Gene regulation
The regulation of gene expression (or gene regulation) by environmental factors and during different stages of development can occur at each step of the process such as transcription, RNA splicing, translation, and post-translational modification of a protein.[86]
The ability of gene transcription to be regulated allows for the conservation of energy as cells will only make proteins when needed.[86] Gene expression can be influenced by positive or negative regulation, depending on which of the two types of regulatory proteins called transcription factors bind to the DNA sequence close to or at a promoter.[86] A cluster of genes that share the same promoter is called an operon, found mainly in prokaryotes and some lower eukaryotes (e.g., Caenorhabditis elegans).[86][87] It was first identified in Escherichia coli—a prokaryotic cell that can be found in the intestines of humans and other animals—in the 1960s by François Jacob and Jacques Monod.[86] They studied the prokaryotic cell's lac operon, which is part of three genes (lacZ, lacY, and lacA) that encode three lactose-metabolizing enzymes (β-galactosidase, β-galactoside permease, and β-galactoside transacetylase).[86] In positive regulation of gene expression, the activator is the transcription factor that stimulates transcription when it binds to the sequence near or at the promoter. In contrast, negative regulation occurs when another transcription factor called a repressor binds to a DNA sequence called an operator, which is part of an operon, to prevent transcription. When a repressor binds to a repressible operon (e.g., trp operon), it does so only in the presence of a corepressor. Repressors can be inhibited by compounds called inducers (e.g., allolactose), which exert their effects by binding to a repressor to prevent it from binding to an operator, thereby allowing transcription to occur.[86] Specific genes that can be activated by inducers are called inducible genes (e.g., lacZ or lacA in E. coli), which are in contrast to constitutive genes that are almost always active.[86] In contrast to both, structural genes encode proteins that are not involved in gene regulation.[86]
In prokaryotic cells, transcription is regulated by proteins called sigma factors, which bind to RNA polymerase and direct it to specific promoters.[86] Similarly, transcription factors in eukaryotic cells can also coordinate the expression of a group of genes, even if the genes themselves are located on different chromosomes.[86] Coordination of these genes can occur as long as they share the same regulatory DNA sequence that bind to the same transcription factors.[86] Promoters in eukaryotic cells are more diverse but tend to contain a core sequence that RNA polymerase can bind to, with the most common sequence being the TATA box, which contains multiple repeating A and T bases.[86] Specifically, RNA polymerase II is the RNA polymerase that binds to a promoter to initiate transcription of protein-coding genes in eukaryotes, but only in the presence of multiple general transcription factors, which are distinct from the transcription factors that have regulatory effects, i.e., activators and repressors.[86] In eukaryotic cells, DNA sequences that bind with activators are called enhances whereas those sequences that bind with repressors are called silencers.[86] Transcription factors such as nuclear factor of activated T-cells (NFAT) are able to identify specific nucleotide sequence based on the base sequence (e.g., CGAGGAAAATTG for NFAT) of the binding site, which determines the arrangement of the chemical groups within that sequence that allows for specific DNA-protein interactions.[86] The expression of transcription factors is what underlies cellular differentiation in a developing embryo.[86]
In addition to regulatory events involving the promoter, gene expression can also be regulated by epigenetic changes to chromatin, which is a complex of DNA and protein found in eukaryotic cells.[86]
Post-transcriptional control of mRNA can involve the alternative splicing of primary mRNA transcripts, resulting in a single gene giving rise to different mature mRNAs that encode a family of different proteins.[86][88] A well-studied example is the Sxl gene in Drosophila, which determines the sex in these animals. The gene itself contains four exons and alternative splicing of its pre-mRNA transcript can generate two active forms of the Sxl protein in female flies and one in inactive form of the protein in males.[86] Another example is the human immunodeficiency virus (HIV), which has a single pre-mRNA transcript that can generate up to nine proteins as a result of alternative splicing.[86] In humans, eighty percent of all 21,000 genes are alternatively spliced.[86] Given that both chimpanzees and humans have a similar number of genes, it is thought that alternative splicing might have contributed to the latter's complexity due to the greater number of alternative splicing in the human brain than in the brain of chimpanzees.[86]
Translation can be regulated in three known ways, one of which involves the binding of tiny RNA molecules called microRNA (miRNA) to a target mRNA transcript, which inhibits its translation and causes it to degrade.[86] Translation can also be inhibited by the modification of the 5' cap by substituting the modified guanosine triphosphate (GTP) at the 5' end of an mRNA for an unmodified GTP molecule.[86] Finally, translational repressor proteins can bind to mRNAs and prevent them from attaching to a ribosome, thereby blocking translation.[86]
Once translated, the stability of proteins can be regulated by being targeted for degradation.[86] A common example is when an enzyme attaches a regulatory protein called ubiquitin to the lysine residue of a targeted protein.[86] Other ubiquitins then attached to the primary ubiquitin to form a polyubiquitinated protein, which then enters a much larger protein complex called proteasome.[86] Once the polyubiquitinated protein enters the proteasome, the polyubiquitin detaches from the target protein, which is unfolded by the proteasome in an ATP-dependent manner, allowing it to be hydrolyzed by three proteases.[86]
Genomes
A genome is an organism's complete set of DNA, including all of its genes.[89] Sequencing and analysis of genomes can be done using high throughput DNA sequencing and bioinformatics to assemble and analyze the function and structure of entire genomes.[90][91][92] The genomes of prokaryotes are small, compact, and diverse. In contrast, the genomes of eukaryotes are larger and more complex such as having more regulatory sequences and much of its genome are made up of non-coding DNA sequences for functional RNA (rRNA, tRNA, and mRNA) or regulatory sequences. The genomes of various model organisms such as arabidopsis, fruit fly, mice, nematodes, and yeast have been sequenced. The Human Genome Project was a major undertaking by the international scientific community to sequence the entire human genome, which was completed in 2003.[93] The sequencing of the human genome has yielded practical applications such as DNA fingerprinting, which can be used for paternity testing and forensics. In medicine, sequencing of the entire human genome has allowed for the identification of mutations that cause tumors as well as genes that cause a specific genetic disorder.[93] The sequencing of genomes from various organisms has led to the emergence of comparative genomics, which aims to draw comparisons of genes from the genomes of those different organisms.[93]
Many genes encode more than one protein, with posttranslational modifications increasing the diversity of proteins within a cell. An organism's proteome is its entire set of proteins expressed by its genome and proteomics seeks to study the complete set of proteins produced by an organism.[93] Because many proteins are enzymes, their activities tend to affects the concentrations of substrates and products. Thus, as the proteome changes, so do the amount of small molecules or metabolites.[93] The complete set of small molecules in a cell or organism is called a metabolome and metabolomics is the study of the metabolome in relation to the physiological activity of a cell or organism.[93]
Biotechnology
Biotechnology is the use of cells or organisms to develop products for humans.[94] One commonly used technology with wide applications is the creation of recombinant DNA, which is a DNA molecule assembled from two or more sources in a laboratory. Before the advent of polymerase chain reaction, biologists would manipulate DNA by cutting it into smaller fragments using restriction enzymes. They would then purify and analyze the fragments using gel electrophoresis and then later recombine the fragments into a novel DNA sequence using DNA ligase.[94] The recombinant DNA is then cloned by inserting it into a host cell, a process known as transformation if the host cells were bacteria such as E. coli, or transfection if the host cells were eukaryotic cells like yeast, plant, or animal cells. Once the host cell or organism has received and integrated the recombinant DNA, it is described as transgenic.[94]
A recombinant DNA can be inserted in one of two ways. A common method is to simply insert the DNA into a host chromosome, with the site of insertion being random.[94] Another approach would be to insert the recombinant DNA as part of another DNA sequence called a vector, which then integrates into the host chromosome or has its own origin of DNA replication, thereby allowing to replicate independently of the host chromosome.[94] Plasmids from bacterial cells such as E. coli are typically used as vectors due to their relatively small size (e.g. 2000–6000 base pairs in E. coli), presence of restriction enzymes, genes that are resistant to antibiotics, and the presence of an origin of replication.[94] A gene coding for a selectable marker such as antibiotic resistance is also incorporated into the vector.[94] Inclusion of this market allows for the selection of only those host cells that contained the recombinant DNA while discarding those that do not.[94] Moreover, the marker also serves as a reporter gene that once expressed, can be easily detected and measured.[94]
Once the recombinant DNA is inside individual bacterial cells, those cells are then plated and allowed to grow into a colony that contains millions of transgenic cells that carry the same recombinant DNA.[95] These transgenic cells then produce large quantities of the transgene product such as human insulin, which was the first medicine to be made using recombinant DNA technology.[94]
One of the goals of molecular cloning is to identify the function of specific DNA sequences and the proteins they encode.[94] For a specific DNA sequence to be studied and manipulated, millions of copies of DNA fragments containing that DNA sequence need to be made.[94] This involves breaking down an intact genome, which is much too large to be introduced into a host cell, into smaller DNA fragments. Although no longer intact, the collection of these DNA fragments still make up an organism's genome, with the collection itself being referred to as a genomic library, due to the ability to search and retrieve specific DNA fragments for further study, analogous to the process of retrieving a book from a regular library.[94] DNA fragments can be obtained using restriction enzymes and other processes such as mechanical shearing. Each obtained fragment is then inserted into a vector that is taken up by a bacterial host cell. The host cell is then allowed to proliferate on a selective medium (e.g., antibiotic resistance), which produces a colony of these recombinant cells, each of which contains many copies of the same DNA fragment.[94] These colonies can be grown by spreading them over a solid medium in Petri dishes, which are incubated at a suitable temperature. One dish alone can hold thousands of bacterial colonies, which can be easily screened for a specific DNA sequence.[94] The sequence can be identified by first duplicating a Petri dish with bacterial colonies and then exposing the DNA of the duplicated colonies for hybridization, which involves labeling them with complementary radioactive or fluorescent nucleotides.[94]
Smaller DNA libraries that contain genes from a specific tissue can be created using complementary DNA (cDNA).[94] The collection of these cDNAs from a specific tissue at a particular time is called a cDNA library, which provides a "snapshot" of transcription patterns of cells at a specific location and time.[94]
Other biotechnology tools include DNA microarrays, expression vectors, synthetic genomics, and CRISPR gene editing.[94][96] Other approaches such as pharming can produce large quantities of medically useful products through the use of genetically modified organisms.[94] Many of these other tools also have wide applications such as creating medically useful proteins, or improving plant cultivation and animal husbandry.[94]
Genes, development, and evolution
Development is the process by which a multicellular organism (plant or animal) goes through a series of a changes, starting from a single cell, and taking on various forms that are characteristic of its life cycle.[98] There are four key processes that underlie development: Determination, differentiation, morphogenesis, and growth. Determination sets the developmental fate of a cell, which becomes more restrictive during development. Differentiation is the process by which specialized cells from less specialized cells such as stem cells.[99][100] Stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell.[101] Cellular differentiation dramatically changes a cell's size, shape, membrane potential, metabolic activity, and responsiveness to signals, which are largely due to highly controlled modifications in gene expression and epigenetics. With a few exceptions, cellular differentiation almost never involves a change in the DNA sequence itself.[102] Thus, different cells can have very different physical characteristics despite having the same genome. Morphogenesis, or development of body form, is the result of spatial differences in gene expression.[98] Specially, the organization of differentiated tissues into specific structures such as arms or wings, which is known as pattern formation, is governed by morphogens, signaling molecules that move from one group of cells to surrounding cells, creating a morphogen gradient as described by the French flag model. Apoptosis, or programmed cell death, also occurs during morphogenesis, such as the death of cells between digits in human embryonic development, which frees up individual fingers and toes. Expression of transcription factor genes can determine organ placement in a plant and a cascade of transcription factors themselves can establish body segmentation in a fruit fly.[98]
A small fraction of the genes in an organism's genome called the developmental-genetic toolkit control the development of that organism. These toolkit genes are highly conserved among phyla, meaning that they are ancient and very similar in widely separated groups of animals. Differences in deployment of toolkit genes affect the body plan and the number, identity, and pattern of body parts. Among the most important toolkit genes are the Hox genes. Hox genes determine where repeating parts, such as the many vertebrae of snakes, will grow in a developing embryo or larva.[103] Variations in the toolkit may have produced a large part of the morphological evolution of animals. The toolkit can drive evolution in two ways. A toolkit gene can be expressed in a different pattern, as when the beak of Darwin's large ground-finch was enlarged by the BMP gene,[104] or when snakes lost their legs as Distal-less (Dlx) genes became under-expressed or not expressed at all in the places where other reptiles continued to form their limbs.[105] Or, a toolkit gene can acquire a new function, as seen in the many functions of that same gene, distal-less, which controls such diverse structures as the mandible in vertebrates,[106][107] legs and antennae in the fruit fly,[108] and eyespot pattern in butterfly wings.[109] Given that small changes in toolbox genes can cause significant changes in body structures, they have often enabled convergent or parallel evolution.
Evolution
Evolutionary processes
A central organizing concept in biology is that life changes and develops through evolution, which is the change in heritable characteristics of populations over successive generations.[110][111] Evolution is now used to explain the great variations of life on Earth. The term evolution was introduced into the scientific lexicon by Jean-Baptiste de Lamarck in 1809.[112][113] He proposed that evolution occurred as a result of inheritance of acquired characteristics, which was unconvincing but there were no alternative explanations at the time.[112] Charles Darwin, an English naturalist, had returned to England in 1836 from his five-year travels on the HMS Beagle where he studied rocks and collected plants and animals from various parts of the world such as the Galápagos Islands.[112] He had also read Principles of Geology by Charles Lyell and An Essay on the Principle of Population by Thomas Malthus and was influenced by them.[114] Based on his observations and readings, Darwin began to formulate his theory of evolution by natural selection to explain the diversity of plants and animals in different parts of the world.[112][114] Alfred Russel Wallace, another English naturalist who had studied plants and animals in the Malay Archipelago, also came to the same idea, but later and independently of Darwin.[112] Both Darwin and Wallace jointly presented their essay and manuscript, respectively, at the Linnaean Society of London in 1858, giving them both credit for their discovery of evolution by natural selection.[112][115][116][117][118] Darwin would later publish his book On the Origin of Species in 1859, which explained in detail how the process of evolution by natural selection works.[112]
To explain natural selection, Darwin drew an analogy with humans modifying animals through artificial selection, whereby animals were selectively bred for specific traits, which has given rise to individuals that no longer resemble their wild ancestors.[114] Darwin argued that in the natural world, it was nature that played the role of humans in selecting for specific traits. He came to this conclusion based on two observations and two inferences.[114] First, members of any population tend to vary with respect to their heritable traits. Second, all species tend to produce more offspring than can be supported by their respective environments, resulting in many individuals not surviving and reproducing.[114] Based on these observations, Darwin inferred that those individuals who possessed heritable traits that are better adapted to their environments are more likely to survive and produce more offspring than other individuals.[114] He further inferred that the unequal or differential survival and reproduction of certain individuals over others will lead to the accumulation of favorable traits over successive generations, thereby increasing the match between the organisms and their environment.[114][119][120] Thus, taken together, natural selection is the differential survival and reproduction of individuals in subsequent generations due to differences in or more heritable traits.[121][114][112]
Darwin was not aware of Mendel's work of inheritance and so the exact mechanism of inheritance that underlie natural selection was not well-understood[122] until the early 20th century when the modern synthesis reconciled Darwinian evolution with classical genetics, which established a neo-Darwinian perspective of evolution by natural selection.[121] This perspective holds that evolution occurs when there are changes in the allele frequencies within a population of interbreeding organisms. In the absence of any evolutionary process acting on a large random mating population, the allele frequencies will remain constant across generations as described by the Hardy–Weinberg principle.[123]
Another process that drives evolution is genetic drift, which is the random fluctuations of allele frequencies within a population from one generation to the next.[124] When selective forces are absent or relatively weak, allele frequencies are equally likely to drift upward or downward at each successive generation because the alleles are subject to sampling error.[125] This drift halts when an allele eventually becomes fixed, either by disappearing from the population or replacing the other alleles entirely. Genetic drift may therefore eliminate some alleles from a population due to chance alone.
Speciation
A species is a group of organisms that mate with one another and speciation is the process by which one lineage splits into two lineages as a result of having evolved independently from each other.[126] For speciation to occur, there has to be reproductive isolation.[126] Reproductive isolation can result from incompatibilities between genes as described by Bateson–Dobzhansky–Muller model. Reproductive isolation also tends to increase with genetic divergence. Speciation can occur when there are physical barriers that divide an ancestral species, a process known as allopatric speciation.[126] In contrast, sympatric speciation occurs in the absence of physical barriers.
Pre-zygotic isolation such as mechanical, temporal, behavioral, habitat, and gametic isolations can prevent different species from hybridizing.[126] Similarly, post-zygotic isolations can result in hybridization being selected against due to the lower viability of hybrids or hybrid infertility (e.g., mule). Hybrid zones can emerge if there were to be incomplete reproductive isolation between two closely related species.
Phylogeny
A phylogeny is an evolutionary history of a specific group of organisms or their genes.[127] It can be represented using a phylogenetic tree, which is a diagram showing lines of descent among organisms or their genes. Each line drawn on the time axis of a tree represents a lineage of descendants of a particular species or population. When a lineage divides into two, it is represented as a node (or split) on the phylogenetic tree. The more splits there are over time, the more branches there will be on the tree, with the common ancestor of all the organisms in that tree being represented by the root of that tree. Phylogenetic trees may portray the evolutionary history of all life forms, a major evolutionary group (e.g., insects), or an even smaller group of closely related species. Within a tree, any group of species designated by a name is a taxon (e.g., humans, primates, mammals, or vertebrates) and a taxon that consists of all its evolutionary descendants is a clade, otherwise known as a monophyletic taxon.[127] Closely related species are referred to as sister species and closely related clades are sister clades. In contrast to a monophyletic group, a polyphyletic group does not include its common ancestor whereas a paraphyletic group does not include all the descendants of a common ancestor.[127]
Phylogenetic trees are the basis for comparing and grouping different species.[127] Different species that share a feature inherited from a common ancestor are described as having homologous features (or synapomorphy).[128][129][127] Homologous features may be any heritable traits such as DNA sequence, protein structures, anatomical features, and behavior patterns. A vertebral column is an example of a homologous feature shared by all vertebrate animals. Traits that have a similar form or function but were not derived from a common ancestor are described as analogous features. Phylogenies can be reconstructed for a group of organisms of primary interests, which are called the ingroup. A species or group that is closely related to the ingroup but is phylogenetically outside of it is called the outgroup, which serves a reference point in the tree. The root of the tree is located between the ingroup and the outgroup.[127] When phylogenetic trees are reconstructed, multiple trees with different evolutionary histories can be generated. Based on the principle of Parsimony (or Occam's razor), the tree that is favored is the one with the fewest evolutionary changes needed to be assumed over all traits in all groups. Computational algorithms can be used to determine how a tree might have evolved given the evidence.[127]
Phylogeny provides the basis of biological classification, which is based on Linnaean taxonomy that was developed by Carl Linnaeus in the 18th century.[127] This classification system is rank-based, with the highest rank being the domain followed by kingdom, phylum, class, order, family, genus, and species.[127] All organisms can be classified as belonging to one of three domains: Archaea (originally Archaebacteria); bacteria (originally eubacteria), or eukarya (includes the protist, fungi, plant, and animal kingdoms).[130] A binomial nomenclature is used to classify different species. Based on this system, each species is given two names, one for its genus and another for its species.[127] For example, humans are Homo sapiens, with Homo being the genus and sapiens being the species. By convention, the scientific names of organisms are italicized, with only the first letter of the genus capitalized.[131][132]
History of life
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The history of life on Earth traces the processes by which organisms have evolved from the earliest emergence of life to present day. Earth formed about 4.5 billion years ago and all life on Earth, both living and extinct, descended from a last universal common ancestor that lived about 3.5 billion years ago.[133][134] The dating of the Earth's history can be done using several geological methods such as stratigraphy, radiometric dating, and paleomagnetic dating.[135] Based on these methods, geologists have developed a geologic time scale that divides the history of the Earth into major divisions, starting with four eons (Hadean, Archean, Proterozoic, and Phanerozoic), the first three of which are collectively known as the Precambrian, which lasted approximately 4 billion years.[135] Each eon can be divided into eras, with the Phanerozoic eon that began 539 million years ago[136] being subdivided into Paleozoic, Mesozoic, and Cenozoic eras.[135] These three eras together comprise eleven periods (Cambrian, Ordovician, Silurian, Devonian, Carboniferous, Permian, Triassic, Jurassic, Cretaceous, Tertiary, and Quaternary) and each period into epochs.[135]
The similarities among all known present-day species indicate that they have diverged through the process of evolution from their common ancestor.[137] Biologists regard the ubiquity of the genetic code as evidence of universal common descent for all bacteria, archaea, and eukaryotes.[138][10][139][140] Microbal mats of coexisting bacteria and archaea were the dominant form of life in the early Archean epoch and many of the major steps in early evolution are thought to have taken place in this environment.[141] The earliest evidence of eukaryotes dates from 1.85 billion years ago,[142][143] and while they may have been present earlier, their diversification accelerated when they started using oxygen in their metabolism. Later, around 1.7 billion years ago, multicellular organisms began to appear, with differentiated cells performing specialised functions.[144]
Algae-like multicellular land plants are dated back even to about 1 billion years ago,[145] although evidence suggests that microorganisms formed the earliest terrestrial ecosystems, at least 2.7 billion years ago.[146] Microorganisms are thought to have paved the way for the inception of land plants in the Ordovician period. Land plants were so successful that they are thought to have contributed to the Late Devonian extinction event.[147]
Ediacara biota appear during the Ediacaran period,[148] while vertebrates, along with most other modern phyla originated about 525 million years ago during the Cambrian explosion.[149] During the Permian period, synapsids, including the ancestors of mammals, dominated the land,[150] but most of this group became extinct in the Permian–Triassic extinction event 252 million years ago.[151] During the recovery from this catastrophe, archosaurs became the most abundant land vertebrates;[152] one archosaur group, the dinosaurs, dominated the Jurassic and Cretaceous periods.[153] After the Cretaceous–Paleogene extinction event 66 million years ago killed off the non-avian dinosaurs,[154] mammals increased rapidly in size and diversity.[155] Such mass extinctions may have accelerated evolution by providing opportunities for new groups of organisms to diversify.[156]
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