GENES & GENOMES
GENES & GENOMES
GLOSSARY
base excision repair (BER) Cellular mechanism that repairs damaged DNA throughout the cell cycle. BER removes small errors in the genome to protect against harmful mutations.
chromatin Complex formed along the DNA in eukaryotic cells. Chromatin is composed of proteins called histones as well as non-histone proteins. The structure of chromatin plays a key role in regulating gene expression.
eukaryote Organism composed of one or many cells each with a distinct nucleus and cytoplasm. There are also living cells without a nucleus, such as bacteria, called prokaryotes.
exons and introns Messenger RNA is edited by a process called splicing that removes introns and maintains parts called exons. The exons are joined together to make the mature mRNA and this information can be used to create proteins. The genome is the complete set of genes and the complete set of exons is called the exome.
genome Complete set of genetic material in an organism or a cell. Genomics is the study of an organism’s genome, focusing on its evolution, function and structure. The genome must be very carefully monitored to make sure any errors are detected and corrected. This is referred to as maintaining genome integrity.
genotoxic Property of chemicals that damage the genetic information within a cell by causing mutations in the DNA. Genotoxic chemicals can kill cells or cause diseases such as cancer.
genotype DNA sequence of a cell or the alleles carried by an organism that determines a specific characteristic (called a trait or a phenotype) of that cell or organism.
germ cell Biological cell that gives rise to the gametes for sexual reproduction. Germ cells undergo meiosis, followed by cellular differentiation to produce mature gametes, either eggs or sperm. Gametes contain the genetic information that will be transmitted to the next generation.
mRNA (messenger RNA) Molecule that represents a copy of DNA and that contains the information to make a protein. One strand of the DNA of a gene is transcribed into a mRNA copy that is translated to produce a protein. The mRNA contains the information for encoding a functional protein.
natural selection Process through which the organisms best adapted to their environment survive and reproduce. Natural selection is a key mechanism in Charles Darwin’s theory of evolution.
nucleotides Building blocks used to make DNA or RNA. Strings of nucleotides are called nucleic acids. In DNA there are four nucleotides (referred to by the letters T, C, G and A) and in RNA there are four ribonucleotides (U, C, G and A). Nucleotides are also called bases. DNA bases can be paired: A pairs with T, and C pairs with G.
phenotype Observable characteristics or traits of a cell or an organism (such as shape, development, biochemical or physiological features or particular behaviours). The phenotype is influenced by the genotype within the genome.
silencing Regulation of a gene by shutting down its expression. As cells only use a fraction of their genes at any given time, the rest of their genes are repressed or silenced. Cells have mechanisms to activate or silence genes at precise times. Researchers can use these silencing mechanisms to reduce gene expression in the laboratory or even to treat disease.
somatic cells Biological cells that form the main body of an organism. There are more than 200 different types of somatic cell in the human body and these make up all the different organs and tissues. Somatic cells are not transmitted to the next generation and are distinct from germ cells and gametes.
splicing Editing of the newly transcribed messenger RNA to remove introns and paste together exons. Splicing is performed by a large protein machine called the spliceosome. Splicing is a way in which the cell can generate different proteins from the same gene by editing together different exons.
transcription Process for turning DNA genetic information into RNA. This is done by an enzyme machine called RNA polymerase that builds an RNA polymer using the DNA as a template. Transcription profiling involves measuring the amount of RNA for every gene in the cell.
transposons DNA sequence that can change its position within a genome. Transposons are sometimes called transposable elements or jumping genes. Scientists have learned to exploit transposons – for example, the ‘Sleeping Beauty transposon’ system is used in genome engineering.
WHAT IS A GENE?
the 30-second theory
Genes can explain part of the differences between us – whether we are tall or short, whether we have brown or blue eyes and why we resemble our parents. Your mother gave you half of her genes, and your father half of his, so that each of us carries a completely unique collection of genes (with the exception of twins, who share identical genes). So why does a daughter have the curly hair typical of her father? Because she received the ‘curly hair’ gene from her father and because ‘curly hair’ is usually dominant over the recessive gene for ‘straight hair’. Genes are detected through trait differences. They correspond to distinct DNA sequences at a given chromosome location. Research into how genes can affect visible traits led to a second definition of the word ‘gene’: it is also a stretch of DNA that is copied into a ribonucleotide molecule or a protein, with a known function. For example, the keratin gene is used to produce the keratin protein that makes up our hair. In mice, dogs and humans, a single mutation in the DNA sequence of the keratin gene can explain the difference between straight hair and curly hair.
3-SECOND THRASH
A gene alone is an inert DNA molecule with no effect. But changing one gene into another within an organism can produce a visible difference.
3-MINUTE THOUGHT
A human being carries as many genes in its genome as a small nematode worm. Many species (including the mouse, the pufferfish, red clover, onions and wheat) appear to have more genes than humans do. Therefore, the complexity of life is not simply determined by the number of genes.
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DNA CARRIES THE GENETIC INFORMATION
3-SECOND BIOGRAPHIES
WILHELM JOHANNSEN
1857–1927
Danish botanist who coined the terms ‘gene’, ‘genotype’ and ‘phenotype’
WILLIAM BATESON
1861–1926
British biologist, the first to coin the term ‘genetics’
THOMAS HUNT MORGAN
1866–1945
American biologist who won the Nobel Prize for his findings on genes and their location on chromosomes
30-SECOND TEXT
Virginie Courtier-Orgogozo
Your genes give you many of your physical traits, including hair colour and texture.
JUMPING GENES
the 30-second theory
Transposable elements or ‘jumping genes’ are DNA sequences that can move to other sites in the genome. They were first described by Barbara McClintock, who observed changes in the colour of corn kernels resulting from moving genes. They can move by ‘copy and paste’ (where the original remains in its location) or ‘cut and paste’ (where the original moves to the new location). Transposable elements, known as ‘transposons’, make up a large fraction of the human genome. Most of the transposons are inactive, but when active they can affect the health of the genome, resulting in mutation and disease or altering how neighbouring genes behave. Transposons can also drive the evolution of the genome by shuttling DNA to new locations and thereby generating genetic diversity. They have been adapted as tools for biologists to mutate and tag genes throughout the genome, enabling identification of the genes responsible for specific traits. The principle of ‘jumping genes’ has also been harnessed to insert DNA sequences into the genome. The ‘Sleeping Beauty transposon’ is a synthetic DNA transposon resurrected in 1997 from a fish genome; it has been used as a tool to insert specific DNA sequences into genomes of vertebrate animals during gene therapy.
3-SECOND THRASH
‘Jumping genes’ are sequences of DNA that can move or ‘jump’ from one location in the genome to another.
3-MINUTE THOUGHT
Transposable elements (transposons) are DNA sequences that can change position in the genome. They make up roughly half of the human genome and are important for the workings and evolution of the genome. They can also be exploited as tools to modify the genome of cells or of a living organism.
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DNA CARRIES THE GENETIC INFORMATION
3-SECOND BIOGRAPHY
BARBARA McCLINTOCK
1902–92
American cytogeneticist who discovered that genes could move from place to place on a chromosome; she received the 1983 Nobel Prize in Physiology or Medicine
30-SECOND TEXT
Matthew Weitzman
McClintock's work on transposable elements in maize wasn't fully recognized and accepted by the field until over 30 years after her initial discoveries.
GENE SPLICING
the 30-second theory
Information coded in the DNA sequences of genes is used to produce proteins. The first step is the transcription of the DNA sequence of a gene into a messenger RNA (mRNA) molecule. A surprising discovery several decades ago was that most of the genes of animals and plants are ‘split’: they have parts that contain information to code for proteins and parts that do not. The protein-coding segments of genes are called exons. They are separated by long sequences that do not encode protein information, called introns. The mRNA first transcribed from a gene contains all the exon and intron sequences. But the introns are then removed by a process called gene splicing and the exons join together in the right order to create the final mRNA. One can imagine the initial mRNA as a mixture of meaningful words (exons) and gibberish (introns). Gene splicing changes the initial mRNA reading ‘thisiscmhazdbwthewayqtrncdbgenestalk’ by removing the gibberish and joining the meaningful words together to generate the final message of the gene reading ‘this is the way genes talk’. Alternative splicing removes different introns and joins exons to make different protein variants from the same gene. Gene splicing is an exact process that precisely removes only intron sequences from mRNA.
3-SECOND THRASH
Gene splicing modifies the initial mRNA by precisely removing introns and joining exons together to create an mRNA that can make a protein.
3-MINUTE THOUGHT
Protein-coding RNAs are much shorter than the DNA sequences of genes that encode them. In some cases, up to 90 per cent of the initial mRNA is intron sequence that is removed to form the protein-coding mRNA. Some genes have just one or two introns, whereas others have several dozen introns. Gene splicing enzymes precisely identify and remove introns by locating the unchanging mRNA sequences at the ends of introns.
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3-SECOND BIOGRAPHIES
RICHARD ROBERTS
1943–
British biochemist and molecular biologist and co-discoverer of ‘split genes’
PHILLIP SHARP
1944–
American molecular biologist who discovered that most genes are ‘split’ into exon and intron segments
THOMAS CECH
1947–
American biologist who described gene splicing
30-SECOND TEXT
Mark Sanders
Gene splicing errors can play a role in genetic diseases and may lead to cancer.
GENOTYPE & PHENOTYPE
the 30-second theory
Most organisms within a population are different from each other. These differences are mostly due to underlying genetic variations. The genotype of an individual describes its genetic make-up, be it at the single-gene or whole-genome level. Most animals can carry a maximum of two versions of each gene – or alleles. The combination of such alleles across the genome is unique to each individual and constitutes its genetic fingerprint. Only identical twins, developing from one fertilized egg, share the same genotype. Yet even they bear differences, owing to small variations that appear after their conception. The phenotype is the set of observable or measurable characteristics of an individual, such as the colour of the eyes, height and so on. For example, in garden peas, the character white flowers (the phenotype) is determined by the genotype pp (homozygous), whereas the underlying genotype for purple flowers is PP or Pp (heterozygous). Identical variations (genotypes) in two individuals may produce the same phenotype, but this is not always so, because the phenotype is the manifestation of the interactions between the genotype and the environment.
3-SECOND THRASH
The genotype of an individual determines its phenotype, through interactions with the rest of the genome and the environment.
3-MINUTE THOUGHT
The genotype (G) for a particular gene does not always lead to the same phenotype (P). This depends on the interaction of the relevant alleles with other alleles elsewhere in the genome, which can reduce or enhance the phenotype. But the environment (E) can deeply influence the expression of the genotype. This is described in the following formula: G + E + GxE → P (G = genotype, E = environment and GxE = their interaction).
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3-SECOND BIOGRAPHY
WILHELM JOHANNSEN
1857–1927
Danish botanist who coined the terms phenotype and genotype to distinguish heredity from its results
30-SECOND TEXT
Reiner Veitia
Everyone's genotype is unique and shared by nobody else. The only exception to this is identical twins, who share practically identical genotypes, although their phenotypes (physical traits) may still differ.
GENE EXPRESSION
the 30-second theory
Nearly all the cells in your body share the same DNA, yet each cell type is equipped for a specific biological function. It turns out that not all your cells read all the genetic information in the genome at the same time. Your DNA contains all the information needed to make more than 25,000 different proteins, but each cell makes only the proteins it requires to function and will ‘read’ just a fraction of all the genes at a given time. To make a protein, cells have to ‘transcribe’ the DNA information into RNA and then ‘translate’ it into the protein. Researchers say that genes are either expressed (turned ‘on’) or repressed (turned ‘off’). Upstream of each gene there is a piece of DNA called the promoter, which works like a kind of switch to turn transcription on or off. There are many regulatory mechanisms to make sure that the switch is on at the right time and that each gene is expressed at the right level for that particular cell function. There are particular proteins that can recognize the switches and regulate the amount of RNA produced. The cell can also control gene expression by determining how quickly the RNA is degraded.
3-SECOND THRASH
Each cell expresses only a fraction of all the genes in the genome so that it makes the right proteins for its cellular needs.
3-MINUTE THOUGHT
Today researchers have sophisticated technologies to measure all the thousands of genes that can be expressed at the same time. By performing gene expression profiling, they can make predictions about the identity of a cell and the functions of the genes that are expressed together. Some essential genes are expressed in most cells, whereas others are expressed only in very specialized tissues.
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3-SECOND BIOGRAPHIES
JACQUES MONOD
1910–76
French geneticist who worked out how genes are expressed by studying gene repression in bacteria
ROGER KORNBERG
1947–
American biochemist who pioneered work into the molecular machinery that turns genes on
30-SECOND TEXT
Jonathan Weitzman
Heat maps, such as those shown here, are used to study how genes are expressed in various experiments.
MUTATIONS & POLYMORPHISMS
the 30-second theory
All DNA molecules, whether part of a gene or not, are subject to changes via mutation. These changes may be small (the addition or deletion of a single DNA base pair or several base pairs) or large (duplication or elimination of a chromosome segment, or changes in the number and structure of chromosomes). Mutations can occur in germ cells (sperm or egg cells in humans) or in somatic cells (those that make up all body tissues). Mutations are rare, occurring once per million bases in the average human cell division cycle. They can result from spontaneous chemical changes of DNA bases or from environmental factors such as chemical or radiation exposure. While rare and sometimes harmful, mutations are also essential, as they result in the inherited genetic variation that forms the basis of evolutionary change. A genetic variant is called a ‘mutant’ when its frequency in a population (the number of copies of the mutant in every 100 copies of the gene) is less than one per cent. When evolution acts to raise the frequency of a mutant above one per cent it is termed a ‘polymorphism’, meaning ‘many forms’. The presence of two or more polymorphic alleles in a population is most often the result of mutation followed by evolution that increases the frequency of the mutant allele.
3-SECOND THRASH
Mutations change the DNA sequence. They are one reason why the members of a population differ from one another and they are required for evolution to occur.
3-MINUTE THOUGHT
Mutations are usually harmful to the organism if they change the function or the production of the protein encoded by a given gene. Thousands of different human hereditary disorders affecting almost every aspect of our physical characteristics are caused by gene mutations. Occasionally, however, a mutation may change the protein product of the gene in a way that is beneficial. Through the action of natural selection on such beneficial mutants, polymorphisms can evolve in populations over many generations.
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DOMINANT & RECESSIVE GENETIC DISEASES
3-SECOND BIOGRAPHIES
SEWALL WRIGHT
1889–1988
British mathematical biologist and a founder of the field of population genetics
HERMANN MULLER
1890–1967
American biologist who demonstrated the mutagenic power of radiation
BRUCE AMES
1928–
American biochemist who developed a test to determine if a compound causes mutations
30-SECOND TEXT
Mark Sanders
The mind-boggling diversity of life on Earth is the direct result of genetic mutations.
DNA DAMAGE & REPAIR
the 30-second theory
DNA is damaged by constant assault from inside and outside the body and cells must do everything they can to maintain the integrity of the genome. DNA can be damaged by reactive metabolites, oxidation, radiation, genotoxic chemicals, ultraviolet light or even by the normal copying process. These areas of damaged DNA negatively affect fundamental cellular processes: they can cause mutations that change the coding genes in the genome or rearrangements that change the structural integrity of the chromosomes. Cells must recognize and repair the damaged DNA to prevent chaos in the genome. A complex apparatus constantly surveys the genome to repair any damaged DNA. Specialized proteins act as sensors to alert the cell to DNA damage. The signals then recruit enzymes that remove damaged sections of DNA. Depending on the type of damage, different sets of enzymes and repair pathways are selected. Some inherited disorders arise from mistakes in the genes that produce these enzymes. When the repair pathways are defective or switched off, genomic instability accumulates and leads to cancer. The cancer cells also become reliant on the remaining repair pathways, and this makes them vulnerable to drugs that target the intact repair pathways.
3-SECOND THRASH
The human genome is under constant attack and a complex apparatus monitors for DNA damage and maintains genome integrity.
3-MINUTE THOUGHT
Every day there are thousands of potentially devastating injuries to the human genome. An intricate machinery recognizes and repairs damaged areas of DNA. DNA damage that is not repaired correctly can result in mutations and instability that can lead to life-threatening diseases such as cancer, neurodegeneration and premature ageing.
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3-SECOND BIOGRAPHIES
HERMANN MULLER
1890–1967
American geneticist who discovered that X-rays could mutate and kill cells
RENATO DULBECCO
1914–2012
Italian-American virologist who discovered that repair enzymes could rescue damaged DNA
TOMAS LINDAHL
1938–
Swedish-born scientist who discovered the machinery that carries out base excision repair
30-SECOND TEXT
Matthew Weitzman
Your DNA can be damaged by exposure to UV light and by smoking tobacco.
GENOME ARCHITECTURE
the 30-second theory
In a mammalian cell, 2 metres (6ft 6in.) of DNA is packaged into a nucleus that is just a few thousandths of a millimetre wide. This packaging is not random; genomes have a specific architecture. Physical interactions within or between chromosomes play important roles in the regulation of genes, replication of DNA and in maintaining the stability of the genome; genome architecture may be both a cause and a consequence of these functions. The packaging begins when DNA wraps around specific proteins to form chromatin. The chromatin forms a fibre that folds upon itself into loops of various sizes – from a few thousand nucleotides to large loops of several hundred thousand nucleotides. These loops are important for regulating genes, but little is known about how they form and how they affect genes. Loops are found in many organisms, including flies and bacteria. Chromosomes are also compartmentalized into different ‘active’ or ‘inactive’ chromatin domains. Stretches of the genome near the nuclear membrane tend to be repressed (non-active) while others in the centre of the nucleus contain active genes. Biologists first defined regions of chromatin more than a century ago. Modern technologies show that the genome architecture is a scaffold that allows DNA to be correctly interpreted and copied.
3-SECOND THRASH
Genomes are not randomly organized in space, but have specific architectures that allow efficient packaging of genetic material into a small volume while facilitating gene expression and other genome functions.
3-MINUTE THOUGHT
Genome architecture is dynamic: the chromosome structures are not permanent and some regions may fold and unfold over time. This is generated by proteins that bind to chromosome sequences; these include structural elements that enable long-range interactions or folding, and also regulatory elements that determine when and where genes are expressed. The organization of chromosomes in the nucleus determines how genetic information is used by the cell.
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3-SECOND BIOGRAPHIES
CARL RABL
1853–1917
Austrian anatomist who first proposed in 1885 that chromosomes are organized into distinct regions within the nucleus
THEODOR BOVERI
1862–1915
German biologist who coined the term ‘chromosome territories’ in 1909
30-SECOND TEXT
Edith Heard
Geneticists are still trying to define the complex influence of genome architecture on how and when genes are expressed.
