adverse effects as above. Through these basic studies, it also became fairly apparent that the genomes of all cereals are related and were derived from the same lineage, million of years ago