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Genetics is the science of heredity and variation in living organisms.[1][2][3] Knowledge that desired characteristics were inherited has been implicitly used since prehistoric times for improving crop plants and animals through selective breeding. However, the modern science of genetics, which seeks to understand the mechanisms of inheritance, only began with the work of Gregor Mendel in the mid-1800s.[4]
Mendel observed that inheritance is fundamentally a discrete process with specific traits that are inherited in an independant manner. These basic units of inheritance is now known as "genes". In the cells of organisms, genes exist physically in the structure of the molecule DNA and the information genes contain is used to create and control the components of cells. Although genetics plays a large role in determining the appearance and behavior of organisms, it is the interaction of genetics with the environment an organism experiences that determines the ultimate outcome. For example, while genes play a role in determining a person's height, the nutrition and health that person experiences in childhood also have a large effect.
At its most fundamental level, inheritance in organisms occurs by means of discrete traits, called "genes".[5] This property was first observed by Gregor Mendel, who studied the segregation of heritable traits in pea plants.[6][7] In his experiments studying the trait for flower color, Mendel observed that the flowers of each pea plant were either purple or white — and never an intermediate between the two colors. These different, discrete versions of the same gene are called "alleles".
In the case of pea plants, each organism has two alleles of each gene, and the plants inherit one allele from each parent.[8] Many organisms, including humans, are diploid, with two alleles for each gene. Organisms with two copies of the same allele are called "homozygous", while organisms with two different alleles are "heterozygous".
The set of alleles for a given organism is called its genotype, while the visible trait the organism has is called its "phenotype". When organisms are heterozygous, often one allele is called "dominant" as its qualities "dominate" the phenotype of the organism, while the other allele is called "recessive" as its qualities "recede" and are not observed. Dominant alleles are often abbreviated with a capital letter, while recessive alleles are given a lowercase version of the same letter.[9] Some alleles do not have complete dominance and instead have incomplete dominance by expressing an intermediate phenotype, or codominance by expressing both alleles at once.[10]
When parents breed to produce children, their children randomly inherit one of the two alleles from each parent. The outcome of these crosses can be visualized by use of a Punnett square. These observations of discrete inheritance and the segregation of alleles are collectively known as "Mendel's first law" or the "Law of Segregation".
Organisms have thousands of genes, and in diploid organism assortment of these genes are generally independent of each other. This means that the inheritance of an allele for yellow or green pea color is unrelated to the inheritance of alleles for white or purple flowers. This phenomenon, known as "Mendel's second law" or the "Law of independent assortment", means that the alleles of different genes get shuffled between parents to form children with many different combinations. (Some genes do not assort independently, demonstrating genetic linkage, a topic discussed later in this article.)
Often different genes can interact in a way that influences the same trait. In the blue-eyed Mary, for example, there exists a gene with alleles that determine the color of flowers: blue or magenta. Another gene, however, controls whether the flowers have color at all: color or white. When a plant has two copies of this white allele, its flowers are white — regardless of whether the first gene has blue or magenta alleles. This interaction between genes is called "epistasis", with the second gene epistatic to the first[11]
Many traits are not discrete features (eg. purple or white flowers) but are instead continuous features (eg. human height and skin color). These "complex traits" are the product of interactions of many genes.[12] The influence of these genes is mediated, to varying degrees, by the enviroment an organism has experienced. The degree to which an organism's genes contribute to a complex trait is called "heritability".[13] Measurement of the heritability of a trait is relative, though — in a more variable environment, the environment has a bigger influence on the total variation of the trait. For example, human height is a complex trait with a heritability of 89% in the United States. In Nigeria, however, where people experience a more variable access to good nutrition and health care, height has a heritability of only 62%.[14]
The molecular basis for genes is deoxyribonucleic acid (DNA). DNA is composed of a chain of nucleotides, of which there are four types: adenine (A), cytosine (C), guanine (G), and thymine (T). Genetic information exists in the sequence of these nucleotides, and genes exist as stretches of sequence along the DNA chain.[15] Viruses are a small exception — the similar molecule RNA instead of DNA is often the genetic material of a virus.[16] In all non-virus organisms, which are composed of cells, each cell contains a full copy of that organism's DNA, called its genome.[17]
In the cell, DNA exists as a double-stranded molecule, coiled into the shape of a double-helix. Each nucleotide in DNA preferentially pairs with its partner nucleotide on the opposite strand: A pairs with T, and C pairs with G. Thus, in its two-stranded form, each strand effectively contains all necessary information, redundant with its partner strand. This structure of DNA is the physical basis for inheritance: DNA replication duplicates the genetic information by splitting the strands and using each strand as a template for a partner strand.[18]
Genes express their functional effect through the production of proteins, which are complex molecules responsible for most functions in the cell. Proteins are chains of amino acids, and the DNA sequence of a gene (through an RNA intermediate) is used to produce a specific protein sequence. Each group of three nucleotides in the sequence, called a codon, corresponds to one of the twenty possibly amino acids in protein — this correspondence is called the genetic code.[19] The specific sequence of amino acids results in a unique three-dimensional structure for that protein, thereby determining its behavior and function.
Genes are arranged linearly along the long chains of DNA sequence, called chromosomes. In bacteria, each cell has a single circular chromosome, while eukaryotic organisms (which includes plants and animals) have their DNA arranged in multiple linear chromosomes. These DNA strands are often extremely long; the largest human chromosome, for example, is about 140 million base pairs in length.[20]The DNA of a chromosome is associated with structural proteins which organize, compact, and control access to the DNA, forming a material called chromatin; in eukaryotes chromatin is usually composed of nucleosomes, repeating units of DNA wound around a core of histone proteins.[21]
While haploid organisms have only one copy of each chromosome, most animals and many plants are diploid, containing two copies of each chromosome and thus two copies of every gene. An exception exists in the sex chromosomes, specialized chromosomes many animals have evolved that play a role in determining the sex of the organism. On the other chromosomes (called autosomes), the two alleles for a gene are located on identical loci of sister chromatids.
The diploid nature of chromosomes allows for genes on different chromosomes to assort independently, thereby recombining to form new combinations of genes. Genes on the same chromosome would theoretically never recombine, however, were it not for the process of chromosomal crossover. During crossover, chromosomes exchange stretches of DNA, effectively shuffling the gene alleles between the chromosomes. This process of chromosomal crossover generally occurs during meiosis, a series of cell divisions that creates haploid germ cells which later combine with other germ cells to form child organisms.
The probability of chromosomal crossover occurring between two given points on the chromosome is related to the distance between them. For an arbitrarily long distance, the probability of crossover is high enough that the inheritance of the genes is effectively uncorrelated. For genes that are closer together, however, the lower probability of crossover means that the genes demonstrate genetic linkage. The linkages between a series of genes can be combined to form a linear linkage map that roughly describes the arrangement of the genes along the chromosome.
Although DNA is the genetic material of life, there are some aspects of cells that are not encoded in DNA sequence (eg. chromatin and DNA modifications) that are inherited by daughter cells when cells divide. These features are called "epigenetic" — the prefix "epi-" means "on top of" or "in addition to". Epigenetic features create differences between cells sharing the same genome, allowing cells to differentiate into different tissues in multicellular organisms. Although epigenetic features are generally dynamic over the development of organisms, some, like the phenomenon of paramutation, have multigenerational inheritance.
Although geneticists originally studied inheritance in a wide range of organisms, researchers began to specialize in studying the genetics of a particular subset of organisms. The fact that significant research already existed for a given organism would encourage new researchers to choose it for further study, and so eventually a few "model organisms" became the basis for most genetics research. Common research topics in model organism genetics include the study of gene regulation and the involvement of genes in development and cancer.
Organisms were chosen, in part, for convenience — short generation times and facile genetic manipulation made some organisms popular genetics research tools. Widely used model organisms include the gut bacterium Escherichia coli, the plant Arabidopsis thaliana, baker's yeast (Saccharomyces cerevisiae), the nematode Caenorhabditis elegans, the common fruit fly (Drosophila melanogaster), and the common house mouse (Mus musculus).
Medical genetics research seeks to find and study the genetic causes of human diseases. When searching for an unknown gene that may be involved in a disease, researchers commonly use genetics linkage and genetic pedigree charts to find the location on the genome associated with the disease. At the population level, researchers take advantage of Mendelian randomization to look for locations in the genome that are associated with diseases, a technique especially useful for multigenic traits not clearly defined by a single gene. Once a candidate gene is found, further research is often done on the same gene (called an orthologous gene) in model organisms.
A variety of techniques exist for manipulating DNA in the laboratory. Restriction enzymes are a commonly used enzyme that cuts DNA at specific sequences, producing predictable fragments of DNA. The use of ligation enzymes allows these fragments to be stitched back together, and by ligating fragments of DNA together from different sources, researchers can create recombinant DNA. Often associated with genetically modified organisms, recombinant DNA is commonly used in the context of plasmids — short circular DNA fragments with a few genes on them. By inserting plasmids into bacteria and growing those bacteria on plates of agar (to isolate clones of bacteria cells), researchers can clonally amplify the inserted fragment of DNA (a process known as molecular cloning). (Cloning can also refer to the creation of clonal organisms, through various techniques.)
DNA can also be amplified using a procedure called the polymerase chain reaction (PCR). By using specific short sequences of DNA, PCR can exponentially amplify a targeted region of DNA. Because it can amplify from extremely small amounts of DNA, PCR is often used to detect the presence of specific DNA sequences.
One of the most fundamental technologies developed to study genetics, DNA sequencing allows researchers to determine the sequence of nucleotides in DNA fragments. Developed in 1978 by Frederick Sanger and coworkers, chain-termination sequencing is now routinely used to sequence DNA fragments. With this technology, researchers have been able to study the molecular sequences associated with many human diseases. As sequencing has become less expensive and with the aid of computational tools, researchers have sequenced the genomes of many organisms by stitching together the sequences of many different fragments (a process called "genome assembly"). The Human genome project was completed in 2005, sequencing the genome to 92% coverage.
The large amount of sequences available has created the field of "genomics", research which uses computational tools to search for and analyze patterns in the full genomes of organisms. Genomics can also be considered a subfield of bioinformatics, which uses computational approaches to analyze of large sets of biological data.
During the process of DNA replication, errors occassionally occur in the polymerization of the second strand (these error rates are generally extremely low, 1 error in every 10-100 million bases).[22] These errors, called mutations, can have an impact on the phenotype of an organism, especially if they occur within the protein coding sequence of a gene. Processes which increase the rate of changes in DNA are called "mutagenic": mutagenic chemicals promote errors in DNA replication, often by interfering with the structure of base-pairing, while UV radiation induces mutations by causing damage to the DNA structure. Chemical damage to DNA occurs naturally as well, and cells use DNA repair mechanisms to repair mismatches and breaks in DNA -- nevertheless, the repair sometimes fails to return the DNA to its original sequence.
In organisms which use chromosomal crossover to exchange DNA and shuffle genes, errors in alignment during meiosis can also cause mutations. Errors in crossover are especially likely when similar sequences cause partner chromosomes to adopt a mistaken alignment, which makes some regions in genomes more prone to mutating in this way. These errors create large structural changes in DNA sequence -- duplications, inversions or deletions of entire regions, or the accidental exchanging of whole parts between different chromosomes (called "translocation").
Mutations produce organisms with different genotypes, and those differences can result in different phenotypes. Many genetic mutations, called "neutral mutations", have a negligible effect on an organism's phenotype, health, and reproductive fitness. Mutations which do have an effect are often deleterious, but occassionally mutations arise which are beneficial in the current environmental context of the organism.
Population genetics research studies the distributions of these genetic differences within populations and how the distributions change over time. Changes in the frequency of an allele in a population can be influenced by natural selection, where a given allele's higher rate of survival and reproduction causes it to become more frequent in the population over time. Genetic drift can also occur, where chance events lead to random changes in allele frequency.
Over many generations, the genomes of organisms can change, resulting in the phenomenon of evolution. Mutations and the selection for beneficial mutations can cause a species to evolve into forms that better survive their environment, a process called adaptation. New species are formed through the process of speciation, a process often caused by geographical separations that allow different populations to genetically diverge.
As sequences diverge and change during the process of evolution, these differences between sequences can be used as a molecular clock to calculate the evolutionary distance between them. Genetic comparisons are generally considered the most accurate method of characterizing the relatedness between species, an improvement over the sometimes deceptive comparison of phenotypic characteristics. The evolutionary distances between species can be combined to form evolutionary trees. These trees are commonly considered the most accurate representation of relatedness, although the transfer of genetic material between unrelated species (known as "horizontal gene transfer" and most common in bacteria) cannot be represented by the tree.
Gregor Johann Mendel, a German-Czech Augustinian monk and scientist, is often called the "father of modern genetics", a title given to him due to his early work on the heredity of plants. In his paper "Versuche über Pflanzenhybriden" ("Experiments on Plant Hybridization"), presented in 1865 to the Brunn Natural History Society, Gregor Mendel traced the inheritance patterns of certain traits in pea plants and showed that they could be described mathematically.[6] Although not all features show these patterns of Mendelian inheritance, his work suggested the utility of the application of statistics to the study of inheritance.
The significance of Mendel's observations was not understood until early in the twentieth century, after his death, when his research was re-discovered by other scientists working on similar problems. The word "genetics" itself was coined by William Bateson, a significant proponent of Mendel's work, in a letter to Adam Sedgwick, dated April 18, 1905.[23] Bateson promoted the term "genetics" publicly in his inaugural address to the Third International Conference on Plant Hybridization (London, England) in 1906.[24]
In the decades following rediscovery and popularization of Mendel's work, numerous experiments sought to elucidate the molecular basis of DNA. In 1910 Thomas Hunt Morgan argued that genes reside on chromosomes, based observations of a sex-linked white eye mutation in fruit flies. In 1913 his student Alfred Sturtevant used the phenomenon of genetic linkage and the associated recombination rates to demonstrate and map the linear arrangement of genes upon the chromosome.
Although chromosomes were known to contain genes, chromosomes were composed of both protein and DNA — it was unknown which was critical for heredity or how the process occurred. In 1928, Frederick Griffith published his discovery of the phenomenon of transformation (see Griffith's experiment); sixteen years later, in 1944, Oswald Theodore Avery, Colin McLeod and Maclyn McCarty used this phenomenon to isolate and identify the molecule responsible for transformation as DNA.[25] The Hershey-Chase experiment in 1952 identified DNA (rather than protein) as the genetic material of viruses, further evidence that DNA was the molecule responsible for inheritance.
James D. Watson and Francis Crick resolved the structure of DNA in 1953, using the X-ray crystallography work of Rosalind Franklin that indicated the molecule had a helical structure. Their double-helix model paired a sequence of nucleotides with a "complement" on the other strand. This structure not only provided a physical explanation for information contained within the order of the nucleotides, but also a physical mechanism for duplication through separation of strands and the reconstruction of a partner strand based on the nucleotide pairings. They famously observed this in their paper, stating: "It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material."
In the following decades, an explosion of research based on this understanding of the molecular nature of DNA became possible. The development of chain-termination DNA sequencing in 1977 enabled the determination of nucleotide sequences on DNA,[26] and the PCR method developed by Kary Banks Mullis in 1983 allowed the isolation and amplification of arbitrary segments of DNA.[27] These and other techniques, through the pooled efforts of the Human Genome Project and parallel private effort by Celera Genomics, culminated in the sequencing of the human genome in 2001.
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