The last chapter ended with a brief introduction to DNA. But, what is DNA? What is it made of? And how can a small molecule like DNA ‘code’ for all of the traits in a living organism? We will address these and other questions in this chapter. Ultimately, what we are doing in this chapter is understanding how the genetic code (DNA) results in variation, because it is this variation that natural selection can act upon and lead to evolutionary changes. We will start by looking at the fundamental unit of all life on Earth: the cell. Inside each cell, the DNA code is structured into packages known as chromosomes. We will see how the DNA molecule can copy itself so that each cell in an organism’s body contains the same DNA information. We will then look at how DNA codes for proteins, which all living organisms are made of. Finally, we will look at a concrete example of how DNA impacts our lives by examining human blood types. Though we have to dive into the microscopic world, do not lose sight of the big picture: DNA is a code for making proteins, and we are made of proteins. If the DNA slightly changes (through mutation, which we met in the last chapter), the protein changes, and thus the organism can change.
*
All living organisms are made of cells; they are the basic units of life. There are many, many organisms that are made of just one cell, and many (including you) that are made of trillions of cells. All of life can be divided into two big categories, depending on the kind of cell they have. The first kind are organisms called prokaryotes. Prokaryotes are single-celled bacteria without nuclei or any special structures called organelles. They often have structures shown here in this image, like a cell wall, an outer membrane, a cytoplasm within which the DNA resides, and they often have locomotor structures like a flagellum. On this slide is a microscopic image of a prokaryotic cell that we have all heard of: Escherichia coli (E. coli), which lives in the guts of many mammals, including humans. Though prokaryotic cells live within us, and have been instrumental factors in driving human evolution, we will turn now to the cells we are made of: eukaryotic cells.
*
All animals, plants, fungi, and many single-celled organisms called protists are made of eukaryotic cells. These cells have a nucleus that contains DNA, and often have membrane-bound parts of the cell called organelles. These include chloroplasts (found in plants) and mitochondria, which help produce the molecular energy that powers cellular processes. Notice in this image that the eukaryotic cell is a bit more complicated than a prokaryotic cell. The microscopic image here is of kidney cells, which clearly have a nucleus, a membrane keeping the components of the cell contained, and a fluid within the cell called a cytoplasm.
*
There are two types of eukaryotic cells in all animals and plants: somatic cells and gametes. Somatic cells, also called body cells, are found all over the body. Shown in the above image are the somatic cells found in the (clockwise from top left) brain, blood, bone, and skin. Somatic cells all contain a complete copy of the organism’s DNA. For example, in humans, somatic cells have all of the DNA packed in 46 chromosomes. Somatic cells also replicate through a process called mitosis, which we will learn about in just a moment. At the bottom right is an image of the other kind of eukaryotic cells: gametes. The large round cell is called an egg, or an ova. The small wiggly structures surrounding the egg are sperm. These are gametes. They contain only half of the organism’s DNA (23 chromosomes in humans) and replicate through a process known as meiosis.
*
Since we just mentioned chromosomes, it is worth examining chromosome number in a bit more detail. Humans have 46 chromosomes in our somatic cells. 23 of these came from our mother, and 23 from our father, for a grand total of 46. But, this number, 46, is not special at all. Other apes, like chimpanzees, have 48 chromosomes. Some primates have fewer chromosomes, like the colobus monkey which has 44. Some organisms we would consider to be less complex than us have fewer chromosomes, like the house fly with 12 or the salamander with 24. But, plenty of organisms have more than we have, like the potato with 48, the camel with 70, or algae, which has 148 chromosomes. Classifying organisms by the number of chromosomes they have would be like organizing books in a library based on the number of pages they have, or by the color of its jacket cover. It wouldn’t make sense. What matters are not the number of chromosomes an organism has, but the similarity in DNA that is packaged in the chromosomes. For instance, humans and chimpanzees share about 98% of their DNA. This is remarkable, and, in some ways, indicates how important 2% of a difference can be.
*
Most likely, you have all heard of DNA, and have probably heard that it is the “blueprint,” or “recipe,” or “code” for life? But, how does this work? It helps first to understand the structure of DNA, and to understand how it is packaged in your cells. It is estimated that there is six feet worth of DNA in every cell in your body. Six feet!? If cells are microscopic, how can this be? As shown in this image, the DNA molecule is wound up into compact structures that we have already encountered: chromosomes. Sections of that DNA specifically code for a specific protein in the body: These are called genes. The genome is all of the genes put together in all of the chromosomes. The DNA that is in the nucleus of our cells is called homoplasmic, meaning it is more or less the exact same in every cell in our body. But, the nucleus is not the only place in a cell that contains DNA. An organelle called the mitochondria also contains DNA. Mitochondrial DNA (mtDNA) is much, much smaller; it only contains 37 genes. And these genes are only inherited from your mother, meaning they can be used to trace one’s maternal lineage (called a matriline). Unlike nuclear DNA, mitochondrial DNA can differ from cell to cell, making it heteroplasmic.
*
We are finally ready to discuss what DNA actually is. It is a molecule; in fact, a very simple one. DNA is made of three things: a type of sugar, a phosphate group, and a nucleotide base pair. The sugar and phosphate form the backbone of the long DNA molecule and these do not vary along the chain. What varies along the chain are the nucleotide base pairs. These bases can be one of four types: adenine (A), thymine (T), guanine (G) and cytosine (C). You can think of DNA as a ladder with the sugar and phosphates forming the uprights, and the bases forming the rungs. The rungs are made of two base pairs that cling together using hydrogen bonds. Critical to understanding DNA is the fact that the base pairs do not randomly cling to each other. Instead, A only clings to T, and C only clings to G. These are called complementary bases. What this means is, if you know one side of the DNA chain, you know the other. If a DNA sequence is CAAAT, the other side MUST be GTTTA. Though any two humans may have over 99% of their DNA base pair order identical, there are, of course, differences. Differences in these single nucleotide regions are called SNPs (pronounced “snips” and short for single nucleotide polymorphisms). These are some of the areas of the genome that can be used to solve crimes using DNA evidence since they can vary from one individual to another.
*
The very structure of DNA explains how it is so easily, and so accurately, replicated. When a cell is going to divide, it copies its entire genome. Remember those nucleotide base pairs? Well, there are 3 billion of them to copy each time a cell divides. And cells divide all the time. It happened when you went from a single fertilized zygote to two cells, to four, eight, sixteen and onwards until you were several trillion cells worth of newborn baby. It continues to happen as old cells divide to form replacement cells. Each time, the DNA faithfully replicates. DNA replicates so easily and accurately because of those As, Gs, Cs, and Ts we discussed a moment ago. A double stranded DNA molecule is unwound by enzymes, and the hydrogen bonds connecting the complementary base pairs are broken. What results are two template strands that have so-called sticky ends. Free floating nucleotide base pairs in the nucleus of the cell (which are acquired through the foods we eat- which have their own DNA), bind to the template strands following the rule of base pairs: A goes with T and C goes with G. In this case CTAT is separated from GATA. These sticky ends become templates to form two new strands that are identical to one another. Again, it is the very structure of DNA that explains how copies of it can be made. We often say that the replication process produces identical copies of DNA, but that is not entirely true. Copying mistakes can occasionally occur- yet another source for genetic variation.
*
Before we get into the nuts and bolts of mitosis, let’s consider those chromosomes one last time. In order to make sure that each copy of the full sequence of DNA gets into each cell, the chromosomes must pair up and replicate. 23 of these chromosomes were inherited from the mother, and 23 from the father and each chromosome number (1 to 23) are different in their length and the genes they contain. These chromosomes pair up into matching, or homologous pairings, in the somatic cells. Though these chromosome pairs (shown in the top image) may look identical, they may very well contain different versions of a gene (known as alleles), since one chromosome was inherited from the mother and the other from the father. 22 of the 23 homologous pairs of chromosomes are what are referred to as autosomes. The other pair determines the sex of the individual and are appropriately named the sex chromosomes X and Y. Females have two X chromosomes, one inherited from their mother and one from their father. Males have an X and a Y—the X from their mother and the Y from their father. Because females have two X chromosomes, they can only contribute an X in the egg cell they produce. Because the male has both an X and a Y, there is a 50-50 chance that a sperm will contain an X or a Y. It is therefore true that the male “determines” the sex of a child by either contributing an X (and therefore producing a female) or a Y (and therefore producing a male), though of course this is not a conscious decision the sperm cells make. One way to visualize the homologous chromosomes is to produce what is called a karyotype—this is shown in the bottom right of the slide. Notice the 22 homologous pairs of autosomes numbered according to their size, and last the sex chromosomes. Based on what you see here, is this karyotype from a female or a male?
LET THE STUDENTS THINK ABOUT THIS AND THEN DISCUSS (THIS IS A FEMALE KARYOTYPE SINCE THERE ARE TWO X CHROMOSOMES)
*
You started as a single fertilized egg, called a zygote. It had 46 chromosomes. Cells with this full set of chromosomes (46) are called diploid. As we’ll soon see, cells with half the number of chromosomes (23) are called haploid. These are the egg and sperm cells, and there is a very obvious reason that they have half the number of chromosomes, which we’ll encounter in just a moment. But, back to that zygote. During embryological development, this little zygote divided to form 2, 4, 8, 16, 32, 64, and eventually trillions of cells. These cells soon form tissues and organs in a process known as embryological development. If the DNA divided as the cells do, your chromosomes would go from 46 to 23 to 11.5 to 5.75. Of course, this did not happen. Instead, every cell contains 46 chromosomes. This occurs because, as we already discussed, DNA can replicate itself and does so before each cell division so that the cell goes from 46 chromosome to 92 before dividing into two cells, each with 46 chromosomes. The process by which this occurs is called mitosis.
*
As shown in this figure, mitosis starts with a single diploid cell that has 23 pairs or homologous chromosomes (or 46 chromosomes). These chromosomes duplicate by unwinding their DNA and attaching free nucleotide bases to the template strands in the manner already discussed. After chromosome duplication, the cells technically have 92 chromosomes, which all line up in the middle of the cells so that one full set is on one side and another full set is on the other side of the cell midline. The cell pulls apart into two daughter cells, each with identical DNA. The microscopic image is of skin cells dividing into two daughter cells. Each of these cells has 23 pairs of homologous chromosomes (or 46 total).
*
If an egg cell had 46 chromosomes and a sperm had 46 chromosomes, the resulting zygote would have 92 chromosomes. This simply would not work. So, gametes have to divide up the DNA a bit differently than somatic cells do. Instead of having a full copy of the organism’s DNA, gametes are haploid, meaning they only contain one chromosome from each pair of chromosomes. This one can be inherited from the mother or the one inherited from the father. With 23 chromosomes, the number of different combinations is exceptionally high, meaning that each egg and each sperm cell contains a unique combination of genes from the organisms’ mother and father. The process by which this occurs is called meiosis. Meiosis starts the same way as mitosis. The DNA replicates and the homologous chromosomes pair up. The cells then divide into two identical daughter cells, just as happens in mitosis. However, unlike mitosis, the cells then divide again, resulting in four daughter cells each with 23 chromosomes, but no pairs. Right before that final cell division, the homologous chromosomes can recombine their chromosomes in a process called crossing-over. A chunk of chromosome 2 from the mother’s line can switch with a chunk of chromosome 2 from the father’s line. So, not only are the 23 chromosomes in the gametes a random assortment of chromosomes from the mother and from the father, but within each chromosome there will be a combination of genes from the individual’s mother and father. Genes that are close together on a chromosome therefore tend to move together and cluster together. These clusters of genes are called haplotypes, which can be used to assess the history of genetic lineages. If chunks of DNA are exchanged on non-homologous chromosomes (called translocations) diseases such as leukemia can result. If the chromosomes fail to divide, the resulting gametes can have too few or too many chromosomes. Too few can result in a monosomy, and too many, a trisomy. Down syndrome is an example of a trisomy, in which there are three rather than two copies of chromosome 21.
*
We’ve obviously been learning about genetics. But, in the last chapter, we learned about Mendel and his genetics experiments on pea plants. What do the two have to do with each other? This is a very important slide that demonstrates how these concepts are linked to one another. Here is another Punnett square in which two pea plants with identical genotypes and phenotypes are crossed. Each plant has yellow seeds in a green pod, and each plant is heterozygous. Remember that this means that both plants have each allele for pod color and seed color, but that the dominant allele is expressed. Breeding identical plants together like this, most would expect that the offspring should be identical to their parents, but genetics does not work that way. During meiosis, the top pea plant will produce a gamete with either big G or little g combined with either big Y or little y. Each has an equal chance of being produced resulting in four possible combinations of genes in the gametes: GY, Gy, gY, and gy. The same applies for the plant on the left of the Punnett square. Now, when these gametes are combined together in all possible ways to produce zygotes, the resulting baby plants will have the genotypes shown on the Punnett square, and a 9:3:3:1 ratio of phenotypes. Nine will have green pods and yellow seeds like the parents, three will have green pods and green seeds, three will have yellow pods and yellow seeds, and one will have yellow pods and green seeds (the exact OPPOSITE of what the parents had!). Notice that having one particular color of pea pod had nothing to do with the color of the seed. This is known as the law of independent assortment. Notice also that the rules of genetics and the process of meiosis produces plentiful variation—the raw material for natural selection to act on.
*
But, those are pea plants. What about humans? Here is an example that applies more to you and I. Suppose the gene for hair color is on the small chromosome and the gene for eye color is on the large chromosome. The blue allele on the small chromosome represents blond hair and on the large chromosome represents blue eyes. The red allele on the small chromosome represents brown hair and on the large chromosome brown eyes. Both parents are heterozygous and, we’ll say for argument sake, brown eyes and hair are dominant, meaning that both parents have brown hair and brown eyes. The parent on the left, we’ll call a female, produces four eggs through meiosis. Because of the law of independent assortment, the alleles for hair and eye color are independent from one another, producing two eggs that pass on the alleles for brown hair and brown eyes and two eggs with the alleles for blond hair and blue eyes. Just as likely is what happens with the male. He produces four sperm cells, two with brown eyes and blond hair and two with blue eyes and brown hair. Choose one egg and one sperm and combine them together. What do you get? Now choose another? Notice that there will be a mixture of these features. Some of the offspring will have blond hair and brown eyes; some will have brown hair and blue eyes. Keep in mind that these combinations were not present in the parents.
Some of you may be saying that hair color and eye color are NOT independent; that they do seem to be present together (brown with brown; blond with blue). You are of course right. One of the reasons for this is that some of the genes that code for these traits are in fact on the same chromosome. The bottom image shows how genes close to one another on the same chromosome will not follow the law of independent assortment and will instead by linked to one another. This is called linkage.
*
But, how does DNA cause a seed to be yellow or hair to be brown? When we talk about DNA as a code, what do we actually mean? Besides replicating itself, the other critically important thing DNA does is to code for proteins. Proteins are what bodies are made of. There are seven types of proteins described here. Some, called enzymes, help with chemical reactions, such as the protein lactase that helps break down the lactose sugar in milk. Others are structural proteins, like the keratin that makes up our hair and nails, or the collagen that helps make up bone—these are shown in this image to the right. There are gas transport proteins like hemoglobin, which transports oxygen throughout the body. Antibodies, which help fight diseases, are proteins. Hormones like insulin, which helps regulate the metabolism of sugar and fats in the body are proteins. Muscles are comprised of the mechanical proteins actin and myosin. Finally, protein can be of the nutrient-form, like ovalbumin, which is found in egg whites. Proteins are critical for the normal functioning of an organism. So, how does DNA code for these proteins? First, it is important to recognize that proteins are made of amino acids. There are 20 different kinds of amino acids; 12 of these humans can manufacture; the other 8 have to be eaten and are therefore called essential amino acids. These 20 different amino acids can combine together into chains of various lengths and different properties. These properties are what makes a protein like keratin different from a protein like hemoglobin.
*
Protein synthesis, or the process by which a DNA code is turned into a chain of amino acids, occurs in cells. First the DNA code is read by enzymes, producing a molecule called messenger RNA. This process, in which messenger RNA is created from a DNA code is called transcription. The messenger RNA then leaves the nucleus of the cell and enters the cytoplasm. It binds to ribosomes, which are organelles that facilitate the translation of messenger RNA into a chain of amino acids, which ultimately form a protein. Let’s look in more detail how this actually happens.
*
Just like during DNA replication, the DNA is unwound, or unzipped, by enzymes. However, unlike replication, only one of the strands of DNA is used during transcription. Also, unlike replication, only a specific section of the DNA is unwound; this region is called a gene. The unwound DNA strand serves as a template for making a single-stranded molecule of messenger RNA. RNA is very similar to DNA, but instead of using A, G, C, and T as base pairs, RNA uses A, G, C, and U. U stands for Uracil and it binds to adenine (A), just like thymine (T) does in DNA. As is shown here, if the gene has the sequence TACTC, the messenger RNA molecule will be AUGAG and so on. Once the gene is fully transcribed, the messenger RNA molecule leaves the nucleus and finds ribosomes in the cytoplasm of the cell.
*
Once messenger RNA binds to a ribosome, translation of the code into amino acids can begin. This process occurs in threes. Three nucleotides, called a codon, are read by the ribosome. These are “read” by matching a complementary anticodon to the codon. For instance, if the messenger RNA codon is AUG, then the anticodon has to be UAC since those are the three nucleotides that are complementary to the codon. Importantly, these anticodons are attached to a specific amino acid, in this case methionine, in a structure called a transfer RNA (tRNA). The next three nucleotides in the codon are AGU, which match with the anticodon UCA, which is attached to the amino acid serine. This goes on and one, in groups of three, until the last codon (UAG) , which is the stop sequence. The amino acid chain is then released into the cytoplasm. The amino acid chain folds into a three-dimensional structure, or bonds with other 3-D proteins, which give these proteins their specific properties. What we have described here happens in only a small percentage of the human genome. In fact, only about 5% of the total genome is composed of structural genes that code for proteins, or regulatory genes that turn genes on and off. We will turn to these genes next.
*
Regulatory genes can be thought of as on/off switches, or, perhaps more accurately, dimmer switches. Regulatory genes determine if a gene is on or off, and can regulate the amount of protein produced, and when. For instance, if the genes controlling connective tissue growth are left on a bit longer during development, what can result are longer, thinner fingers as is shown in this image. This is characteristic of a disease called Marfan syndrome. Regulatory genes have also allowed us to understand major evolutionary events. For instance, paleontological evidence demonstrates that modern birds evolved from a group of feathered dinosaurs. But, anyone who has visited a science museum knows that dinosaurs have teeth. Birds do not. Where did their teeth go? Scientists have recently discovered that birds still have the structural genes to make teeth. But, the regulatory genes controlling those structural genes have been turned off. A similar thing has happened with human body hair. Humans have less body hair than other primates. We still have the genes for full body hair coverage, but these genes have been down-regulated. Similarly, all baby mammals have the ability to digest milk. This is because they produce the enzyme lactase, which breaks down lactose. However, these genes are turned off in most adult mammals. However, some humans have lactose persistence, meaning that the genes are not turned off and they can continue to digest milk as adults. Those who retain the typical mammalian condition of losing lactase production into adulthood are said to be lactose intolerant. Notice that natural selection can act upon the products of structural genes, but can also operate on the products of variation in regulatory genes. In fact, research on human and chimpanzee genomes have discovered that while our structural genes are very similar, there are important differences in those regulatory genes.
*
One of the best examples of regulatory genes are those of the homeotic, or Hox, family of genes. These are master switches that determine the general form of an animal’s body. Notice that whether you are a human, a mouse, or a fruit fly, heads are where heads should be, bodies are where bodies should be, and limbs are where limbs should be. Why is this? Researchers have discovered that a group of genes, called Hox genes, regulate the position of the major body parts during embryological development. What was amazing to researchers was that the very same genes regulate this process of body formation in organisms as different as flies, mice, and humans. Small changes in how long these genes are switched on, or where they are expressed, can result in differences in overall body form. For instance, the genes for the neck region are positioned differently in birds and snakes giving bird long necks and snakes short necks (but long bodies). The Hox genes that determine forelimb and finger length are switched on for a longer period of development in bats, compared to other mammals. Again, selection can favor the products of variation in regulatory genes as effectively as structural genes.
*
Let’s look at one more Punnett square to consider how variations in specific genes can result in even more possible combinations of traits. As we have already discussed, the mother and father contribute equally to the genetic makeup of the offspring. This is known as the Law of segregation. Consider this example in which a pure red sweet pea is crossed with a pure white sweet pea. The offspring in the first generation will all be heterozygous, meaning that they will inherit the red allele from one parent and the white allele from the other. If the resulting flowers are all red, then the red allele is said to be dominant over the white allele. But, what if the flowers are all pink? This can happen, it means that these two alleles are both expressed, neither is dominant over the other, and they are said to be codominant. If these flowers care crossed, the offspring will be a combination of pure red (genotype big R big R), pure white (genotype little r little r), and pink, or shown here as hybrid white.
*
Let’s apply these principles to humans again. Human blood type is a great example of a trait with multiple alleles. A person can be blood type O, A, B, or AB. Because there can be more than one kind of blood type, this is referred to as a polymorphic trait. But, what do these blood types mean in terms of genetics? Every person has two blood type alleles (one from mom and one from dad). These can be allele A, B, or O. The A allele codes for a protein that we call A. The B allele codes for a protein that we call B. If someone has the A allele on one chromosome and the B allele on the other, they are blood type AB. This is because these alleles are codominant and both blood proteins are produced. So, do people with the O allele make an O protein? No. In fact, they do not make a protein at all. This is why the O blood type is referred to as the universal donor. Because there are no proteins on the surface of the cells, the recipient of this blood type will not attack these cells. Someone with blood type AB does not make antibodies against either A or B, and therefore can receive blood from any blood type. However, someone with blood type A will make antibodies against B and cannot receive that blood type without fatal complications. Likewise, someone with blood type O makes antibodies against all other blood types, and cannot receive any other blood type except O. Let’s look at this again in the context of genetics. Can parents with blood type A and blood type B have a baby with blood type O? The answer is yes. Draw a Punnett square to try to work this out. Can either of the parents be homozygous, or must they both be heterozygous? Try this one: Can a man with blood type AB be the father of a child with blood type O? Why or why not?
*
By this point, you are probably realizing that genetics is complicated business. But, it is MUCH more complicated than I’ve described in this lecture. Many traits are polygenic, meaning that multiple genes are responsible for the phenotype observed. For instance, a person’s height, or skin coloration can be influenced by hundreds of different genes. In addition, these and many other traits can be highly influenced by the environment. For instance, height can be strongly impacted by nutrition. Remember that natural selection can only work on traits that are passed from generation to generation, so quantifying the role that genetics has in shaping a particular phenotype can be quite important in determining the role of natural selection in shaping it. Complicating matters even further is the reality that the same gene can influence many different phenotypes. The sickle-cell gene, for instance, influences both the individual’s ability to combat malaria as well as the ability to transport oxygen through the body. It turns out, most traits are both polygenic and pleiotropic (modeled on the bottom right), making genetics a fascinating, but quite complicated, science.
