Chen, Wei-Chia, Zhou, Juannan, Sheltzer, Jason M, Kinney, Justin B, McCandlish, David M
(October 2021)
*Field-theoretic density estimation for biological sequence space with applications to 5' splice site diversity and aneuploidy in cancer.*
Proceedings of the National Academy of Sciences of USA, 118 (40).
ISSN 1091-6490

## Abstract

Density estimation in sequence space is a fundamental problem in machine learning that is also of great importance in computational biology. Due to the discrete nature and large dimensionality of sequence space, how best to estimate such probability distributions from a sample of observed sequences remains unclear. One common strategy for addressing this problem is to estimate the probability distribution using maximum entropy (i.e., calculating point estimates for some set of correlations based on the observed sequences and predicting the probability distribution that is as uniform as possible while still matching these point estimates). Building on recent advances in Bayesian field-theoretic density estimation, we present a generalization of this maximum entropy approach that provides greater expressivity in regions of sequence space where data are plentiful while still maintaining a conservative maximum entropy character in regions of sequence space where data are sparse or absent. In particular, we define a family of priors for probability distributions over sequence space with a single hyperparameter that controls the expected magnitude of higher-order correlations. This family of priors then results in a corresponding one-dimensional family of maximum a posteriori estimates that interpolate smoothly between the maximum entropy estimate and the observed sample frequencies. To demonstrate the power of this method, we use it to explore the high-dimensional geometry of the distribution of 5' splice sites found in the human genome and to understand patterns of chromosomal abnormalities across human cancers.

Item Type: | Paper |
---|---|

Subjects: | bioinformatics diseases & disorders > cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics diseases & disorders > neoplasms bioinformatics > computational biology bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > splice site |

CSHL Authors: | |

Communities: | CSHL labs > Kinney lab CSHL labs > McCandlish lab CSHL labs > Sheltzer lab CSHL Cancer Center Program CSHL Cancer Center Program > Gene Regulation and Inheritance Program |

SWORD Depositor: | CSHL Elements |

Depositing User: | CSHL Elements |

Date: | 5 October 2021 |

Date Deposited: | 06 Oct 2021 18:30 |

Last Modified: | 09 Feb 2024 21:15 |

PMCID: | PMC8501885 |

URI: | https://repository.cshl.edu/id/eprint/40382 |

### Actions (login required)

Administrator's edit/view item |