Genetics

All About Genetics:

 

I   INTRODUCTION

 

 

Gregor Mendel

Known as the father of modern genetics, Gregor Mendel developed the principles of heredity while studying seven pairs of inherited characteristics in pea plants. Although the significance of his work was not recognized during his lifetime, it has become the basis for the present-day field of genetics.

 

 

Genetics, scientific study of how physical, biochemical, and behavioural traits are transmitted from parents to their offspring. The word itself was coined in 1906 by the British biologist William Bateson. Geneticists determine the mechanisms of inheritance whereby the offspring of sexually reproducing organisms do not exactly resemble their parents, and the differences and similarities between parents and offspring recur from generation to generation in repeated patterns. The investigation of these patterns has led to some of the most exciting discoveries in modern biology.

II    EMERGENCE OF GENETICS

 

The science of genetics began in 1900, when several plant breeders independently discovered the work of the Austrian monk Gregor Mendel, which, although published in 1866, had been virtually ignored. Working with garden peas, Mendel described the patterns of inheritance in terms of seven pairs of contrasting traits that appeared in different pea-plant varieties. He observed that the traits were inherited as separate units, each of which was inherited independently of the others (see Mendel's Laws). He suggested that each parent has pairs of units but contributes only one unit from each pair to its offspring. The units that Mendel described were later given the name genes.

III    PHYSICAL BASIS OF HEREDITY

 

 

Human Male Karyotype

Different groups of organisms have different numbers of chromosomes; for example, humans have 23 pairs (46 in total) of chromosomes. One chromosome in each pair comes from the mother, the other from the father. This photo of the human male karyotype shows the chromosome pairs labelled 1 to 22, called autosomes, which have a similar appearance in males and females. The 23rd pair, shown on the bottom right, represents the sex chromosomes. Females have two identical-looking sex chromosomes that are both labelled X, whereas males have a single X chromosome and a smaller chromosome labelled Y. Chromosomes contain the genetic blueprints for a specific organism. The variation present in individuals is a reflection of the genetic recombination of these sets of chromosomes from generation to generation.

 

Soon after Mendel's work was rediscovered, scientists realized that the patterns of inheritance he had described paralleled the action of chromosomes in dividing cells, and they proposed that the Mendelian units of inheritance, the genes, are carried by the chromosomes. This led to intensive studies of cell division.

Mitosis

This interactivity outlines the stages involved in mitosis, the division of a cell to produce two identical cells.

 

Every cell comes from the division of a pre-existing cell. All the cells that make up a human being, for example, are derived from the successive divisions of a single cell, the zygote (see Fertilization), which is formed by the union of an egg and a sperm. The great majority of the cells produced by the division of the zygote are, in the composition of their hereditary material, identical to one another and to the zygote itself (assuming that no mutations occur; see below). Each cell of a higher organism is composed of a jellylike layer of material, the cytoplasm, which contains many small structures. This cytoplasmic material surrounds a prominent body called the nucleus. Every nucleus contains a number of minute, threadlike chromosomes. Some relatively simple organisms, such as cyanobacteria and bacteria, have no distinct nucleus but do have cytoplasm, which contains one or more chromosomes.

Fruit Fly Chromosomes

The chromosomes of the fruit fly, Drosophila melanogaster, lend themselves well to genetic experiments. There are only 4 pairs—one of which, marked here X and Y, determines the fly’s sex—compared with the human complement of 23 pairs. In addition, the fly’s chromosomes are very large. Thomas Hunt Morgan and his associates based their theory of heredity on studies using Drosophila. They found that chromosomes were passed from parent to offspring in a way that Gregor Mendel ascribed to inherited characteristics. They proposed, correctly, that genes in fact occupy specific physical locations on chromosomes.

 

Chromosomes vary in size and shape and usually occur in pairs. The members of each pair, called homologues, closely resemble each other. Most cells in the human body contain 23 pairs of chromosomes, whereas most cells of the fruit fly Drosophila contain four pairs, and the bacterium Escherichia coli has a single chromosome in the form of a ring. Every chromosome in a cell is now known to contain many genes, and each gene is located at a particular site, or locus, on the chromosome.

Meiosis

 

The process of cell division by which a new cell comes to have an identical number of chromosomes as the parent cell is called mitosis (see Reproduction). In mitotic division each chromosome divides into two equal parts, and the two parts travel to opposite ends of the cell. After the cell divides, each of the two resulting cells has the same number of chromosomes and genes as the original cell (see Cell: Division, Reproduction, and Differentiation). Every cell formed in this process thus has the same genetic material. Simple one-celled organisms and some multicellular forms reproduce by mitosis; it is also the process by which complex organisms achieve growth and replace worn-out tissue.

Higher organisms that reproduce sexually are formed from the union of two special sex cells known as gametes. Gametes are produced by meiosis, the process by which germ cells divide. It differs from mitosis in one important way: in meiosis a single chromosome from each pair of chromosomes is transmitted from the original cell to each of the new cells. Thus, each gamete contains half the number of chromosomes that are found in the other body cells. When two gametes unite in fertilization, the resulting cell, called the zygote, contains the full, double set of chromosomes. Half of these chromosomes normally come from one parent and half from the other.

IV   THE TRANSMISSION OF GENES

 

 

Albinism

Albinism, the lack of normal pigmentation, occurs in all groups of people. A rare condition, albinism occurs when a person inherits a recessive allele, or group of genes, for pigmentation from each parent. In this case, production of the enzyme tyrosinase is defective. Tyrosinase is necessary to the formation of melanin, the normal human skin pigment. Without melanin, the skin lacks protection from the sun and is subject to premature ageing and skin cancer. The eyes, too, colourless except for the red blood vessels of the retina that show through, cannot tolerate light. Albinos tend to squint even in normal indoor lighting and frequently have vision problems. Tinted glasses or contact lenses can help.

 

 

The union of gametes brings together two sets of genes, one set from each parent. Each gene—that is, each specific site on a chromosome that affects a particular trait—is therefore represented by two copies, one coming from the mother and one from the father (for exceptions to this rule, see Sex and Sex Linkage, below). Each copy is located at the same position on each of the paired chromosomes of the zygote. When the two copies are identical, the individual is said to be homozygous for that particular gene. When they are different—that is, when each parent has contributed a different form, or allele, of the same gene—the individual is said to be heterozygous for that gene. Both alleles are carried in the genetic material of the individual, but if one is dominant, only that one will be manifested. In later generations, however, as was shown by Mendel, the recessive trait may show itself again (in individuals homozygous for its allele).

For example, the ability of a person to form pigment in the skin, hair, and eyes depends on the presence of a particular allele (A), whereas the lack of this ability, known as albinism, is caused by another allele (a) of the same gene. (For convenience, alleles are usually designated by a single letter; the dominant allele is represented by a capital letter and the recessive allele by a small letter.) The effects of A are dominant; of a, recessive. Therefore, heterozygous people (Aa), as well as people homozygous (AA) for the pigment-producing allele, have normal pigmentation. People homozygous for the allele that results in a lack of pigment (aa) are albinos. Each child of a couple who are both heterozygous (Aa) has a probability of one in four of being homozygous AA, one in two of being heterozygous Aa, and one in four of being homozygous aa. Only the individuals carrying aa will be albino. Note that each child has a one-in-four chance of being affected with albinism; it is not accurate to say that one-quarter of the children in a family will be affected. Both alleles will be carried in the genetic material of heterozygous offspring, who will produce gametes bearing one or the other allele. A distinction is made between the appearance, or outward characteristics, of an organism and the genes and alleles it carries. The observable traits constitute the organism's phenotype, and the genetic makeup is known as its genotype.

It is not always the case that one allele is dominant and the other recessive. The four-o'clock plant, for example, may have flowers that are red, white, or pink. Plants with red flowers have two copies of the allele R for red flower colour and hence are homozygous RR. Plants with white flowers have two copies of the allele r for white flower colour and are homozygous rr. Plants with one copy of each allele, heterozygous Rr, are pink—a blend of the colours produced by the two alleles.

The action of genes is seldom a simple matter of a single gene controlling a single trait. Often one gene may control more than one trait, and one trait may depend on many genes. For example, the action of at least two dominant genes is required to produce purple pigment in the purple-flowered sweet pea. Sweet peas that are homozygous for either or both of the recessive alleles involved in the colour traits produce white flowers. Thus, the effects of a gene can depend on which other genes are present.

V   QUANTITATIVE INHERITANCE

 

Traits that are expressed as variations in quantity or extent, such as weight, height, or degree of pigmentation, usually depend on many genes as well as on environmental influences. Often the effects of different genes appear to be additive—that is, each gene seems to produce a small increment or decrement independent of the other genes. The height of a plant, for example, might be determined by a series of four genes: A, B, C, and D. Suppose that the plant has an average height of 25 cm (10 in) when its genotype is aabbccdd, and that each replacement by a pair of dominant alleles increases the average height by approximately 10 cm (4 in). In that case a plant that is AABBccdd will be 45 cm (18 in) tall, and one that is AABBCCDD will be 65 cm (26 in) tall. In reality, the results are rarely as regular as this. Different genes may make different contributions to the total measurement, and some genes may interact so that the contribution of one depends on the presence of another. The inheritance of quantitative characteristics that depend on several genes is called polygenic inheritance. A combination of genetic and environmental influences is known as multifactorial inheritance.

VI   GENE LINKAGE AND GENE MAPPING

 

 

Genetic Mapping

This gel scan, showing the arrangement of specific polymorphisms within different DNA samples, allows experts to take a closer look at the genetic make-up of each individual. With the completion of the human genome sequence in 2003, geneticists hope to compile a map identifying and locating every gene in the human body, and to use it to catalogue the genetic differences between individuals in the population.

 

Mendel's principle that genes controlling different traits are inherited independently of one another turns out to be true only when the genes occur on different chromosomes. The American geneticist Thomas Hunt Morgan and his co-workers, in an extensive series of experiments using fruit flies (which breed rapidly), showed that genes are arranged on the chromosomes in a linear fashion; and that when genes occur on the same chromosome, they are inherited as a single unit for as long as the chromosome itself remains intact. Genes inherited in this way are said to be linked.

Morgan and his group also found, however, that such linkage is rarely complete. Combinations of alleles characteristic of each parent can become reshuffled among some of their offspring. During meiosis, a pair of homologous chromosomes may exchange material in a process called recombination, or crossing-over. (The effect of crossing-over can be seen under a microscope as an X-shaped joint between the two chromosomes.) Crossovers occur more or less at random along the length of the chromosomes, so the frequency of recombination between two genes depends on their distance from each other on the chromosome. If the genes are relatively far apart, recombinant gametes will be common; if they are relatively close, recombinant gametes will be rare. In the offspring produced by the gametes, the crossovers show up as new combinations of visible traits. The more crossovers that occur, the greater the percentage of offspring that show the new combinations. Consequently, by arranging suitable breeding experiments, scientists can plot, or map, the relative positions of the genes along the chromosome.

VII    SEX AND SEX LINKAGE

 

 

Red-Green Colour Blindness Test

This image is part of the standard test for colour blindness. Individuals with normal colour vision see the number 57, whereas those with red-green deficiencies see the number 35. Colour blindness, an inability to distinguish between red and green and sometimes between blue and yellow, is caused by a defect in one of the three colour-sensitive cells in the retina. Colour blindness affects approximately one person in thirty.

 

Another contribution to genetic studies made by Morgan was his observation in 1910 of sexual differences in the inheritance of traits, a pattern known as sex-linked inheritance.

Sex is usually determined by the action of a single pair of chromosomes. Abnormalities of the endocrine system or other disturbances may alter the expression of secondary sexual characteristics, but they almost never completely reverse the sex. A human female, for example, has 23 pairs of chromosomes, and the members of each pair are much alike. A human male, however, has 22 similar pairs and one pair consisting of two chromosomes that are dissimilar in size and structure. The 22 pairs of chromosomes that are alike in both males and females are called autosomes. The remaining chromosomes, in both sexes, are called the sex chromosomes. The two identical sex chromosomes in the female are called X chromosomes. One of the sex chromosomes in the male is also an X chromosome, but the other, shorter one is called the Y chromosome. When gametes are formed, each egg produced by the female contains one X chromosome, but the sperm produced by the male can contain either an X or a Y chromosome. The union of an egg, which always bears an X chromosome, with a sperm also bearing an X chromosome produces a zygote with two Xs: a female offspring. The union of an egg with a sperm that bears a Y chromosome produces a male offspring. Modifications of this mechanism occur in various plants and animals.

The human Y chromosome is approximately one-third as long as the X, and apart from its role in determining maleness, it appears to be genetically inactive. Thus, most genes on the X have no counterpart on the Y. These genes, said to be sex-linked, have a characteristic pattern of inheritance. The disease called haemophilia, for example, is usually caused by a sex-linked recessive gene (h). A female with HH or Hh is normal; a female with hh has haemophilia. A male is never heterozygous for the gene because he inherits only the gene that is on the X chromosome. A male with H is normal; with h he has haemophilia. When a normal man (H) and a woman who is heterozygous (Hh) have offspring, the female children are normal, but half of them carry the h gene—that is, none of them is hh, but half of them bear the genotype Hh. The male children inherit only the H or the h; therefore, half the male children have haemophilia. Thus, in normal circumstances a female carrier passes on the disease to half her sons, and she also passes on the recessive h gene to half her daughters, who in turn become carriers of haemophilia. Many other conditions—including red-green colour blindness, hereditary nearsightedness, night blindness, and ichthyosis (a skin disease)—have been identified as sex-linked traits in humans.

VIII    GENE ACTION: DNA AND THE CODE OF LIFE

 

That chromosomes were almost entirely composed of two kinds of chemical substances, protein and nucleic acids, had long been known. Partly because of the close relationship established between genes and enzymes, which are proteins, protein at first seemed the fundamental substance that determined heredity. In 1944, however, the Canadian bacteriologist Oswald Theodore Avery proved that deoxyribonucleic acid (DNA) performed this role. He extracted DNA from one strain of bacteria and introduced it into another strain. The second strain not only acquired characteristics of the first but passed them on to subsequent generations. By this time DNA was known to be made up of substances called nucleotides. Each nucleotide consists of a phosphate, a sugar known as deoxyribose, and any one of four nitrogen-containing bases. The four nitrogen bases are adenine (A), thymine (T), guanine (G), and cytosine (C).

In 1953, putting together the accumulated chemical knowledge, geneticists James Dewey Watson of the United States and Francis Harry Compton Crick of Great Britain worked out the structure of DNA. This knowledge immediately provided the means of understanding how hereditary information is copied. Watson and Crick found that the DNA molecule is composed of two long strands in the form of a double helix, somewhat resembling a long, spiral ladder. The strands, or sides of the ladder, are made up of alternating phosphate and sugar molecules. The nitrogen bases, joining in pairs, act as the rungs. Each base is attached to a sugar molecule and is linked by a hydrogen bond to a complementary base on the opposite strand. Adenine always binds to thymine, and guanine always binds to cytosine. To make a new, identical copy of the DNA molecule, the two strands need only unwind and separate at the bases (which are weakly bound); with more nucleotides available in the cell, new complementary bases can link with each separated strand, and two double helixes result. If the sequence of bases were AGATC on one existing strand, the new strand would contain the complementary, or “mirror image”, sequence TCTAG. Since the “backbone” of every chromosome is a single long, double-stranded molecule of DNA, the production of two identical double helixes will result in the production of two identical chromosomes.

The DNA backbone is actually a great deal longer than the chromosome but is tightly coiled up within it. This packing is now known to be based on minute particles of protein known as nucleosomes, just visible under the most powerful electron microscope. The DNA is wound around each nucleosome in succession to form a beaded structure. The structure is then further folded so that the beads associate in regular coils. Thus, the DNA has a “coiled-coil” configuration, like the filament of an electric light bulb.

After the discoveries of Watson and Crick, the question that remained was how the DNA directs the formation of proteins, compounds central to all the processes of life. Proteins are not only the major components of most cell structures, they also control virtually all the chemical reactions that occur in living matter. The ability of a protein to act as part of a structure, or as an enzyme affecting the rate of a particular chemical reaction, depends on its molecular shape. This shape, in turn, depends on its composition. Every protein is made up of one or more components called polypeptides, and each polypeptide is a chain of subunits called amino acids. Twenty different amino acids are commonly found in polypeptides. The number, type, and order of amino acids in a chain ultimately determine the structure and function of the protein of which the chain is a part.

A   The Genetic Code

 

 

Transcription

The synthesis of a strand of messenger, transfer, or ribosomal RNA from a DNA template is called transcription. The helical DNA molecule unwinds, leaving the sense strand (the sequence from which the RNA is assembled) accessible. The enzyme that controls the reaction recognizes a “start” region, called the promoter, in the DNA sequence and builds from there. Nucleotides are added one by one in complementary order: cytosine (C) in the DNA molecule gives rise to guanine (G) in RNA, G to C, thymine (T) to adenosine (A), and A to uracil (U).

 

 

Since proteins were shown to be products of genes, and each gene was shown to be composed of sections of DNA strands, scientists reasoned that a genetic code must exist by which the order of the four nucleotide bases in the DNA could direct the sequence of amino acids in the formation of polypeptides. In other words, a process must exist by which the nucleotide bases transmit information that dictates protein synthesis. This process would explain how the genes control the forms and functions of cells, tissues, and organisms. Because only four different kinds of nucleotides occur in DNA, but 20 different kinds of amino acids occur in proteins, the genetic code could not be based on one nucleotide specifying one amino acid. Combinations of two nucleotides could only specify 16 amino acids (4² = 16), so the code must be made up of combinations of three or more successive nucleotides. The order of the triplets—or, as they came to be called, codons—could define the order of the amino acids in the polypeptide.

Ten years after Watson and Crick reported the DNA structure, the genetic code was worked out and proved biologically. Its solution depended on a great deal of research involving another group of nucleic acids, the ribonucleic acids (RNA). The specification of a polypeptide by the DNA was found to take place indirectly, through an intermediate molecule known as messenger RNA (mRNA). Part of the DNA somehow uncoils from its chromosome packing, and the two strands become separated for a portion of their length. One of them serves as a template upon which the mRNA is formed (with the aid of an enzyme called RNA polymerase). The process is very similar to the formation of a complementary strand of DNA during the division of the double helix, except that RNA contains uracil (U) instead of thymine as one of its four nucleotide bases, and the uracil (which is similar to thymine) joins with the adenine in the formation of complementary pairs. Thus, a sequence adenine-guanine-adenine-thymine-cytostine (AGATC) in the coding strand of the DNA produces a sequence uracil-cytosine-uracil-adenine-guanine (UCUAG) in the mRNA.

B   Transcription

 

 

Protein Synthesis

The assembly of proteins takes place in the cytoplasm of a cell. There are three main steps. In initiation, far left, all the necessary parts of the process are brought together by a small molecule called a ribosome. During elongation, amino acids, the building blocks of proteins, are joined to one another in a long chain. The sequence in which the amino acids are added is determined by messenger RNA (mRNA), a transcribed copy of the cell’s DNA. Termination, far right, takes place when the mRNA sequence contains one of several “stop” codons. At these, the ribosome-mRNA complex binds a release factor that causes release of the completed (protein) chain of amino acids. The released chain is called the primary structure of a protein.

 

The production of a strand of messenger RNA by a particular sequence of DNA is called transcription. While the transcription is still taking place, the mRNA begins to detach from the DNA. Eventually one end of the new mRNA molecule, which is now a long, thin strand, becomes inserted into a small structure called a ribosome, in a manner much like the insertion of a thread into a bead. As the ribosome bead moves along the mRNA thread, the end of the thread may be inserted into a second ribosome, and so on. Using a very high-powered microscope and special staining techniques, scientists can photograph mRNA molecules with their associated ribosome beads.

Ribosomes are made up of protein and RNA. A group of ribosomes linked by mRNA is called a polyribosome or polysome. As each ribosome passes along the mRNA molecule, it “reads” the code, that is, the sequence of nucleotide bases on the mRNA. The reading, called translation, takes place by means of a third type of RNA molecule called transfer RNA (tRNA), which is produced on another segment of the DNA. On one side of the tRNA molecule is a triplet of nucleotides. On the other side is a region to which one specific amino acid can become attached (with the aid of a specific enzyme). The triplet on each tRNA is complementary to one particular sequence of three nucleotides—the codon—on the mRNA strand. Because of this complementarity, the triplet is able to “recognize” and adhere to the codon. For example, the sequence uracil-cytosine-uracil (UCU) on the strand of mRNA attracts the triplet adenine-guanine-adenine (AGA) of the tRNA. The tRNA triplet is known as the anticodon.

As tRNA molecules move up to the strand of mRNA in the ribosome beads, each bears an amino acid. The sequence of codons on the mRNA therefore determines the order in which the amino acids are brought by the tRNA to the ribosome. In association with the ribosome, the amino acids are then chemically bonded together into a chain, forming a polypeptide. The new chain of polypeptide is released from the ribosome and folds up into a characteristic shape that is determined by the sequence of amino acids. The shape of a polypeptide and its electrical properties, which are also determined by the amino acid sequence, dictate whether it remains single or becomes joined to other polypeptides, as well as what chemical function it subsequently fulfils within the organism.

In bacteria, viruses, and blue-green algae, the chromosome lies free in the cytoplasm, and the process of translation may start even before the process of transcription (mRNA formation) is completed. In higher organisms, however, the chromosomes are isolated in the nucleus and the ribosomes are contained only in the cytoplasm. Thus, translation of mRNA into protein can occur only after the mRNA has become detached from the DNA and has moved out of the nucleus.