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See detailIdentification of pathogenic variant enriched regions across genes and gene families
Perez-Palma, Eduardo; May, Patrick UL; Iqbal, Sumaiya et al

in Genome Research (2020), 30(1), 62-71

Missense variant interpretation is challenging. Essential regions for protein function are conserved among gene family members, and genetic variants within these regions are potentially more likely to ... [more ▼]

Missense variant interpretation is challenging. Essential regions for protein function are conserved among gene family members, and genetic variants within these regions are potentially more likely to confer risk to disease. Here, we generated 2,871 gene family protein sequence alignments involving 9,990 genes and performed missense variant burden analyses to identify novel essential protein regions. We mapped 2,219,811 variants from the general population into these alignments and compared their distribution with 76,153 missense variants from patients. With this gene family approach, we identified 465 regions enriched for patient variants spanning 41,463 amino acids in 1,252 genes. As a comparison, testing the same genes individually we identified less patient variant enriched regions involving only 2,639 amino acids and 215 genes. Next, we selected de novo variants from 6,753 patients with neurodevelopmental disorders and 1,911 unaffected siblings, and observed an 8.33-fold enrichment of patient variants in our identified regions (95% C.I.=3.90-Inf, p-value = 2.72x10-11). Using the complete ClinVar variant set, we found that missense variants inside the identified regions are 106-fold more likely to be classified as pathogenic in comparison to benign classification (OR = 106.15, 95% C.I = 70.66-Inf, p-value < 2.2 x 10-16). All pathogenic variant enriched regions (PERs) identified are available online through the “PER viewer” a user-friendly online platform for interactive data mining, visualization and download. In summary, our gene family burden analysis approach identified novel pathogenic variant enriched regions in protein sequences. This annotation can empower variant interpretation. [less ▲]

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See detailTrue single-molecule DNA sequencing of a pleistocene horse bone.
Orlando, Ludovic; Ginolhac, Aurélien UL; Raghavan, Maanasa et al

in Genome research (2011), 21(10), 1705-19

Second-generation sequencing platforms have revolutionized the field of ancient DNA, opening access to complete genomes of past individuals and extinct species. However, these platforms are dependent on ... [more ▼]

Second-generation sequencing platforms have revolutionized the field of ancient DNA, opening access to complete genomes of past individuals and extinct species. However, these platforms are dependent on library construction and amplification steps that may result in sequences that do not reflect the original DNA template composition. This is particularly true for ancient DNA, where templates have undergone extensive damage post-mortem. Here, we report the results of the first "true single molecule sequencing" of ancient DNA. We generated 115.9 Mb and 76.9 Mb of DNA sequences from a permafrost-preserved Pleistocene horse bone using the Helicos HeliScope and Illumina GAIIx platforms, respectively. We find that the percentage of endogenous DNA sequences derived from the horse is higher among the Helicos data than Illumina data. This result indicates that the molecular biology tools used to generate sequencing libraries of ancient DNA molecules, as required for second-generation sequencing, introduce biases into the data that reduce the efficiency of the sequencing process and limit our ability to fully explore the molecular complexity of ancient DNA extracts. We demonstrate that simple modifications to the standard Helicos DNA template preparation protocol further increase the proportion of horse DNA for this sample by threefold. Comparison of Helicos-specific biases and sequence errors in modern DNA with those in ancient DNA also reveals extensive cytosine deamination damage at the 3' ends of ancient templates, indicating the presence of 3'-sequence overhangs. Our results suggest that paleogenomes could be sequenced in an unprecedented manner by combining current second- and third-generation sequencing approaches. [less ▲]

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See detailA benchmark for methods in reverse engineering and model discrimination: problem formulation and solutions.
Kremling, Andreas; Fischer, Sophia; Gadkar, Kapil et al

in Genome Research (2004), 14(9), 1773-85

A benchmark problem is described for the reconstruction and analysis of biochemical networks given sampled experimental data. The growth of the organisms is described in a bioreactor in which one ... [more ▼]

A benchmark problem is described for the reconstruction and analysis of biochemical networks given sampled experimental data. The growth of the organisms is described in a bioreactor in which one substrate is fed into the reactor with a given feed rate and feed concentration. Measurements for some intracellular components are provided representing a small biochemical network. Problems of reverse engineering, parameter estimation, and identifiability are addressed. The contribution mainly focuses on the problem of model discrimination. If two or more model variants describe the available experimental data, a new experiment must be designed to discriminate between the hypothetical models. For the problem presented, the feed rate and feed concentration of a bioreactor system are available as control inputs. To verify calculated input profiles an interactive Web site (http://www.sysbio.de/projects/benchmark/) is provided. Several solutions based on linear and nonlinear models are discussed. [less ▲]

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