Genetics

Genetics is the science of heredity and variation in living organisms.^[1][2] Knowledge of the inheritance of characteristics 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.^[3] Although he did not know the physical basis for heredity, Mendel observed that inheritance is fundamentally a discrete process with specific traits that are inherited in an independent manner %u2014 these basic units of inheritance are now called genes.

Following the rediscovery of Mendel's observations in the early 1900s, research in 1910s yielded the first physical understanding of inheritance %u2014 that genes are arranged linearly along large cellular structures called chromosomes. By the 1950s it was understood that the core of a chromosome was a long molecule called DNA and genes existed as linear sections within the molecule. A single strand of DNA is a chain of four types of nucleotides; hereditary information is contained within the sequence of these nucleotides. Solved by Watson and Crick in 1953, DNA's three-dimensional structure is a double-stranded helix, with the nucleotides on each strand complementary to each other. Each strand acts as a template for synthesis of a new partner strand, providing the physical mechanism for the inheritance of information.

The sequence of nucleotides in DNA is used to produce specific sequences of amino acids, creating proteins %u2014 a correspondence known as the "genetic code". This sequence of amino acids in a protein determines how it folds into a three-dimensional structure, this structure is in turn responsible for the protein's function. Proteins are responsible for almost all functional roles in the cell. A change to DNA sequence can change a protein's structure and behavior, and this can have dramatic consequences in the cell and on the organism as a whole.

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.

History of genetics

Main article: History of genetics

Morgan's observation of sex-linked inheritance of a mutation causing white eyes in Drosophila led him to the hypothesis that genes are located upon chromosomes.

Although the science of genetics has its origins in the work of Gregor Mendel in the mid-1800s, various theories of inheritance preceded Mendel. These theories generally assumed that there existed an inheritance of acquired characteristics (also known as "soft inheritance"): the belief that individuals inherit traits that have been strengthened in their parents. Today, the theory is commonly associated with Jean-Baptiste Lamarck, who used this pattern of inheritance to explain the evolution of various traits within species (these changes are now understood to be the product of natural selection rather than a product of soft inheritance).

Mendelian and classical genetics

The modern science of genetics traces its roots to the observations made by Gregor Johann Mendel, a German-Czech Augustinian monk and scientist who made detailed studies of the nature of inheritance in 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.^[4] 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 in 1905 by William Bateson, a significant proponent of Mendel's work, in a letter to Adam Sedgwick.^[5] The adjective "genetic" (derived from the Greek word "genno" %u03B3%u03B5%u03BD%u03BD%u03CE: to give birth) predates the noun, dating back to the 1830's and first used in the biological sense in 1859 by Charles Darwin in the The Origin of Species.^[6] Bateson publicly promoted and popularized usage of word "genetics" to describe the study of inheritance in his inaugural address to the Third International Conference on Plant Hybridization in London, England, in 1906.^[7]

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 on 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.

Francis Crick's first sketch of a DNA double helix.

Molecular genetics

Although chromosomes were known to contain genes, chromosomes were composed of both protein and DNA %u2014 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 THIS IS ALL TRUE transformation as DNA.^[8] 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. Although the structure explained the process of inheritance, it was still unknown how DNA influenced the behavior of cells. In the following years many scientists sought to understand how DNA controls the process of protein production within ribosomes, eventually discovering the transcription of DNA into messenger RNA and uncovering the genetic code which links the nucleotide sequence of messenger RNA to the amino acid sequence of protein.

With this molecular understanding of DNA, 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,^[9] and the PCR method developed by Kary Banks Mullis in 1983 allowed the isolation and amplification of arbitrary segments of DNA.^[10] 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.

Features of inheritance

Discrete inheritance and Mendel's laws

Main article: Mendelian inheritance

At its most fundamental level, inheritance in organisms occurs by means of discrete traits, called "genes".^[11] This property was first observed by Gregor Mendel, who studied the segregation of heritable traits in pea plants.^[4][12] In his experiments studying the trait for flower color, Mendel observed that the flowers of each pea plant were either purple or white %u2014 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.^[13] Many organisms, including humans, have this pattern of inheritance. 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 observable 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.^[14] 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.^[15]

When a pair of organisms reproduce sexually, their offspring 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".

Assortment and interactions of multiple genes

Human height is a complex genetic trait. Francis Galton's data from 1889 shows the relationship between offsping height as a function of mean parent height. While correlated, the remaining variation in offspring heights indicates environment is also an important factor in this trait.

Organisms have thousands of genes, and in sexually reproducing organisms 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 offspring 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 %u2014 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.^[16]

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.^[17] The influence of these genes is mediated, to varying degrees, by the environment an organism has experienced. The degree to which an organism's genes contribute to a complex trait is called "heritability".^[18] Measurement of the heritability of a trait is relative, though %u2014 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%.^[19]

The molecular basis for inheritance

DNA and chromosomes

Main articles: DNA and Chromosome

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.^[20] Viruses are the only exception to this rule %u2014 sometimes viruses use the very similar molecule RNA instead of DNA as their genetic material.^[21] The full set of all hereditary material in an organism is called its "genome".

DNA normally 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 synthesis of a new partner strand.^[22]

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 247 million base pairs in length.^[23] 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.^[24] The full set of hereditary material in an organism (usually the combined DNA sequences of all chromosomes) is called the "genome".

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.^[25] The two alleles for a gene are located on identical loci of sister chromatids, each allele inherited from a different parent.

Walther Flemming's 1882 diagram of eukaryotic cell division. Chromosomes are copied, condensed, and organized. Then, as the cell divides, chromosome copies separate into the daughter cells.

An exception exists in the sex chromosomes, specialized chromosomes many animals have evolved that play a role in determining the sex of the organism.^[26] In humans and other mammals the Y chromosome has very few genes and triggers the development of male sexual characteristics, while the X chromosome is similar to the other chromosomes and contains many genes unrelated to sex determination. Females have two copies of the X chromosome, but males have one Y and only one X chromosome %u2014 this difference in X chromosome copy numbers leads to the unusual inheritance patterns of sex linked disorders.

Reproduction

Main articles: Asexual reproduction and Sexual reproduction

When cells divide, their full genome is copied and each daughter cell inherits one copy. This is a simplest form of reproduction and is the basis for asexual reproduction. Asexual reproduction can also occur in multicellular organisms, always producing offspring which each inherit a full copy of a single parental genome. When asexual reproduction occurs, the child organisms are "clones" as they contain the same genetic material as the parent.

Eukaryotic organisms often use sexual reproduction to generate offspring which contain a mixture of genetic material inherited from two different parents. The process of sexual reproduction generally alternates between forms which contain single copies of the genome (haploid) and double copies (diploid).^[25] Haploid cells fuse and combine genetic material to create a diploid cell with paired chromosomes. Diploid organisms form haploids by dividing, without replicating their DNA, to create daughter cells that randomly inherit one of each pair of chromosomes. Most animals and many plants are diploid for the majority of their lifespan, with the haploid form reduced to single cell gametes.

Although they do not use the haploid/diploid method of sexual reproduction, bacteria have many methods of acquiring new genetic information. Some bacteria can undergo conjugation, transferring a small circular piece of DNA to another bacterium.^[27] Bacteria can also take up raw DNA fragments found in the environment and integrate them into their genome, a phenomenon known as transformation.^[28] This processes result in horizontal gene transfer, transmitting fragments of genetic information between organisms that would otherwise be unrelated.

Genetic recombination and linkage

Main articles: Chromosomal crossover and Genetic linkage

The diploid nature of chromosomes allows for genes on different chromosomes to assort independently during sexual reproduction, 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.^[29] 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 %u2014 alleles for the two genes tend to be inherited together. The amounts of linkage 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.^[30]

Gene expression and the creation of phenotype

The genetic code

Main article: Genetic code

The dynamic structure of hemoglobin is responsible for its ability to transport oxygen within mammalian blood.

Genes generally express their functional effect through the production of proteins, which are complex molecules responsible for most functions in the cell.^[31] 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 possible amino acids in protein %u2014 this correspondence is called the genetic code.^[32] The flow of information is unidirectional: information is transferred from nucleotide sequences into the amino acid sequence of proteins, but never from protein back into the sequence of DNA %u2014 a phenomenon Francis Crick called the central dogma of molecular biology.^[33]

The specific sequence of amino acids results in a unique three-dimensional structure for that protein, and the three-dimensional structures of protein are related to their function.^[34][35] Some are simple structural molecules, like the fibers formed by the protein collagen. Proteins can bind to other proteins and simple molecules, sometimes acting as enzymes by facilitating chemical reactions within the bound molecules (without changing the structure of the protein itself). Protein structure is dynamic; the protein hemoglobin bends into slightly different forms as it facilitates the capture, transport, and release of oxygen molecules within mammalian blood.

A single nucleotide difference within DNA can cause a single change in the amino acid sequence of a protein. Because protein structures are the result of their amino acid sequences, some changes can dramatically change the properties of a protein by destabilizing the structure or changing the surface of the protein in a way that changes its interaction with other proteins and molecules. For example, sickle-cell anemia is a human genetic disease that results from a single base difference within the coding region for the %u03B2-globin section of hemoglobin, causing a single amino acid change that changes hemoglobin's physical properties.^[36] Sickle-cell versions of hemoglobin stick to themselves, stacking to form fibers that distort the shape of red blood cells carrying the protein. These sickle-shaped cells no longer flow smoothly through blood vessels, having a tendency to clot or degrade, causing the medical problems associated with the disease.

Nature vs. nurture

Siamese cats have a temperature-sensitive mutation in pigment production.

Although genes contain all the information an organism uses to function, the environment plays an important role in determining the ultimate phenotype %u2014 a dichotomy often referred to as "nature vs. nurture". The phenotype of an organism depends on the interaction of genetics with the environment. One example of this is the case of temperature-sensitive mutations. Often, a single amino acid change within the sequence of a protein does not change its behavior and interactions with other molecules, but it does destabilize the structure. In a high temperature environment, where molecules are moving more quickly and hitting each other, this results in the protein losing its structure and failing to function. In a low temperature environment, however, the protein's structure is stable and functions normally. This sort of mutation is visible in the coat coloration of Siamese cats, where a mutation in an enzyme responsible for pigment production causes it to destabilize and lose function at high temperatures.^[37] The protein remains functional in areas of skin that are colder %u2014 legs, ears, tail, and face %u2014 and so the cat has dark fur at its extremities.

Environment also plays a dramatic role in effects of the human genetic disease phenylketonuria.^[38] The mutation that causes phenylketonuria disrupts the ability of the body to break down the amino acid phenylalanine, causing toxic build-up of an intermediate molecule that, in turn, causes severe symptoms of progressive mental retardation and seizures. If someone with the phenylketonuria mutation is kept on a strict diet that avoids this amino acid, however, they remain normal and healthy.

Gene regulation

Main article: Regulation of gene expression

The genome of a given organism contains thousands of genes, but not all these genes need to be active at any given moment. A gene is "expressed" when it is being transcribed into mRNA (and translated into protein), and there exist many cellular methods of controlling the expression of genes such that proteins are produced only when needed by the cell. Transcription factors are regulatory proteins that bind to the start of genes, either promoting or inhibiting the transcription of the gene.^[39] Within the genome of Escherichia coli bacteria, for example, there exists a series of genes necessary for the synthesis of the amino acid tryptophan. However, when tryptophan is already available to the cell, these genes for tryptophan synthesis are no longer needed. The presence of tryptophan directly affects the activity of the genes %u2014 the tryptophan molecules bind to the tryptophan repressor (a transcription factor), changing the repressor's structure such that the repressor is "active" and binding to the genes. The tryptophan repressor blocks the transcription and prevents expression of the genes, thus creating negative feedback regulation of the tryptophan synthesis process.^[40]

Differences in gene expression are especially clear within multicellular organisms, where cells all contain the same genome but have very different structures and behaviors due to the expression of different sets of genes. All the cells in a multicellular organism derive from a single cell, differentiating into different cell types in response to external and intercellular signals and gradually establishing different patterns of gene expression to create different behaviors. No single gene is responsible for the development of structures within multicellular organisms, these patterns arise from the complex interactions between many cells.

Within eukaryotes there exist structural features of chromatin which influence the transcription of genes, often in the form of modifications to DNA and chromatin that are stably inherited by daughter cells.^[41] These features are called "epigenetic" because they exist "on top" of the DNA sequence and retain inheritance from one cell generation to the next. Because of epigenetic features, different cell types grown within the same medium can retain very different properties. Although epigenetic features are generally dynamic over the development of organisms, some, like the phenomenon of paramutation, have multigenerational inheritance and exist as rare exceptions to the general rule of DNA as the basis for inheritance.^[42]

Mutations and natural selection

Mutations

Main article: Mutation

During the process of DNA replication, errors occasionally occur in the polymerization of the second strand (these error rates are generally extremely low, 1 error in every 10-100 million bases).^[43][44] 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.^[45] 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.^[46] 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").

Natural selection and evolution

Main article: Evolution

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 occasionally 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%