Machine learning applications in genetics and genomics

Journal name:
Nature Reviews Genetics
Year published:
Published online


The field of machine learning, which aims to develop computer algorithms that improve with experience, holds promise to enable computers to assist humans in the analysis of large, complex data sets. Here, we provide an overview of machine learning applications for the analysis of genome sequencing data sets, including the annotation of sequence elements and epigenetic, proteomic or metabolomic data. We present considerations and recurrent challenges in the application of supervised, semi-supervised and unsupervised machine learning methods, as well as of generative and discriminative modelling approaches. We provide general guidelines to assist in the selection of these machine learning methods and their practical application for the analysis of genetic and genomic data sets.

At a glance


  1. A canonical example of a machine learning application.
    Figure 1: A canonical example of a machine learning application.

    A training set of DNA sequences is provided as input to a learning procedure, along with binary labels indicating whether each sequence is centred on a transcription start site (TSS) or not. The learning algorithm produces a model that can then be subsequently used, in conjunction with a prediction algorithm, to assign predicted labels (such as 'TSS' or 'not TSS') to unlabelled test sequences. In the figure, the red–blue gradient might represent, for example, the scores of various motif models (one per column) against the DNA sequence.

  2. A gene-finding model.
    Figure 2: A gene-finding model.

    A simplified gene-finding model that captures the basic properties of a protein-coding gene is shown. The model takes the DNA sequence of a chromosome, or a portion thereof, as input and produces detailed gene annotations as output. Note that this simplified model is incapable of identifying overlapping genes or multiple isoforms of the same gene. UTR, untranslated region.

  3. Two models of transcription factor binding.
    Figure 3: Two models of transcription factor binding.

    a | Generative and discriminative models are different in their interpretability and prediction accuracy. If we were to separate two groups of points, the generative model characterizes both classes completely, whereas the discriminative model focuses on the boundary between the classes. b | In a position-specific frequency matrix (PSFM) model, the entry in row i and column j represents the frequency of the ith base occurring at position j in the training set. Assuming independence, the probability of the entire sequence is the product of the probabilities associated with each base. c | In a linear support vector machine (SVM) model of transcription factor binding, labelled positive and negative training examples (red and blue, respectively) are provided as input, and a learning procedure adjusts the weights on the edges to predict the given label. d | The graph plots the mean accuracy (±95% confidence intervals) of PSFM and SVM, on a set of 500 simulated test sets, of predicting transcription factor binding as a function of the number of training examples.

  4. Incorporating a probabilistic prior into a position-specific frequency matrix.
    Figure 4: Incorporating a probabilistic prior into a position-specific frequency matrix.

    A simple, principled method for putting a probabilistic prior on a position-specific frequency matrix involves augmenting the observed nucleotide counts with pseudocounts and then computing frequencies with respect to the sum. The magnitude of the pseudocount corresponds to the weight assigned to the prior.

  5. Three ways to accommodate heterogeneous data in machine learning.
    Figure 5: Three ways to accommodate heterogeneous data in machine learning.

    The task of predicting gene function labels requires methods that take as input data such as gene expression profiles, genetic interaction networks and amino acid sequences. These diverse data types can be encoded into fixed-length features, represented using pairwise similarities (that is, kernels) or directly accommodated by a probability model.

  6. Inferring network structure.
    Figure 6: Inferring network structure.

    Methods that infer each relationship in a network separately, such as by computing the correlation between each pair, can be confounded by indirect relationships. Methods that infer the network as a whole can identify only direct relationships. Inferring the direction of causality inherent in networks is generally more challenging than inferring the network structure68; as a result, many network inference methods, such as Gaussian graphical model learning, infer only the network.


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Author information


  1. Department of Computer Science and Engineering, University of Washington, 185 Stevens Way, Seattle, Washington 98195–2350, USA.

    • Maxwell W. Libbrecht &
    • William Stafford Noble
  2. Department of Genome Sciences, University of Washington, 3720 15th Ave NE Seattle, Washington 98195–5065, USA.

    • William Stafford Noble

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The authors declare no competing interests.

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Author details

  • Maxwell W. Libbrecht

    Maxwell W. Libbrecht graduated with a degree in computer science from Stanford University, California, USA, where he was advised by Serafim Batzoglou, in 2011. He is currently a Ph.D. student at the Department of Computer Science and Engineering at the University of Washington, Seattle, USA, and is advised by William Noble. He works on developing methods that integrate diverse types of data in order to understand gene regulation.

  • William Stafford Noble

    William Stafford Noble received his Ph.D. in computer science and cognitive science from University of California, San Diego, USA. His research group develops and applies statistical and machine learning techniques for modelling and understanding biological processes at the molecular level. He is the recipient of a US National Science Foundation (NSF) CAREER award and is a Sloan Research Fellow. William Stafford Noble's homepage.

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