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Biomedical subjects

Nick Goldman

Publications and source records attributed to Nick Goldman.

7 recordsLinked to original sources

Detecting Interspecific Positive Selection Using Convolutional Neural Networks.

Traditional statistical methods using maximum likelihood and Bayesian inference can detect positive selection from an interspecific phylogeny and a codon sequence alignment based on model assumptions, but they are prone to false positives due to alignment errors and can lack power. These problems are particularly pronounced when faced with high levels of indels and divergence. To address these issues, we trained and tested convolutional neural network models on simulated data and achieved higher accuracy in detecting selection across a specific range of phylogenetic scenarios and evolutionary modes. This advantage is particularly evident when performing inference on noisy data prone to misalignments. Our method shows some ability to account for these errors, where most statistical frameworks fail to do so in a tractable manner. We explore the generalizability of our convolutional neural network models to unseen evolutionary scenarios and identify future avenues to achieve broader utility. Once trained, our convolutional neural network model is faster at test time, making it a scalable alternative to traditional statistical methods for large-scale, multigene analyses. In addition to binary classification (inference of the presence or absence of positive selection during the evolution of the sequences), we use saliency maps to understand what the model learns and observe how this could be leveraged for sitewise inference of positive selection.

Neural Networks, Computer↗

Pandit: a database of protein and associated nucleotide domains with inferred trees.

MOTIVATION: A large, high-quality database of homologous sequence alignments with good estimates of their corresponding phylogenetic trees will be a valuable resource to those studying phylogenetics. It will allow researchers to compare current and new models of sequence evolution across a large variety of sequences. The large quantity of data may provide inspiration for new models and methodology to study sequence evolution and may allow general statements about the relative effect of different molecular processes on evolution. RESULTS: The Pandit 7.6 database contains 4341 families of sequences derived from the seed alignments of the Pfam database of amino acid alignments of families of homologous protein domains (Bateman et al., 2002). Each family in Pandit includes an alignment of amino acid sequences that matches the corresponding Pfam family seed alignment, an alignment of DNA sequences that contain the coding sequence of the Pfam alignment when they can be recovered (overall, 82.9% of sequences taken from Pfam) and the alignment of amino acid sequences restricted to only those sequences for which a DNA sequence could be recovered. Each of the alignments has an estimate of the phylogenetic tree associated with it. The tree topologies were obtained using the neighbor joining method based on maximum likelihood estimates of the evolutionary distances, with branch lengths then calculated using a standard maximum likelihood approach.

Algorithms↗

Protein evolution with dependence among codons due to tertiary structure.

Markovian models of protein evolution that relax the assumption of independent change among codons are considered. With this comparatively realistic framework, an evolutionary rate at a site can depend both on the state of the site and on the states of surrounding sites. By allowing a relatively general dependence structure among sites, models of evolution can reflect attributes of tertiary structure. To quantify the impact of protein structure on protein evolution, we analyze protein-coding DNA sequence pairs with an evolutionary model that incorporates effects of solvent accessibility and pairwise interactions among amino acid residues. By explicitly considering the relationship between nonsynonymous substitution rates and protein structure, this approach can lead to refined detection and characterization of positive selection. Analyses of simulated sequence pairs indicate that parameters in this evolutionary model can be well estimated. Analyses of lysozyme c and annexin V sequence pairs yield the biologically reasonable result that amino acid replacement rates are higher when the replacements lead to energetically favorable proteins than when they destabilize the proteins. Although the focus here is evolutionary dependence among codons that is associated with protein structure, the statistical approach is quite general and could be applied to diverse cases of evolutionary dependence where surrogates for sequence fitness can be measured or modeled.

Annexin A5↗

Covariation in frequencies of substitution, deletion, transposition, and recombination during eutherian evolution.

Six measures of evolutionary change in the human genome were studied, three derived from the aligned human and mouse genomes in conjunction with the Mouse Genome Sequencing Consortium, consisting of (1) nucleotide substitution per fourfold degenerate site in coding regions, (2) nucleotide substitution per site in relics of transposable elements active only before the human-mouse speciation, and (3) the nonaligning fraction of human DNA that is nonrepetitive or in ancestral repeats; and three derived from human genome data alone, consisting of (4) SNP density, (5) frequency of insertion of transposable elements, and (6) rate of recombination. Features 1 and 2 are measures of nucleotide substitutions at two classes of "neutral" sites, whereas 4 is a measure of recent mutations. Feature 3 is a measure dominated by deletions in mouse, whereas 5 represents insertions in human. It was found that all six vary significantly in megabase-sized regions genome-wide, and many vary together. This indicates that some regions of a genome change slowly by all processes that alter DNA, and others change faster. Regional variation in all processes is correlated with, but not completely accounted for, by GC content in human and the difference between GC content in human and mouse.

Animals↗

Initial sequencing and comparative analysis of the mouse genome.

The sequence of the mouse genome is a key informational tool for understanding the contents of the human genome and a key experimental tool for biomedical research. Here, we report the results of an international collaboration to produce a high-quality draft sequence of the mouse genome. We also present an initial comparative analysis of the mouse and human genomes, describing some of the insights that can be gleaned from the two sequences. We discuss topics including the analysis of the evolutionary forces shaping the size, structure and sequence of the genomes; the conservation of large-scale synteny across most of the genomes; the much lower extent of sequence orthology covering less than half of the genomes; the proportions of the genomes under selection; the number of protein-coding genes; the expansion of gene families related to reproduction and immunity; the evolution of proteins; and the identification of intraspecies polymorphism.

Animals↗

Modeling mitochondrial protein evolution using structural information.

We present two new models of protein sequence evolution based on structural properties of mitochondrial proteins. We compare these models with others currently used in phylogenetic analyses, investigating their performance over both short and long evolutionary distances. We find that our models that incorporate secondary structure information from mitochondrial proteins are statistically comparable with existing models when studying 13 mitochondrial protein data sets from eutherian mammals. However, our models give a significantly improved description of the evolutionary process when used with 12 mitochondrial proteins from a broader range of organisms including fungi, plants, protists, and bacteria. Our models may thus be of use in estimating mitochondrial protein phylogenies and for the study of processes of mitochondrial protein evolution, in particular for distantly related organisms.

Evolution, Molecular↗

A novel use of equilibrium frequencies in models of sequence evolution.

Current mathematical models of amino acid sequence evolution are often applied in variants that match their expected amino acid frequencies to those observed in a data set under analysis. This has been achieved by setting the instantaneous rate of replacement of a residue i by another residue j proportional to the observed frequency of the resulting residue j. We describe a more general method that maintains the match between expected and observed frequencies but permits replacement rates to be proportional to the frequencies of both the replaced and resulting residues, raised to powers other than 1. Analysis of a database of amino acid alignments shows that the description of the evolutionary process in a majority (approximately 70% of 182 alignments) is significantly improved by use of the new method, and a variety of analyses indicate that parameter estimation with the new method is well-behaved. Improved evolutionary models increase our understanding of the process of molecular evolution and are often expected to lead to improved phylogenetic inferences, and so it seems justified to consider our new variants of existing standard models when performing evolutionary analyses of amino acid sequences. Similar methods can be used with nucleotide substitution models, but we have not found these to give corresponding significant improvements to our ability to describe the processes of nucleotide sequence evolution.

Amino Acid Sequence↗