From DNA sequences to cell types by detecting regulatory genomic regions in sequencing data
Bibliographic record
Abstract
One of the big questions in biology today is to understand which genetic and epigenetic factors are involved in the regulation of gene expression, and in which cases their deregulation can contribute to the development of abnormal phenotypes or diseases. Innovations in genome sequencing techniques and corresponding data processing algorithms have enabled unbiased interrogation of the different genomic and epigenomic components of transcription at nucleotide resolution. Therefore, it is now possible to use and integrate different types of data for both bulk and single-cell samples, and to understand the molecular components of gene expression regulation using ad-hoc reproducible computational analysis. As an interdisciplinary field, bioinformatics takes advantage of different quantitative disciplines, such as statistics and machine learning. This allows the implementation of detailed analyses to support and elucidate specific fundamental discoveries, and also to test unexpected predictions coming from exploratory data analysis. In particular, the use of bioinformatics is a necessity in the study of the genomic basis of gene regulation given the complexity of the data produced. Thus, the application of existing and the development of novel bioinformatics methods improves the interpretation of new data by integrating several data types from multiple sources. In this thesis I applied and developed bioinformatics methods to help investigate basic biological questions in the genomic study of epigenetic gene regulation: i) I created a pipeline for whole-genome bisulfite sequencing data analysis to improve the understanding of the way genes and DNA sequences are demethylated by GADD45 proteins and how this might be linked to a key stage of development in mouse embryonic stem cells (mESCs), ii) I developed a metric based on the Gini index to evaluate unsupervised clustering results obtained using several computational methods that were tested to identify various types of peripheral blood mononuclear cells (PBMCs) from single-cell ATAC-seq samples in which the labels of the cells were not provided and iii) I developed an algorithm to extract variable regions in ChIP-seq data that can improve the identification of target-specific binding sites of different proteins in several cell lines of the ENCODE project. Together, these three studies are a significant contribution to the improvement of the interpretation of genomic data for the study of epigenetic gene regulation by bioinformatics.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.005 | 0.018 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.008 | 0.008 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.003 | 0.002 |
| Open science | 0.001 | 0.002 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.002 | 0.003 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".