Understanding genetic variation, e.g., through mutations, in organisms is crucial to

We propose a novel class of Bayesian nonparametric models for sequential data called fragmentation-coagulation processes (FCPs).

Pedigrees, or family trees, are directed graphs used to identify sites of the genome that are correlated with the presence or absence of a disease. With the advent of genotyping and sequencing technologies, there has been an explosion in the amount of data available, both in the number of individuals and in the number of sites.

Understanding genetic variation, e.g., through mutations, in organisms is crucial to unravel their effects on the environment and human health. A fundamental characterization can be obtained by solving the haplotype assembly problem, which yields the variation across multiple copies of chromosomes. Variations among fast evolving viruses that lead to different strains (called quasispecies) are also deciphered with similar approaches. In both these cases, high-throughput sequencing technologies that provide oversampled mixtures of large noisy fragments (reads) of genomes, are used to infer constituent components (haplotypes or quasispecies). The problem is harder for polyploid species where there are more than two copies of chromosomes. State-of-the-art neural approaches to solve this NP-hard problem do not adequately model relations among the reads that are important for deconvolving the input signal. We address this problem by developing a new method, called NeurHap, that combines graph representation learning with combinatorial optimization. Our experiments demonstrate substantially better performance of NeurHap in real and synthetic datasets compared to competing approaches.

There are currently 25 vaccines to fight COVID-19 in clinical evaluation, another 139 vaccines in a pre-clinical stage, and many more being researched. But many of those vaccines, if they are at all successful, might not produce an immune response in portions of the population. That's because some people's bodies will react differently to the materials in the vaccine that are supposed to stimulate virus-fighting T cells. And so just figuring out how much coverage a vaccine has, meaning, how many people it will stimulate to mount an immune response, is a big part of the vaccine puzzle. With that challenge in mind, scientists at Massachusetts Institute of Technology on Monday unveiled a machine learning approach that can predict the probability that a particular vaccine design will reach a certain proportion of the population.

Reconstructing components of a genomic mixture from data obtained by means of DNA sequencing is a challenging problem encountered in a variety of applications including single individual haplotyping and studies of viral communities. High-throughput DNA sequencing platforms oversample mixture components to provide massive amounts of reads whose relative positions can be determined by mapping the reads to a known reference genome; assembly of the components, however, requires discovery of the reads' origin -- an NP-hard problem that the existing methods struggle to solve with the required level of accuracy. In this paper, we present a learning framework based on a graph auto-encoder designed to exploit structural properties of sequencing data. The algorithm is a neural network which essentially trains to ignore sequencing errors and infers the posteriori probabilities of the origin of sequencing reads. Mixture components are then reconstructed by finding consensus of the reads determined to originate from the same genomic component. Results on realistic synthetic as well as experimental data demonstrate that the proposed framework reliably assembles haplotypes and reconstructs viral communities, often significantly outperforming state-of-the-art techniques.

Pedigrees, or family trees, are directed graphs used to identify sites of the genome that are correlated with the presence or absence of a disease. With the advent of genotyping and sequencing technologies, there has been an explosion in the amount of data available, both in the number of individuals and in the number of sites. Some pedigrees number in the thousands of individuals. Meanwhile, analysis methods have remained limited to pedigrees of <100 individuals which limits analyses to many small independent pedigrees. Disease models, such those used for the linkage analysis log-odds (LOD) estimator, have similarly been limited. This is because linkage anlysis was originally designed with a different task in mind, that of ordering the sites in the genome, before there were technologies that could reveal the order. LODs are difficult to interpret and nontrivial to extend to consider interactions among sites. These developments and difficulties call for the creation of modern methods of pedigree analysis. Drawing from recent advances in graphical model inference and transducer theory, we introduce a simple yet powerful formalism for expressing genetic disease models. We show that these disease models can be turned into accurate and efficient estimators. The technique we use for constructing the variational approximation has potential applications to inference in other large-scale graphical models. This method allows inference on larger pedigrees than previously analyzed in the literature, which improves disease site prediction.

We propose a novel class of Bayesian nonparametric models for sequential data called fragmentation-coagulation processes (FCPs). FCPs model a set of sequences using a partition-valued Markov process which evolves by splitting and merging clusters. An FCP is exchangeable, projective, stationary and reversible, and its equilibrium distributions are given by the Chinese restaurant process. As opposed to hidden Markov models, FCPs allow for flexible modelling of the number of clusters, and they avoid label switching non-identifiability problems. We develop an efficient Gibbs sampler for FCPs which uses uniformization and the forward-backward algorithm. Our development of FCPs is motivated by applications in population genetics, and we demonstrate the utility of FCPs on problems of genotype imputation with phased and unphased SNP data.

The perennial problem of "how many clusters?" remains an issue of substantial interest in data mining and machine learning communities, and becomes particularly salient in large data sets such as populational genomic data where the number of clusters needs to be relatively large and open-ended. This problem gets further complicated in a co-clustering scenario in which one needs to solve multiple clustering problems simultaneously because of the presence of common centroids (e.g., ancestors) shared by clusters (e.g., possible descents from a certain ancestor) from different multiple-cluster samples (e.g., different human subpopulations). In this paper we present a hierarchical nonparametric Bayesian model to address this problem in the context of multi-population haplotype inference. Uncovering the haplotypes of single nucleotide polymorphisms is essential for many biological and medical applications. While it is uncommon for the genotype data to be pooled from multiple ethnically distinct populations, few existing programs have explicitly leveraged the individual ethnic information for haplotype inference. In this paper we present a new haplotype inference program, Haploi, which makes use of such information and is readily applicable to genotype sequences with thousands of SNPs from heterogeneous populations, with competent and sometimes superior speed and accuracy comparing to the state-of-the-art programs. Underlying Haploi is a new haplotype distribution model based on a nonparametric Bayesian formalism known as the hierarchical Dirichlet process, which represents a tractable surrogate to the coalescent process. The proposed model is exchangeable, unbounded, and capable of coupling demographic information of different populations.