Doctor of Philosophy, Pennsylvania State University (2011)
J. Michael Cherry, Postdoctoral Faculty Sponsor
Many software tools for comparative analysis of genomic sequence data have been released in recent decades. Despite this, it remains challenging to determine evolutionary relationships in gene clusters due to their complex histories involving duplications, deletions, inversions, and conversions. One concept describing these relationships is orthology. Orthologs derive from a common ancestor by speciation, in contrast to paralogs, which derive from duplication. Discriminating orthologs from paralogs is a necessary step in most multispecies sequence analyses, but doing so accurately is impeded by the occurrence of gene conversion events. We propose a refined method of orthology assignment based on two paradigms for interpreting its definition: by genomic context or by sequence content. X-orthology (based on context) traces orthology resulting from speciation and duplication only, while N-orthology (based on content) includes the influence of conversion events. We developed a computational method for automatically mapping both types of orthology on a per-nucleotide basis in gene cluster regions studied by comparative sequencing, and we make this mapping accessible by visualizing the output. All of these steps are incorporated into our newly extended CHAP 2 package. We evaluate our method using both simulated data and real gene clusters (including the well-characterized ?-globin and ?-globin clusters). We also illustrate use of CHAP 2 by analyzing four more loci: CCL (chemokine ligand), IFN (interferon), CYP2abf (part of cytochrome P450 family 2), and KIR (killer cell immunoglobulin-like receptors). These new methods facilitate and extend our understanding of evolution at these and other loci by adding automated accurate evolutionary inference to the biologist's toolkit. The CHAP 2 package is freely available from http://www.bx.psu.edu/miller_lab.
View details for DOI 10.1093/gbe/evs032
View details for PubMedID 22454131
Gene clusters containing multiple similar genomic regions in close proximity are of great interest for biomedical studies because of their associations with inherited diseases. However, such regions are difficult to analyze due to their structural complexity and their complicated evolutionary histories, reflecting a variety of large-scale mutational events. In particular, conversion events can mislead inferences about the relationships among these regions, as traced by traditional methods such as construction of phylogenetic trees or multi-species alignments.To correct the distorted information generated by such methods, we have developed an automated pipeline called CHAP (Cluster History Analysis Package) for detecting conversion events. We used this pipeline to analyze the conversion events that affected two well-studied gene clusters (?-globin and ?-globin) and three gene clusters for which comparative sequence data were generated from seven primate species: CCL (chemokine ligand), IFN (interferon), and CYP2abf (part of cytochrome P450 family 2). CHAP is freely available at http://www.bx.psu.edu/miller_lab.These studies reveal the value of characterizing conversion events in the context of studying gene clusters in complex genomes.
View details for DOI 10.1186/1471-2148-11-226
View details for Web of Science ID 000294183300001
View details for PubMedID 21798034
Gene clusters are genetically important, but their analysis poses significant computational challenges. One of the major reasons for these difficulties is gene conversion among the duplicated regions of the cluster, which can obscure their true relationships. Many computational methods for detecting gene conversion events have been released, but their performance has not been assessed for wide deployment in evolutionary history studies due to a lack of accurate evaluation methods.We designed a new method that simulates gene cluster evolution, including large-scale events of duplication, deletion, and conversion as well as small mutations. We used this simulation data to evaluate several different programs for detecting gene conversion events.Our evaluation identifies strengths and weaknesses of several methods for detecting gene conversion, which can contribute to more accurate analysis of gene cluster evolution.
View details for DOI 10.1186/1471-2105-12-S1-S45
View details for Web of Science ID 000290221000046
View details for PubMedID 21342577
Much important evolutionary activity occurs in gene clusters, where a copy of a gene may be free to acquire new functions. Current computational methods to extract evolutionary information from sequence data for such clusters are suboptimal, in part because accurate sequence data are often lacking in these genomic regions, making existing methods difficult to apply. We describe a new method for reconstructing the recent evolutionary history of gene clusters, and evaluate its performance on both simulated data and actual human gene clusters.
View details for DOI 10.1089/cmb.2010.0094
View details for Web of Science ID 000282275800010
View details for PubMedID 20874406
Clusters of genes that have evolved by repeated segmental duplication present difficult challenges throughout genomic analysis, from sequence assembly to functional analysis. These clusters are one of the major sources of evolutionary innovation, and they are linked to multiple diseases, including HIV and a variety of cancers. Understanding their evolutionary histories is a key to the application of comparative genomics methods in these regions of the genome. We propose a probabilistic model of gene cluster evolution on a phylogeny, and an MCMC algorithm for reconstruction of duplication histories from genomic sequences in multiple species. Several projects are underway to obtain high quality BAC-based assemblies of duplicated clusters in multiple species, and we anticipate use of our methods in their analysis.
View details for DOI 10.1089/cmb.2010.0090
View details for Web of Science ID 000282275800012
View details for PubMedID 20874408
Clusters of genes that evolved from single progenitors via repeated segmental duplications present significant challenges to the generation of a truly complete human genome sequence. Such clusters can confound both accurate sequence assembly and downstream computational analysis, yet they represent a hotbed of functional innovation, making them of extreme interest. We have developed an algorithm for reconstructing the evolutionary history of gene clusters using only human genomic sequence data, which allows the tempo of large-scale evolutionary events in human gene clusters to be estimated. We further propose an extension of the method to simultaneously reconstructing the evolutionary histories of orthologous gene clusters in multiple primates, which will facilitate primate comparative sequencing studies that aim to reconstruct their evolutionary history more fully.
View details for DOI 10.1089/cmb.2009.0040
View details for Web of Science ID 000269639100007
View details for PubMedID 19645598
Genomic intervals that contain a cluster of similar genes are of extreme biological interest, but difficult to sequence and analyze. One goal for interspecies comparisons of such intervals is to reconstruct a parsimonious series of duplications, deletions, and speciation events (a putative evolutionary history) that could have created the contemporary clusters from their last common ancestor. We describe a new method for reconstructing such an evolutionary scenario for a given set of intervals from present-day genomes, based on the statistical technique of Sequential Importance Sampling. An implementation of the method is evaluated using (1) artificial datasets generated by simulating the operations of duplication, deletion, and speciation starting with featureless "ancestral" sequences, and (2) by comparing the inferred evolutionary history of the amino-acid sequences for the CYP2 gene family from human chromosome 19, chimpanzee, orangutan, rhesus macaque, and dog, as computed by a standard phylogenetic-tree reconstruction method.
View details for Web of Science ID 000263639700016
View details for PubMedID 19209701