Let’s start with the basics of genetics. The word “genome” refers to an organism’s complete set of DNA. The fundamental building block of our genome is the molecule known as DNA. You’ve no doubt heard of DNA many times before – in the news, in movies, on television. Yet in order to understand Huntington’s disease, it is important to gain a good understanding of DNA and how DNA is related to genes. Our goal in this section is to review the basic features of the structure and function of the main molecule of heredity.
Table of Contents
What is DNA? …Making the single strand.^
If you have seen images of DNA before, you probably saw it in a shape or form similar to that shown in Figure B-1. The “double helix” is how DNA is most often found in living cells. In every double helix, there are actually two long strands of DNA; hence, you will often hear scientists refer to a double helix as a double-stranded DNA molecule. As we examine the basic underlying structure of DNA, try to keep in mind the overall arrangement of the double helix; it will help you see how the various components of DNA fit together.
The name DNA stands for deoxyribonucleic acid. By breaking down the name, we can understand the structure of the molecule. DNA is a long string of nucleotide units attached to one another. In a single nucleotide there are three components: 1) a sugar molecule, 2) a phosphate group, and 3) a nitrogenous base. (See Figure B-2.) In DNA, the sugar molecule happens to called deoxyribose, hence the name deoxyribonucleic acid.
The nitrogenous bases are what make DNA variable. There are 4 different types of bases in DNA:adenine, guanine, thymine, and cytosine. Biologists commonly abbreviate these bases as the letters A, G, T, and C, respectively. (See Figure B-3.) Each one of the bases is chemically distinguishable from the others; as we shall see, it is the variability of these bases that constitutes the genetic code.
Unlike the four nitrogenous bases, the sugars and phosphates remain the same throughout the DNA molecule. In a single nucleotide, the sugar is attached at one end to a phosphate group. Because the sugar of that nucleotide can attach to another phosphate at its other end, we can string together many nucleotides in a long chain. This gives us a complete DNA molecule: a structural backbone of deoxyribose sugars linked by phosphate groups, with an orderly sequence of nitrogenous bases sticking out of the sugars toward the middle of the helix. (See Figure B-4.) In terms of our double helix, the single strand provides one-half of the spiraling molecule shown in Figure B-1.
Why is DNA so important?^
What makes DNA so exciting to scientists is that it shows how living organisms store information in biological molecules. The structure of DNA is nicely suited to such a task. The structural backbone creates a simple, consistent chain upon which many, many bases can be laid out in an orderly, linear sequence. If we think of these four bases – A, T, G, and C – as the “letters” of a genetic “alphabet,” we have the building blocks necessary to encode lots of information within these relatively compact DNA molecules.
DNA therefore shows how living organisms can pass information along to their offspring. DNA tells us how a child can be born with “his mother’s eyes,” for example, or “his father’s nose.” For quite some time, scientists had no viable explanation for this phenomenon. No biological molecule was compact yet complex enough to carry the information needed to guide the development of an entire organism. We now know that when a couple have a baby, the DNA of both parents is the crucial ingredient that is passed on to the child. This amazing molecule is thus responsible for the inherited features of every newborn child.
So how can a DNA molecule ever provide enough information for a living organism? The simple answer is that DNA molecules are very, very long. For example, the DNA molecule of a simple bacteria called E. Coli is four million nucleotides long. In computer terms, this corresponds to the information-storing capacity of an 8 MB hard drive – quite a bit of memory for a small bacteria! The human genome totals approximately 3 billion nucleotides – a 3 GB hard drive! Thus, we can think of DNA as a “genetic database” for organisms.
What are complementary strands? …Making the double helix.^
Now that we have a single chain of DNA, we are ready to return to the famous “double helix,” in which two single strands of DNA spiral around one another.
In order to understand the double helix we must first go back to our original DNA strand with its sugar and phosphate backbone. Each connection between a sugar and a phosphate group is at an angle. (Look at Figure B-5 here and compare to Figure B-4.) The end result is a backbone that is curved rather than straight, and hence the DNA chain spirals around itself. The bases, in turn, jut inward from the backbones, looking almost like the steps of a spiral staircase.
Another important feature of the four bases is that they pair up with one another in a particular way: adenine (A) always pairs with thymine (T), and guanine (G) always pairs with cytosine (C). Two bases linked up in this fashion are known as “base pairs.” Look at the arrangements of the bases in Figure B-6. Notice how the chemical structure of each base allows it to line up perfectly with its pair, but not with any other base. Because of this fact, the two intertwined strands of the DNA helix are said to be complementary.
In summary, a double helix of DNA is composed of two spiraling, complementary strands of DNA. Each strand is composed of a sugar and phosphate backbone with varying nitrogenous bases sticking in towards the center. The two strands are joined together at the center by pairing bases lined up with one another. DNA is often described structurally as a twisting ladder. In this ladder, the “rungs” are the pairs of bases linked together, and the “sides” are the two separate sugar and phosphate backbones. (Examine Figure B-7.)
The double helix is important because it preserves all of the information-carrying features of a single DNA strand while at the same time introducing elements that make it easier for living cells to make copies of their DNA. Because every base pair in the double helix must match its pairing partner (A with T, C with G), we can easily determine the sequence of an unknown strand of DNA if its matching strand is known. For example, if one strand of a double helix has the nucleotide sequence GATTCGTACG, then its complementary strand will be CTAAGCATGC. Figure B-8 shows an example of two complmentary strands.
Having reviewed the chemical basis of heredity in DNA, let us now examine how the “genetic code” is packaged into living cells.
What is a chromosome?
As you might have guessed, chromosomes (Figure B-9) are indeed bundles of DNA. However, in most cells they are present only for a brief moment. In fact, most of the time DNA is spread out in a large, diffuse mass – something like a big plate of spaghetti. When a cell needs to produce more cells, it does so by dividing in two. Think of the problems that this “spaghetti” might cause during cell division, when a dividing cell must bestow each of its successor cells with its own complete set of DNA. Imagine trying to separate and transport a tangled mass of noodles! For this reason, the DNA condenses before cell division into the thick, rod-like form that we recognize as chromosomes.
Chromosomes have several important features. First of all, the DNA packs so tightly that one can see it under a simple light microscope. Secondly, recall that because the cell is getting ready to divide in two, the DNA of a visible chromosome has already been duplicated, so that each successor cell will have its own copy. This means that, on close inspection, a cell that is ready to divide will have four strands of DNA, two helices of two strands each. Each of these double strands of DNA condenses into a single rod called a sister chromatid (as in Figure B-9). The two chromatids are therefore exact replicas of one another, and the center of each is joined together prior to the division of the cell. As a result, most chromosomes take on the appearance of the letter X.
OK, so what are homologous chromosomes?
The human genome (Figure B-10) is composed of 23 kinds of chromosomes. However, because humans conceive through sexual reproduction, every child receives two sets of 23 chromosomes – one from his or her mother and one from his or her father. As a result, every individual has 23 pairs of chromosomes, for a total of 46. Of these 23 pairs, one pair is responsible for determining sex. The chromosomes in this pair are therefore called sex chromosomes. The chromosomes in the remaining 22 pairs are called autosomes.
The two chromosomes in a pair of autosomes are called homologues, or a “homologous pair,” meaning that they contain corresponding sequences of DNA (Figure B-11). These two chromosomes come from separate parents. Don’t be misled; homologous chromosomes contain DNA sequences that are similar, but they are not identical copies of each other!
How is DNA passed on to new cells?^
In earlier sections, we have seen that DNA is a molecule found in living cells that contains the chemical code of heredity. Because all cells, whether they are nerve cells, muscle cells, skin cells, etc., have the same DNA, all of this DNA must be passed on when cells replicate during the process of cell division. Cells start dividing from the time a zygote is formed (the single cell that results from the fusion of egg and sperm in animals, or from pollen and ova in plants), allowing it to develop and grow. You, too, began as a zygote and much of your early development took place through cell division. Cell division slows as you age but continues throughout life, keeping you healthy and replacing cells that are damaged or have died. Most of the cells in your body undergo a type of division called mitosis, in which one cell fully replicates its DNA and then divides into two identical daughter cells.
Mitosis consists of several programmed stages. The stage in which the cell spends the most time, while it is between divisions, is aptly named interphase. During interphase, DNA replicates and the cell synthesizes proteins that it will need for the other stages. You can think of interphase as the preparatory stage of mitosis.
The first stage of division is called prophase. During prophase, DNA condenses into tightly coiled chromosomes. Because DNA has already replicated, each chromosome appears as a joined pair of identical sister chromatids, forming the X shape that you can see in Figure B-9. Another important part of this stage is the formation of the mitotic spindle. The mitotic spindle is a structure that will be responsible for physically separating the sister chromatids into the two daughter cells. It consists of two organizing structures called centrosomes (one of which was replicated during interphase) and a set of microtubules. Think of the microtubules as tiny fibrous strings that will be used to pull the sister chromatids apart.
In the next stage, prometaphase, each centrosome arrives at opposite poles of the cell. Each centrosome has its own set of microtubules that extend out across the cell. Also during prometaphase, the nuclear membrane (which separates the nucleus from the rest of the cell) breaks down, allowing the chromosomes to move freely. Microtubules then attach to the centers of the chromosomes, where the sister chromatids are joined, and guide them toward the equator of the cell.
The cell has reached metaphase when each of the chromosomes is attached to two microtubules, one on each side, and are lined up in one long row across the middle of the cell.
In anaphase, the two centrosomes move further apart and the microtubules shorten. These changes pull the pairs of sister chromatids apart. The newly separated chromosomes can then be sorted into two groups.
During telophase, the chromosomes arrive at the centrosomes, and a new nuclear membrane forms around each group, creating two complete nuclei. Inside, the chromosomes begin to decondense. Also during telophase, the equator of the cell begins to be pinched by a contractile ring.
The final step of mitosis is cytokinesis (pronounced CY-TOH-KIN-EE-SIS). During cytokinesis, the contractile ring divides the cytoplasm, or the contents of the cell, in two. The result is two complete daughter cells, each containing DNA that is identical to the original parent cell.
How is DNA passed on to the next generation?^
When humans reproduce, they pass on their genetic information to their offspring. However, if each parent passed on his or her entire genetic code, their child would have twice as many chromosomes as each parent. If this pattern were to continue, the number of chromosomes would double each and every generation, which would quickly become unworkable for cells. In order for a baby to have a non-increasing number of chromosomes, he or she must receive half the normal number of chromosomes from each parent. Therefore, the reproductive cells known as eggs in adult females and sperm in adult males–collectively termed germ cells–must have only half the normal number of chromosomes. Hence, gametes have only 23 chromosomes instead of 23 pairs (46 chromosomes total) like the rest of the cells in your body. These cells are called haploid, as opposed to cells with two pairs of each chromosome that are called diploid.
A special kind of cell division called meiosis generates haploid gametes from diploid parental cells. Meiosis occurs only for the formation of eggs and sperm, but it is clearly a very important process. To get daughter cells with half the number of chromosomes, cells replicate their DNA and then divide twice, instead of once as in mitosis. The result is four daughter cells that are normally genetically different from the parent cell and from each other.
Before we start describing the phases of meiosis, let’s take a moment to clarify the concepts regarding homologous chromosomes and sister chromatids. Homologous chromosomes each have the same type of information, but one was inherited from your mother and the other was inherited from your father. In other words, at the same location or “gene locus” on each homologous chromosome is the gene for a certain trait, such as eye color. Because each homologous chromosome comes from a different parent, however, the alleles, or versions of the gene, can be different. You could get a blue-eyed allele from your father and a brown-eyed allele from your mother, for example. Sister chromatids, on the other hand, only form once a cell has replicated its DNA. They are two identical copies of one chromosome, joined at the middle to form the familiar X-shape. Sister chromatids are pulled apart during mitosis (and, as we will see, during the second phase of meiosis). To summarize: each chromosome has a matching homologue, which carries similar but not identical information. A pair of identical sister chromatids is the result of a chromosome replicating itself.
Now we can begin with a closer look at meiosis. Cells that undergo meiosis first have an interphase, during which they replicate their DNA, followed by two special rounds of cell division. The stages of division have the same names as in mitosis, but are distinguished from each other by roman numerals: the first round, meiosis I, consists of prophase I, metaphase I, etc. and the second round, meiosis II, consists of prophase II, metaphase II, etc. The second division proceeds a lot like mitosis, with the separation of sister chromatids. The first division, however, is different from mitosis in important ways, as we will see.
Prophase I is more complex than mitosis prophase (or prophase II of meiosis). In prophase I, the X-shaped chromosomes (pairs of sister chromatids) also become visible, but this time homologous chromosomes pair up instead of remaining independent. Each pair is held tightly together, forming what is called a bivalent and allowing a process called “crossing over” to take place. Crossing over is a very important phenomenon in genetics. When chromosomes overlap, genetic material from one chromosome (inherited from the mother, say) can trade places with genetic material from the other chromosome (inherited from the father). For example, your mother’s brown-eyed allele could switch places with your father’s blue-eyed one. This process shuffles the genetic information, creating chromosomes that are unique combinations of maternal and paternal alleles, and not just copies from one parent or the other. For this reason, crossing over is said to promote genetic recombination. Crossing over is an important source of genetic variation, which helps make every single person genetically unique (unless you have an identical twin). Interestingly, cells can remain in this state of paired homologous chromosomes for a very long time, even for years. For example, a female baby’s reproductive cells begin meiosis before she is born, but they only progress as far as prophase I. Meiosis later resumes when she reaches puberty.
At the start of prometaphase I, the nuclear membrane breaks down and microtubules attach to the chromosomes, just like in mitotic prometaphase, and meiosis I proceeds. In metaphase I, all the bivalents line up on the equator of the cell. Then, during anaphase I, the homologues are pulled apart as the attached microtubules shorten and the centrosomes move outward. The cell then continues to divide until there are two daughter cells, marking the end of meiosis I.
Before the start of meiosis II, DNA replication does not occur. Instead, meiosis II begins like mitosis, with the chromosomes (still in the form of paired sister chromatids) lining up at the equator of the cell. They are then pulled apart by the microtubules, and the cell divides in two. The result of meiosis II is that now we have only 23 chromosomes in each daughter cell, whereas in mitosis there were a full 46 chromosomes in each daughter cell. Remember that at the beginning of meiosis II there are two cells each undergoing a division, so the final product will be four daughter cells. Observe that there are only 23 chromosomes (the haploid number) in each resulting germ cell and how each one has a unique combination of chromosomes.
What is genetic variation, and why is it important?^
Recall that each of the four daughter cells resulting from meiosis is unique. You can see in Figure B-20 in Part 7 that each daughter cell has different combinations of chromosomes. Unlike the daughter cells resulting from mitosis, the products of meiosis are not identical to each other or to the parent cell. By creating distinctive germ cells each with only one chromosome of each kind (remember this is called haploid) the genetic information of the parent cell is reshuffled. This reshuffling or “recombination” is accomplished through two aspects of meiosis. The first is called independent assortment, which refers simply to the fact that each homologous pair of chromosomes is separated into different daughter cells. Thus, the two alleles of any given gene in the parent cell—one on each of the homologous chromosomes—do not maintain any association with each other as meiosis works its way along. Each daughter cell receives a random mixture of maternal and paternal chromosomes, which leads to a huge number of possible combinations. Theoretically, a daughter cell could have 8,400,000 different combinations of chromosomes! But independent assortment is not the only means of creating genetic variation. In the section on prophase I, remember how we discussed the process of crossing over? When homologous chromosomes overlap and trade some of their genetic material, many, many more combinations of alleles are possible in the resulting daughter cells. Crossing over thus contributes to genetic recombination.
So why is variation important? Geneticists are not sure exactly why, but they generally agree that species, such as humans, that reproduce sexually (and make use of independent assortment and recombination) have a competitive advantage over species that reproduce asexually and basically clone themselves. Sexual reproduction leads to immense genetic variation, and therefore immense variation in the individuals that are produced. Evolutionary theory suggests that when environments are highly variable there is an advantage to producing variable offspring: then it is likely that at least some of the offspring will be able to survive the environmental challenges that arise. (For more information on the genetics of populations, click here).
Unfortunately, there is a drawback to the complexity of meiotic division. Sometimes, it does not proceed correctly and the resulting gametes are abnormal. One kind of mistake that can be made is nondisjunction. Nondisjunction occurs when either homologous chromosomes or sister chromatids fail to separate properly. This situation can occur during either anaphase I or anaphase II, and results in one gamete that lacks a particular chromosome and another one that has two copies. Usually these gametes do not survive, but nondisjunction of certain chromosomes can still produce viable offspring. The offspring will, however, have serious deficits. Down’s Syndrome or “trisomy 21″ is a relatively common nondisjunction disorder that results from an extra copy of chromosome 21. Other problems that can arise from meiosis, though they are more unusual, are expansions and contractions of genes. These occur during crossing over, in which there is not an equal exchange of genetic material. An expansion of the CAG series in the Huntington gene, for example, can (but only very rarely) lead to a spontaneous appearance of the HD allele in a child, when neither parent had HD. (For more information on expansions in HD, click here).
Genetic variation can occur by means other than independent assortment and recombination as well.Mutations, or changes in the genetic code, appear frequently in humans and are an important source of variation. Expansions and contractions of genes are considered to be mutations, but there are also other kinds. (For more information on mutations, click here). Yet more variation comes from transposable elements. Transposable elements are relatively small pieces of DNA that can exist separately from chromosomes and can be inserted in new locations in the genome. Other species have evolved many creative ways of increasing genetic variation. Many plants, for example, have an elaborate life cycle that includes a longer, more significant single-chromosome (haploid) stage (For more information on plants, click here).
In conclusion, genetic variation is crucial to the evolution and survival of all species. Its advantages to living organisms have encouraged the evolution of complex and elegant processes of chromosome shuffling within dividing cells during the process of meiosis. These same processes also serve to make each of us genetically unique, except in the special case of identical twins.
For Further Reading:^
- Alberts, B., Bray, D., Johnson, A., Lewis, J., Raff, M., Roberts, K., & Walter, P. “Essential Cell Biology: An Introduction to the Molecular Biology of the Cell”. Garland Publishing, Inc., 1998.
This textbook covers many topics in molecular biology. It provides a great deal of detail, but it is quite dense.
- McGraw Hill Online Learning Center. Mitosis Movie. http://highered.mcgraw-hill.com/sites/0073031216/student_view0/exercise13/
This tutorial is short and straightforward, and shows mitosis with animation.
- Price, H., Snustad, D., & Simmons, M. “Principles of Genetics: Study Guide and Problems Workbook” (2nd ed.). John Wiley & Sons, Inc., 2000.
Contains some helpful outlines of the concepts of mitosis and meiosis. It also has exercises that help solidify understanding.
To learn more about DNA, a number of resources exist on the web:
S. Fu, 8-04-01 (sections 0-5), -C. Tobin 4-25-06 (6-8)