Comparative genomics

Comparative genomics is a branch of biological research that examines genome sequences across a spectrum of species, spanning from humans and mice to a diverse array of organisms from bacteria to chimpanzees. This large-scale holistic approach compares two or more genomes to discover the similarities and differences between the genomes and to study the biology of the individual genomes. Comparison of whole genome sequences provides a highly detailed view of how organisms are related to each other at the gene level. By comparing whole genome sequences, researchers gain insights into genetic relationships between organisms and study evolutionary changes. The major principle of comparative genomics is that common features of two organisms will often be encoded within the DNA that is evolutionarily conserved between them. Therefore, Comparative genomics provides a powerful tool for studying evolutionary changes among organisms, helping to identify genes that are conserved or common among species, as well as genes that give unique characteristics of each organism. Moreover, these studies can be performed at different levels of the genomes to obtain multiple perspectives about the organisms. The comparative genomic analysis begins with a simple comparison of the general features of genomes such as genome size, number of genes, and chromosome number. Table 1 presents data on several fully sequenced model organisms, and highlights some striking findings. For instance, while the tiny flowering plant Arabidopsis thaliana has a smaller genome than that of the fruit fly Drosophila melanogaster (157 million base pairs v. 165 million base pairs, respectively) it possesses nearly twice as many genes (25,000 v. 13,000). In fact, A. thaliana has approximately the same number of genes as humans (25,000). Thus, a very early lesson learned in the genomic era is that genome size does not correlate with evolutionary status, nor is the number of genes proportionate to genome size.

In comparative genomics, synteny is the preserved order of genes on chromosomes of related species indicating their descent from a common ancestor. Synteny provides a framework in which the conservation of homologous genes and gene order is identified between genomes of different species. Synteny blocks are more formally defined as regions of chromosomes between genomes that share a common order of homologous genes derived from a common ancestor. Alternative names such as conserved synteny or collinearity have been used interchangeably. Comparisons of genome synteny between and within species have provided an opportunity to study evolutionary processes that lead to the diversity of chromosome number and structure in many lineages across the tree of life; early discoveries using such approaches include chromosomal conserved regions in nematodes and yeast, evolutionary history and phenotypic traits of extremely conserved Hox gene clusters across animals and MADS-box gene family in plants, and karyotype evolution in mammals and plants. Furthermore, comparing two genomes not only reveals conserved domains or synteny but also aids in detecting copy number variations, single nucleotide polymorphisms (SNPs), indels, and other genomic structural variations. Virtually started as soon as the whole genomes of two organisms became available (that is, the genomes of the bacteria Haemophilus influenzae and Mycoplasma genitalium) in 1995, comparative genomics is now a standard component of the analysis of every new genome sequence. With the explosion in the number of genome projects due to the advancements in DNA sequencing technologies, particularly the next-generation sequencing methods in late 2000s, this field has become more sophisticated, making it possible to deal with many genomes in a single study. Comparative genomics has revealed high levels of similarity between closely related organisms, such as humans and chimpanzees, and, more surprisingly, similarity between seemingly distantly related organisms, such as humans and the yeast Saccharomyces cerevisiae. It has also showed the extreme diversity of the gene composition in different evolutionary lineages.

== History ==

Comparative genomics has a root in the comparison of virus genomes in the early 1980s. For example, small RNA viruses infecting animals (picornaviruses) and those infecting plants (cowpea mosaic virus) were compared and turned out to share significant sequence similarity and, in part, the order of their genes. In 1986, the first comparative genomic study at a larger scale was published, comparing the genomes of varicella-zoster virus and Epstein-Barr virus that contained more than 100 genes each. The first complete genome sequence of a cellular organism, that of Haemophilus influenzae Rd, was published in 1995. The second genome sequencing paper was of the small parasitic bacterium Mycoplasma genitalium published in the same year. Starting from this paper, reports on new genomes inevitably became comparative-genomic studies. Microbial genomes. The first high-resolution whole genome comparison system of microbial genomes of 10-15kbp was developed in 1998 by Art Delcher, Simon Kasif and Steven Salzberg and applied to the comparison of entire highly related microbial organisms with their collaborators at the Institute for Genomic Research (TIGR). The system is called MUMMER and was described in a publication in Nucleic Acids Research in 1999. The system helps researchers to identify large rearrangements, single base mutations, reversals, tandem repeat expansions and other polymorphisms. In bacteria, MUMMER enables the identification of polymorphisms that are responsible for virulence, pathogenicity, and anti-biotic resistance. The system was also applied to the Minimal Organism Project at TIGR and subsequently to many other comparative genomics projects. Eukaryote genomes. Saccharomyces cerevisiae, the baker's yeast, was the first eukaryote to have its complete genome sequence published in 1996. After the publication of the roundworm Caenorhabditis elegans genome in 1998 and together with the fruit fly Drosophila melanogaster genome in 2000, Gerald M. Rubin and his team published a paper titled "Comparative Genomics of the Eukaryotes", in which they compared the genomes of the eukaryotes D. melanogaster, C. elegans, and S. cerevisiae, as well as the prokaryote H. influenzae. At the same time, Bonnie Berger, Eric Lander, and their team published a paper on whole-genome comparison of human and mouse. With the publication of the large genomes of vertebrates in the 2000s, including human, the Japanese pufferfish Takifugu rubripes, and mouse, precomputed results of large genome comparisons have been released for downloading or for visualization in a genome browser. Instead of undertaking their own analyses, most biologists can access these large cross-species comparisons and avoid the impracticality caused by the size of the genomes. Next-generation sequencing methods, which were first introduced in 2007, have produced an enormous amount of genomic data and have allowed researchers to generate multiple (prokaryotic) draft genome sequences at once. These methods can also quickly uncover single-nucleotide polymorphisms, insertions and deletions by mapping unassembled reads against a well annotated reference genome, and thus provide a list of possible gene differences that may be the basis for any functional variation among strains.

== Evolutionary principles ==

One character of biology is evolution, evolutionary theory is also the theoretical foundation of comparative genomics, and at the same time the results of comparative genomics unprecedentedly enriched and developed the theory of evolution. When two or more of the genome sequence are compared, one can deduce the evolutionary relationships of the sequences in a phylogenetic tree. Based on a variety of biological genome data and the study of vertical and horizontal evolution processes, one can understand vital parts of the gene structure and its regulatory function. Similarity of related genomes is the basis of comparative genomics. If two creatures have a recent common ancestor, the differences between the two species genomes are evolved from the ancestors' genome. The closer the relationship between two organisms, the higher the similarities between their genomes. If there is close relationship between them, then their genome will display a linear behaviour (synteny), namely some or all of the genetic sequences are conserved. Thus, the genome sequences can be used to identify gene function, by analyzing their homology (sequence similarity) to genes of known function.

Orthologous sequences are related sequences in different species: a gene exists in the original species, the species divided into two species, so genes in new species are orthologous to the sequence in the original species. Paralogous sequences are separated by gene cloning (gene duplication): if a particular gene in the genome is copied, then the copy of the two sequences is paralogous to the original gene. A pair of orthologous sequences is called orthologous pairs (orthologs), a pair of paralogous sequence is called collateral pairs (paralogs). Orthologous pairs usually have the same or similar function, which is not necessarily the case for collateral pairs. In collateral pairs, the sequences tend to evolve into having different functions. Comparative genomics exploits both similarities and differences in the proteins, RNA, and regulatory regions of different organisms to infer how selection has acted upon these elements. Those elements that are responsible for similarities between different species should be conserved through time (stabilizing selection), while those elements responsible for differences among species should be divergent (positive selection). Finally, those elements that are unimportant to the evolutionary success of the organism will be unconserved (selection is neutral). One of the important goals of the field is the identification of the mechanisms of eukaryotic genome evolution. It is however often complicated by the multiplicity of events that have taken place throughout the history of individual lineages, leaving only distorted and superimposed traces in the genome of each living organism. For this reason comparative genomics studies of small model organisms (for example the model Caenorhabditis elegans and closely related Caenorhabditis briggsae) are of great importance to advance our understanding of general mechanisms of evolution.

== Role of CNVs in evolution == Comparative genomics plays a crucial role in identifying copy number variations (CNVs) and understanding their significance in evolution. CNVs, which involve deletions or duplications of large segments of DNA, are recognized as a major source of genetic diversity, influencing gene structure, dosage, and regulation. While single nucleotide polymorphisms (SNPs) are more common, CNVs impact larger genomic regions and can have profound effects on phenotype and diversity. Recent studies suggest that CNVs constitute around 4.8–9.5% of the human genome and have a substantial functional and evolutionary impact. In mammals, CNVs contribute significantly to population diversity, influencing gene expression and various phenotypic traits. Comparative genomics analyses of human and chimpanzee genomes have revealed that CNVs may play a greater role in evolutionary change compared to single nucleotide changes. Research indicates that CNVs affect more nucleotides than individual base-pair changes, with about 2.7% of the genome affected by CNVs compared to 1.2% by SNPs. Moreover, while many CNVs are shared between humans and chimpanzees, a significant portion is unique to each species. Additionally, CNVs have been associated with genetic diseases in humans, highlighting their importance in human health. Despite this, many questions about CNVs remain unanswered, including their origin and contributions to evolutionary adaptation and disease. Ongoing research aims to address these questions using techniques like comparative genomic hybridization, which allows for a detailed examination of CNVs and their significance. When investigators examined the raw sequence data of the human and chimpanzee.

== Significance of comparative genomics == Comparative genomics holds profound significance across various fields, including medical research, basic biology, and biodiversity conservation. For instance, in medical research, predicting how genomic variants limited ability to predict which genomic variants lead to changes in organism-level phenotypes, such as increased disease risk in humans, remains challenging due to the immense size of the genome, comprising about three billion nucleotides. To tackle this challenge, comparative genomics offers a solution by pinpointing nucleotide positions that have remained unchanged over millions of years of evolution. These conserved regions indicate potential sites where genetic alterations could have detrimental effects on an organism's fitness, thus guiding the search for disease-causing variants. Moreover, comparative genomics holds promise in unraveling the mechanisms of gene evolution, environmental adaptations, gender-specific differences, and population variations across vertebrate lineages. Furthermore, comparative studies enable the identification of genomic signatures of selection—regions in the genome that have undergone preferential increase and fixation in populations due to their functional significance in specific processes. For instance, in animal genetics, indigenous cattle exhibit superior disease resistance and environmental adaptability but lower productivity compared to exotic breeds. Through comparative genomic analyses, significant genomic signatures responsible for these unique traits can be identified. Using insights from this signature, breeders can make informed decisions to enhance breeding strategies and promote breed development.

== Methods == Computational approaches are necessary for genome comparisons, given the large amount of data encoded in genomes. Many tools are now publicly available, ranging from whole genome comparisons to gene expression analysis. This includes approaches from systems and control, information theory, string analysis and data mining. Computational approaches will remain critical for research and teaching, especially when information science and genome biology is taught in conjunction.

Comparative genomics starts with basic comparisons of genome size and gene density. For instance, genome size is important for coding capacity and possibly for regulatory reasons. High gene density facilitates genome annotation, analysis of environmental selection. By contrast, low gene density hampers the mapping of genetic disease as in the human genome.

=== Sequence alignment === Alignments are used to capture information about similar sequences such as ancestry, common evolutionary descent, or common structure and function. Alignments can be done for both nucleotide and protein sequences. Alignments consist of local or global pairwise alignments, and multiple sequence alignments. One way to find global alignments is to use a dynamic programming algorithm known as Needleman-Wunsch algorithmwhereas Smith–Waterman algorithm used to find local alignments. With the exponential growth of sequence databases and the emergence of longer sequences, there's a heightened interest in faster, approximate, or heuristic alignment procedures. Among these, the FASTA and BLAST algorithms are prominent for local pairwise alignment. Recent years have witnessed the development of programs tailored to aligning lengthy sequences, such as MUMmer (1999), BLASTZ (2003), and AVID (2003). While BLASTZ adopts a local approach, MUMmer and AVID are geared towards global alignment. To harness the benefits of both local and global alignment approaches, one effective strategy involves integrating them. Initially, a rapid variant of BLAST known as BLAT is employed to identify homologous "anchor" regions. These anchors are subsequently scrutinized to identify sets exhibiting conserved order and orientation. Such sets of anchors are then subjected to alignment using a global strategy. Additionally, ongoing efforts focus on optimizing existing algorithms to handle the vast amount of genome sequence data by enhancing their speed. Furthermore, MAVID stands out as another noteworthy pairwise alignment program specifically designed for aligning multiple genomes. Pairwise Comparison: The Pairwise comparison of genomic sequence data is widely utilized in comparative gene prediction. Many studies in comparative functional genomics lean on pairwise comparisons, wherein traits of each gene are compared with traits of other genes across species. his method yields many more comparisons than unique observations, making each comparison dependent on others. Multiple comparisons: The comparison of multiple genomes is a natural extension of pairwise inter-specific comparisons. Such comparisons typically aim to identify conserved regions across two phylogenetic scales: 1. Deep comparisons, often referred to as phylogenetic footprinting reveal conservation across higher taxonomic units like vertebrates. 2. Shallow comparisons, recently termed Phylogenetic shadowing, probe conservation across a group of closely related species.

=== Whole-genome alignment === Whole-genome alignment (WGA) involves predicting evolutionary relationships at the nucleotide level between two or more genomes. It integrates elements of colinear sequence alignment and gene orthology prediction, presenting a greater challenge due to the vast size and intricate nature of whole genomes. Despite its complexity, numerous methods have emerged to tackle this problem because WGAs play a crucial role in various genome-wide analyses, such as phylogenetic inference, genome annotation, and function prediction. Thereby, SyRI (Synteny and Rearrangement Identifier) is one such method that utilizes whole genome alignment and it is designed to identify both structural and sequence differences between two whole-genome assemblies. By taking WGAs as input, SyRI initially scans for disparities in genome structures. Subsequently, it identifies local sequence variations within both rearranged and non-rearranged (syntenic) regions.

=== Phylogenetic reconstruction === Another computational method for comparative genomics is phylogenetic reconstruction. It is used to describe evolutionary relationships in terms of common ancestors. The relationships are usually represented in a tree called a phylogenetic tree. Similarly, coalescent theory is a retrospective model to trace alleles of a gene in a population to a single ancestral copy shared by members of the population. This is also known as the most recent common ancestor. Analysis based on coalescence theory tries predicting the amount of time between the introduction of a mutation and a particular allele or gene distribution in a population. This time period is equal to how long ago the most recent common ancestor existed. The inheritance relationships are visualized in a form similar to a phylogenetic tree. Coalescence (or the gene genealogy) can be visualized using dendrograms.

=== Genome maps === An additional method in comparative genomics is genetic mapping. In genetic mapping, visualizing synteny is one way to see the preserved order of genes on chromosomes. It is usually used for chromosomes of related species, both of which result from a common ancestor. This and other methods can shed light on evolutionary history. A recent study used comparative genomics to reconstruct 16 ancestral karyotypes across the mammalian phylogeny. The computational reconstruction showed how chromosomes rearranged themselves during mammal evolution. It gave insight into conservation of select region...

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Genomics - Biotechnology