Reading Chapters In The Genome

Every cell in the body stems from just one cell: the fertilized egg.
Every cell contains the same library of instructions, but the cells read and use different genetic chapters.
Reading Chapters from the Genome

Every cell in the body contains all of the DNA sequence, but the composition of each cell depends on which sections of the DNA are used. We know that each cell reads only those chapters from the library of instructions that it needs. The selective reading process creates many different kinds of cells, such as skin, muscle, neural, and bone cells, all of which develop from the many cells of the embryo produced by the growth and division of one cell: the fertilized egg. Studies of the fruit fly, Drosophila melanogaster, have been useful in revealing how organisms develop these cell types, with each cell knowing what chapters to read according to its position in the developing embryo.
Grassroots Cooperation

The human body has between 50 and 100 trillion cells and no single cell is in charge. Throughout a lifetime, each cell interacts with many other cells to determine which instructions to use at a particular time and place.

DNA Is Like A Library Of Instructions

The genome is like a library of instructions.
A gene is a sequence of A’s, T’s, G’s, and C’s that usually provides the instructions for a single protein component of an organism.
The letters of the genetic alphabet – A, T, G, and C – are meaningless on their own, but they are combined into useful instructions in genes. Some genes carry enough information for one complete characteristic of an organism, but most characteristics result from combinations of genes. Genes are like chapters in the books that fill the library of the genome.
DNA Sequencing

The sequence of letters within a gene is like the letters in a book of instructions. Deciphering the enormously long sequence of A’s, T’s, G’s, and C’s in an organism’s genome reveals useful information. For example, finding a difference in a gene sequence that governs muscle structure raises questions. Could the difference affect health? Just as changing one letter in a word can change its meaning – for example, mice to rice to nice – so changing one DNA letter can sometimes cause illness.
Not all of the sequences in the genes of two humans are identical. For example, because your face is unique, the precise set of sequences in the large group of genes that control the shape of your face are presumably unique too. Some special parts of the DNA sequence vary from person to person with unusually high frequency. As you will see, finding sequences in DNA samples can be used to identify individuals and help solve crimes, even when there are no eyewitnesses.

Reading the Sequences

The sequence of nucleotides in a gene gives it meaning by storing the instructions for building the other molecules necessary for life. These instructions are read as a string of A’s, T’s, G’s, and C’s, such as ACGGTAACT. In the sense that there are 26 letters in the English alphabet, there are four letters in the alphabet of DNA.
The four letters in the DNA alphabet are actually abbreviations for the chemicals that make up the library of instructions.
A for Adenine
T for Thymine
G for Guanine
C for Cytosine

Unzipping DNA

The Sequence On One Strand
The DNA molecule is composed of two very long strands of A’s, T’s, G’s and C’s, which are tightly paired with each other. An A on one strand is always paired with a T on the other strand, and a G is always paired with a C. This means that if the sequence of nucleotides on one strand is known, the sequence of the other strand will be automatically known as well.
One strand of DNA is like a photographic negative of the other strand. A negative can be used to make many copies of a photograph because it contains all of the information that is part of that photograph. Similarly, to read the sequence of A’s, T’s, G’s, and C’s in a genome, it is only necessary to read one strand of DNA to be able to deduce the sequence of the other strand.

One Strand of DNA Is Like a Photographic Negative to the Other An adenine (A) on one strand is always paired with a thymine (T) on the other strand, and a guanine (G) is always paired with a cytosine (C). If the sequence of nucleotides on one strand is known, the sequence of the other strand will be automatically known as well.

The DNA Sequence

The extremely long DNA molecule is actually made of a long string of chemical building blocks called “nucleotides.” There are four different nucleotides, which are labeled adenine (A), thymine (T), guanine (G), and cytosine (C). The human genome is made of a sequence of roughly three billion of these nucleotides, and it is about the same size as the genome of a chimpanzee or a mouse. In contrast, a fruit fly has 180 million, a yeast has 12 million, and the flowering weed “thale cress” has 100 million nucleotides of DNA in its genome.
Learn more about how to read the DNA sequence and probe the sequence for matches in the following sections:

Inheritance

Two Copies of the Genome
You Inherit One Copy From Each Parent

A person has two copies of every gene sequence, one inherited from the mother, and the other inherited from the father. A child thus inherits one copy from each parent's own pair, and this copy is selected from the parent randomly. In order to fully understand a person's DNA sequences, both inherited copies of a gene need to be examined.
These sequences are often not identical. Gene sequences for so-called "dominant" traits are expressed over "recessive" traits. Do you have a cleft chin? It is an indentation at the tip of your chin. If so, you have at least one copy of the dominant gene for cleft chin. But if your chin has no indentation, you have two copies of the recessive gene for this trait.

Two Copies of Each Chromosome You inherit one copy of every chromosome from each parent. Therefore you have two copies of every gene sequence.

Tracing Similarities And Differences In Our DNA

What percent of their genes match yours?

Another human?	100% - All humans have the same genes, but some of these genes contain sequence differences that make each person unique.
A chimpanzee?	98% - Chimpanzees are the closest living species to humans.
A mouse?	92% - All mammals are quite similar genetically.
A fruit fly?	44% - Studies of fruit flies have shown how shared genes govern the growth and structure of both insects and mammals.
Yeast?	26% - Yeasts are single-celled organisms, but they have many housekeeping genes that are the same as the genes in humans, such as those that enable energy to be derived from the breakdown of sugars.
A weed (thale cress)?	18% - Plants have many metabolic differences from humans. For example, they use sunlight to convert carbon dioxide gas to sugars. But they also have similarities in their housekeeping genes.

Why Were Genes Used In This Comparison, and How Do They Relate To DNA?

Genes are the fundamental units of DNA function. In DNA terms, genes are discrete sections of the DNA sequence that are part of much longer DNA molecules. They provide the biochemical instructions for producing all of the components of biological organisms. Some genes specify visible physical traits, while others govern metabolic processes. Most traits, such as the shape of your face, require the actions of many genes.
Why Are We So Similar?

The DNA of these species is so similar because the basic organization of life is widely shared, with the largest differences found between plants and animals, or between tiny single-celled organisms like yeast and large multicellular organisms like ourselves. The similarities reflect a common ancestry that appears to be shared by all life on Earth.
Are People Really Identical?

Even though humans share 100% of the same genes, the instructions contained within the genes are not entirely identical. Each person is unique. People have different hair colors, facial structures, and other traits. These differences between individuals result from very small differences in their DNA sequences. DNA also contains many so-called "housekeeping genes" that control important metabolic processes. As you will see, some of the differences in these genes can cause illness.
Although the DNA of any two people on Earth is, in fact, 99.9% identical, even a tiny difference can have a big effect if this difference is located in a critical gene.

Where Is DNA Found?

Throughout the body - in cells...

Our bodies are formed from between 50 and 100 trillion cells (a trillion is a thousand billion, or a thousand, thousand million). These cells are organized into tissues, such as skin, muscle, and bone. Each cell contains all of the organism's genetic instructions stored as DNA. However, each cell uses only the instructions from part of the DNA. For example, a muscle cell uses the DNA that specifies the muscle apparatus, whereas a nerve cell uses DNA that specifies the nervous system. It is as if each cell reads only that part of a book of instructions that it needs.
Within the cell - in chromosomes...

Each very long DNA molecule is tightly wound and packaged as a chromosome. Humans have two sets of 23 chromosomes in every cell, one set inherited from each parent. A human cell therefore contains 46 of these chromosomal DNA molecules.
Within each chromosome - in genes...

Each DNA molecule that forms a chromosome can be viewed as a set of shorter DNA sequences. These are the units of DNA function, called genes, each of which guides the production of one particular component of an organism. A set of human chromosomes contains one copy of each of the roughly 30,000 genes in the human "genome" - the term used to refer to the complete genetic instructions for an organism.

DNA is found throughout the body. Each cell contains all of the organism's genetic instructions stored as DNA. Each very long DNA molecule is tightly wound and packaged as a chromosome. Each DNA molecule that forms a chromosome can be viewed as a set of shorter DNA sequences. These are the units of DNA function, called genes, each of which guides the production of one particular component of an organism.

Understanding Gene Testing

What are genes?

Genes are working subunits of DNA. DNA is a vast chemical information database that carries the complete set of instructions for making all the proteins a cell will ever need. Each gene contains a particular set of instructions, usually coding for a particular protein.
DNA exists as two long, paired strands spiraled into the famous double helix. Each strand is made up of millions of chemical building blocks called bases. While there are only four different chemical bases in DNA (adenine, thymine, cytosine, and guanine), the order in which the bases occur determines the information available, much as specific letters of the alphabet combine to form words and sentences.
DNA resides in the core, or nucleus, of each of the body's trillions of cells. Every human cell (with the exception of mature red blood cells, which have no nucleus) contains the same DNA. Each cell has 46 molecules of double-stranded DNA. Each molecule is made up of 50 to 250 million bases housed in a chromosome.
The DNA in each chromosome constitutes many genes (as well as vast stretches of noncoding DNA, the function of which is unknown). A gene is any given segment along the DNA that encodes instructions that allow a cell to produce a specific product - typically, a protein such as an enzyme - that initiates one specific action. There are between 50,000 and 100,000 genes, and every gene is made up of thousands, even hundreds of thousands, of chemical bases.
Human cells contain two sets of chromosomes, one set inherited from the mother and one from the father. (Mature sperm and egg cells carry a single set of chromosomes.) Each set has 23 single chromosomes - 22 autosomes and an X or Y sex chromosome. (Females inherit an X from each parent, while males get an X from the mother and a Y from the father.)

For a cell to make protein, the information from a gene is copied, base by base, from DNA into new strands of messenger RNA (mRNA). Then mRNA travels out of the nucleus into the cytoplasm, to cell organelles called ribosomes. There, mRNA directs the assembly of amino acids that fold into completed protein molecule.

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Each human cell contains 23 pairs of chromosomes, which can be distinguished by size and by unique banding patterns. This set is from a male, since it contains a Y chromosome. Females have two X chromosomes.

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Different genes are activated in different cells, creating the specific proteins that give a particular cell type its character.

Ethical, Legal, and Social Concerns about DNA Databanking

The primary concern is privacy. DNA profiles are different from fingerprints, which are useful only for identification. DNA can provide insights into many intimate aspects of people and their families including susceptibility to particular diseases, legitimacy of birth, and perhaps predispositions to certain behaviors and sexual orientation. This information increases the potential for genetic discrimination by government, insurers, employers, schools, banks, and others.
Collected samples are stored, and many state laws do not require the destruction of a DNA record or sample after a conviction has been overturned. So there is a chance that a person's entire genome may be available —regardless of whether they were convicted or not. Although the DNA used is considered "junk DNA", single tandem repeated DNA bases (STRs), which are not known to code for proteins, in the future this information may be found to reveal personal information such as susceptibilities to disease and certain behaviors.
Practicality is a concern for DNA sampling and storage. An enormous backlog of over half a million DNA samples waits to be entered into the CODIS system. The statute of limitations has expired in many cases in which the evidence would have been useful for conviction.
Who is chosen for sampling also is a concern. In the United Kingdom, for example, all suspects can be forced to provide a DNA sample. Likewise, all arrestees --regardless of the degree of the charge and the possibility that they may not be convicted--can be compelled to comply. This empowers police officers, rather than judges and juries, to provide the state with intimate evidence that could lead to "investigative arrests."
In the United States each state legislature independently decides whether DNA can be sampled from arrestees or convicts. In 2006, the New Mexico state legislature passed Katie's Bill, a law that requires the police to take DNA samples from suspects in most felony arrests. Previous New Mexico laws required DNA to be sampled only from convicted felons. The bill is named for Katie Sepich, whose 2003 murder went unsolved until her killer's DNA entered the database in 2005 when he was convinced of another felony. Her killer had been arrested, but not convicted, for burglary prior to 2005.

Opponents of the law assert that it infringes on the privacy and rights of the innocent. While Katie’s Law does allow cleared suspects to petition to have their DNA samples purged from the state database, the purging happens only after the arrest. Civil liberties advocates say that Katie's Bill still raises the question of Fourth Amendment violations against unreasonable search and seizure and stress that the law could be abused to justify arrests made on less than probable cause just to obtain DNA evidence.
As of September 2007, all 50 states have laws that require convicted sex offenders to submit DNA, 44 states have laws that require convicted felons to submit DNA, 9 states require DNA samples from those convicted of certain misdemeanors, and 11 states—including Alaska, Arizona, California, Kansas, Louisiana, Minnesota, New Mexico, North Dakota, Tennessee, Texas, and Virginia—have laws authorizing arrestee DNA sampling.

What are some of the DNA technologies used in forensic investigations?

Restriction Fragment Length Polymorphism (RFLP)
RFLP is a technique for analyzing the variable lengths of DNA fragments that result from digesting a DNA sample with a special kind of enzyme. This enzyme, a restriction endonuclease, cuts DNA at a specific sequence pattern know as a restriction endonuclease recognition site. The presence or absence of certain recognition sites in a DNA sample generates variable lengths of DNA fragments, which are separated using gel electrophoresis. They are then hybridized with DNA probes that bind to a complementary DNA sequence in the sample.
RFLP was one of the first applications of DNA analysis to forensic investigation. With the development of newer, more efficient DNA-analysis techniques, RFLP is not used as much as it once was because it requires relatively large amounts of DNA. In addition, samples degraded by environmental factors, such as dirt or mold, do not work well with RFLP.
PCR Analysis
Polymerase chain reaction (PCR) is used to make millions of exact copies of DNA from a biological sample. DNA amplification with PCR allows DNA analysis on biological samples as small as a few skin cells. With RFLP, DNA samples would have to be about the size of a quarter. The ability of PCR to amplify such tiny quantities of DNA enables even highly degraded samples to be analyzed. Great care, however, must be taken to prevent contamination with other biological materials during the identifying, collecting, and preserving of a sample.
STR Analysis
Short tandem repeat (STR) technology is used to evaluate specific regions (loci) within nuclear DNA. Variability in STR regions can be used to distinguish one DNA profile from another. The Federal Bureau of Investigation (FBI) uses a standard set of 13 specific STR regions for CODIS. CODIS is a software program that operates local, state, and national databases of DNA profiles from convicted offenders, unsolved crime scene evidence, and missing persons. The odds that two individuals will have the same 13-loci DNA profile is about one in a billion.
Mitochondrial DNA Analysis
Mitochondrial DNA analysis (mtDNA) can be used to examine the DNA from samples that cannot be analyzed by RFLP or STR. Nuclear DNA must be extracted from samples for use in RFLP, PCR, and STR; however, mtDNA analysis uses DNA extracted from another cellular organelle called a mitochondrion. While older biological samples that lack nucleated cellular material, such as hair, bones, and teeth, cannot be analyzed with STR and RFLP, they can be analyzed with mtDNA. In the investigation of cases that have gone unsolved for many years, mtDNA is extremely valuable.
All mothers have the same mitochondrial DNA as their offspring. This is because the mitochondria of each new embryo comes from the mother's egg cell. The father's sperm contributes only nuclear DNA. Comparing the mtDNA profile of unidentified remains with the profile of a potential maternal relative can be an important technique in missing-person investigations.
Y-Chromosome Analysis
The Y chromosome is passed directly from father to son, so analysis of genetic markers on the Y chromosome is especially useful for tracing relationships among males or for analyzing biological evidence involving multiple male contributors.

How is DNA typing done?

Only one-tenth of a single percent of DNA (about 3 million bases) differs from one person to the next. Scientists can use these variable regions to generate a DNA profile of an individual, using samples from blood, bone, hair, and other body tissues and products.
In criminal cases, this generally involves obtaining samples from crime-scene evidence and a suspect, extracting the DNA, and analyzing it for the presence of a set of specific DNA regions (markers).
Scientists find the markers in a DNA sample by designing small pieces of DNA (probes) that will each seek out and bind to a complementary DNA sequence in the sample. A series of probes bound to a DNA sample creates a distinctive pattern for an individual. Forensic scientists compare these DNA profiles to determine whether the suspect's sample matches the evidence sample. A marker by itself usually is not unique to an individual; if, however, two DNA samples are alike at four or five regions, odds are great that the samples are from the same person.
If the sample profiles don't match, the person did not contribute the DNA at the crime scene.
If the patterns match, the suspect may have contributed the evidence sample. While there is a chance that someone else has the same DNA profile for a particular probe set, the odds are exceedingly slim. The question is, How small do the odds have to be when conviction of the guilty or acquittal of the innocent lies in the balance? Many judges consider this a matter for a jury to take into consideration along with other evidence in the case. Experts point out that using DNA forensic technology is far superior to eyewitness accounts, where the odds for correct identification are about 50:50.
The more probes used in DNA analysis, the greater the odds for a unique pattern and against a coincidental match, but each additional probe adds greatly to the time and expense of testing. Four to six probes are recommended. Testing with several more probes will become routine, observed John Hicks (Alabama State Department of Forensic Services). He predicted that DNA chip technology (in which thousands of short DNA sequences are embedded in a tiny chip) will enable much more rapid, inexpensive analyses using many more probes and raising the odds against coincidental matches.

Is DNA effective in identifying persons?

DNA identification can be quite effective if used intelligently. Portions of the DNA sequence that vary the most among humans must be used; also, portions must be large enough to overcome the fact that human mating is not absolutely random.
Consider the scenario of a crime scene investigation . . .
Assume that type O blood is found at the crime scene. Type O occurs in about 45% of Americans. If investigators type only for ABO, finding that the "suspect" in a crime is type O really doesn't reveal very much.
If, in addition to being type O, the suspect is a blond, and blond hair is found at the crime scene, you now have two bits of evidence to suggest who really did it. However, there are a lot of Type O blonds out there.
If you find that the crime scene has footprints from a pair of Nike Air Jordans (with a distinctive tread design) and the suspect, in addition to being type O and blond, is also wearing Air Jordans with the same tread design, you are much closer to linking the suspect with the crime scene.
In this way, by accumulating bits of linking evidence in a chain, where each bit by itself isn't very strong but the set of all of them together is very strong, you can argue that your suspect really is the right person.
With DNA, the same kind of thinking is used; you can look for matches (based on sequence or on numbers of small repeating units of DNA sequence) at many different locations on the person's genome; one or two (even three) aren't enough to be confident that the suspect is the right one, but thirteen sites are used. A match at all thirteen is rare enough that you (or a prosecutor or a jury) can be very confident ("beyond a reasonable doubt") that the right person is accused.

How does forensic identification work?

Any type of organism can be identified by examination of DNA sequences unique to that species. Identifying individuals within a species is less precise at this time, although when DNA sequencing technologies progress farther, direct comparison of very large DNA segments, and possibly even whole genomes, will become feasible and practical and will allow precise individual identification.
To identify individuals, forensic scientists scan 13 DNA regions, or loci, that vary from person to person and use the data to create a DNA profile of that individual (sometimes called a DNA fingerprint). There is an extremely small chance that another person has the same DNA profile for a particular set of 13 regions.
Some Examples of DNA Uses for Forensic Identification

• Identify potential suspects whose DNA may match evidence left at crime scenes
• Exonerate persons wrongly accused of crimes
• Identify crime and catastrophe victims
• Establish paternity and other family relationships
• Identify endangered and protected species as an aid to wildlife officials (could be used for prosecuting poachers)
• Detect bacteria and other organisms that may pollute air, water, soil, and food
• Match organ donors with recipients in transplant programs
• Determine pedigree for seed or livestock breeds
• Authenticate consumables such as caviar and wine

Exceptions to Mendel's Laws

There are many examples of inheritance that appear to be exceptions to Mendel's laws. Usually, they turn out to represent complex interactions among various allelic conditions. For example, co-dominant alleles both contribute to a phenotype. Neither is dominant over the other. Control of the human blood group system provides a good example of co-dominant alleles.

The Four Basic Blood Types There are four basic blood types, and they are O, A, B, and AB. We know that our blood type is determined by the "alleles" that we inherit from our parents. For the blood type gene, there are three basic blood type alleles: A, B, and O. We all have two alleles, one inherited from each parent. The possible combinations of the three alleles are OO, AO, BO, AB, AA, and BB. Blood types A and B are "co-dominant" alleles, whereas O is "recessive". A codominant allele is apparent even if only one is present; a recessive allele is apparent only if two recessive alleles are present. Because blood type O is recessive, it is not apparent if the person inherits an A or B allele along with it. So, the possible allele combinations result in a particular blood type in this way: OO = blood type O AO = blood type A BO = blood type B AB = blood type AB AA = blood type A BB = blood type B You can see that a person with blood type B may have a B and an O allele, or they may have two B alleles. If both parents are blood type B and both have a B and a recessive O, then their children will either be BB, BO, or OO. If the child is BB or BO, they have blood type B. If the child is OO, he or she will have blood type O.

Pleiotropism, or pleotrophy, refers to the phenomenon in which a single gene is responsible for producing multiple, distinct, and apparently unrelated phenotypic traits, that is, an individual can exhibit many different phenotypic outcomes. This is because the gene product is active in many places in the body. An example is Marfan's syndrome, where there is a defect in the gene coding for a connective tissue protein. Individuals with Marfan's syndrome exhibit abnormalities in their eyes, skeletal system, and cardiovascular system. Some genes mask the expression of other genes just as a fully dominant allele masks the expression of its recessive counterpart. A gene that masks the phenotypic effect of another gene is called an epistatic gene; the gene it subordinates is the hypostatic gene. The gene for albinism in humans is an epistatic gene. It is not part of the interacting skin-color genes. Rather, its dominant allele is necessary for the development of any skin pigment, and its recessive homozygous state results in the albino condition, regardless of how many other pigment genes may be present. Because of the effects of an epistatic gene, some individuals who inherit the dominant, disease-causing gene show only partial symptoms of the disease. Some, in fact, may show no expression of the disease-causing gene, a condition referred to as nonpenetrance. The individual in whom such a nonpenetrant mutant gene exists will be phenotypically normal but still capable of passing the deleterious gene on to offspring, who may exhibit the full-blown disease. Then we have traits that are multigenic, that is, they result from the expression of several different genes. This is true for human eye color, in which at least three different genes are responsible for determining eye color. A brown/blue gene and a central brown gene are both found on chromosome 15, whereas a green/blue gene is found on chromosome 19. The interaction between these genes is not well understood. It is speculated that there may be other genes that control other factors, such as the amount of pigment deposited in the iris. This multigenic system explains why two blue-eyed individuals can have a brown-eyed child. Speaking of eye color, have you ever seen someone with one green eye and one brown eye? In this case, somatic mosaicism may be the culprit. This is probably easier to describe than explain. In multicellular organisms, every cell in the adult is ultimately derived from the single-cell fertilized egg. Therefore, every cell in the adult normally carries the same genetic information. However, what would happen if a mutation occurred in only one cell at the two-cell stage of development? Then the adult would be composed of two types of cells: cells with the mutation and cells without. If a mutation affecting melanin production occurred in one of the cells in the cell lineage of one eye but not the other, then the eyes would have different genetic potential for melanin synthesis. This could produce eyes of two different colors. Penetrance refers to the degree to which a particular allele is expressed in a population phenotype. If every individual carrying a dominant mutant gene demonstrates the mutant phenotype, the gene is said to show complete penetrance.

How Does Inheritance Work?

Our discussion here is restricted to sexually reproducing organisms where each gene in an individual is represented by two copies, called alleles—one on each chromosome pair. There may be more than two alleles, or variants, for a given gene in a population, but only two alleles can be found in an individual. Therefore, the probability that a particular allele will be inherited is 50:50, that is, alleles randomly and independently segregate into daughter cells, although there are some exceptions to this rule. The term diploid describes a state in which a cell has two sets of homologous chromosomes, or two chromosomes that are the same. The maturation of germ line stem cells into gametes requires the diploid number of each chromosome be reduced by half. Hence, gametes are said to be haploid—having only a single set of homologous chromosomes. This reduction is accomplished through a process called meiosis, where one chromosome in a diploid pair is sent to each daughter gamete. Human gametes, therefore, contain 23 chromosomes, half the number of somatic cells—all the other cells of the body. Because the chromosome in one pair separates independently of all other chromosomes, each new gamete has the potential for a totally new combination of chromosomes. In humans, the independent segregation of the 23 chromosomes can lead to as many as 16 to 17 million different combinations in one individual's gametes. Only one of these gametes will combine with one of the nearly 17 million possible combinations from the other parent, generating a staggering potential for individual variation. Yet, this is just the beginning. Even more variation is possible when you consider the recombination between sections of chromosomes during meiosis as well as the random mutation that can occur during DNA replication. With such a range of possibilities, it is amazing that siblings look so much alike!

Expression of Inherited Genes Gene expression, as reflected in an organism's phenotype, is based on conditions specific for each copy of a gene. As we just discussed, for every human gene there are two copies, and for every gene there can be several variants or alleles. If both alleles are the same, the gene is said to be homozygous. If the alleles are different, they are said to be heterozygous. For some alleles, their influence on phenotype takes precedence over all other alleles. For others, expression depends on whether the gene appears in the homozygous or heterozygous state. Still other phenotypic traits are a combination of several alleles from several different genes. Determining the allelic condition used to be accomplished solely through the analysis of pedigrees, much the way Mendel carried out his experiments on peas. However, this method can leave many questions unanswered, particularly for traits that are a result of the interaction between several different genes. Today, molecular genetic techniques exist that can assist researchers in tracking the transmission of traits by pinpointing the location of individual genes, identifying allelic variants, and identifying those traits that are caused by multiple genes.

The Nature of Alleles A dominant allele is an allele that is almost always expressed, even if only one copy is present. Dominant alleles express their phenotype even when paired with a different allele, that is, when heterozygous. In this case, the phenotype appears the same in both the heterozygous and homozygous states. Just how the dominant allele overshadows the other allele depends on the gene, but in some cases the dominant gene produces a gene product that the other allele does not. Well-known dominant alleles occur in the human genes for Huntington disease, a form of dwarfism called achondroplasia, and polydactylism (extra fingers and toes). On the other hand, a recessive allele will be expressed only if there are two identical copies of that allele, or for a male, if one copy is present on the X chromosome. The phenotype of a recessive allele is only seen when both alleles are the same. When an individual has one dominant allele and one recessive allele, the trait is not expressed because it is overshadowed by the dominant allele. The individual is said to be a carrier for that trait. Examples of recessive disorders in humans include sickle cell anemia, Tay-Sachs disease, and phenylketonuria (PKU). A particularly important category of genetic linkage has to do with the X and Y sex chromosomes. These chromosomes not only carry the genes that determine male and female traits, but also those for some other characteristics as well. Genes that are carried by either sex chromosome are said to be sex linked. Men normally have an X and a Y combination of sex chromosomes, whereas women have two X's. Because only men inherit Y chromosomes, they are the only ones to inherit Y-linked traits. Both men and women can have X-linked traits because both inherit X chromosomes. X-linked traits not related to feminine body characteristics are primarily expressed in the phenotype of men. This is because men have only one X chromosome. Subsequently, genes on that chromosome that do not code for gender are expressed in the male phenotype, even if they are recessive. In women, a recessive allele on one X chromosome is often masked in their phenotype by a dominant normal allele on the other. This explains why women are frequently carriers of X-linked traits but more rarely have them expressed in their own phenotypes. In humans, at least 320 genes are X-linked. These include the genes for hemophilia, red–green color blindness, and congenital night blindness. There are at least a dozen Y-linked genes, in addition to those that code for masculine physical traits. It is now known that one of the X chromosomes in the cells of human females is completely, or mostly, inactivated early in embryonic life. This is a normal self-preservation action to prevent a potentially harmful double dose of genes. Recent research points to the "Xist" gene on the X chromosome as being responsible for a sequence of events that silences one of the X chromosomes in women. The inactivated X chromosomes become highly compacted structures known as Barr bodies. The presence of Barr bodies has been used at international sport competitions as a test to determine whether an athlete is a male or a female.

Mutations and the Next Generation

There are two places where mutations can be introduced and carried into the next generation. In the first stages of development, a sperm cell and egg cell fuse. They then begin to divide, giving rise to cells that differentiate into tissue-specific cell types. One early type of differentiated cell is the germ line cell, which may ultimately develop into mature gametes. If a mutation occurs in the developing germ line cell, it may persist until that individual reaches reproductive age. Now the mutation has the potential to be passed on to the next generation. Mutations may also be introduced during meiosis, the mode of cell replication for the formation of sperm and egg cells. In this case, the germ line cell is healthy, and the mutation is introduced during the actual process of gamete replication. Once again, the sperm or egg will contain the mutation, and during the reproductive process, this mutation may then be passed on to the offspring. One should bear in mind that not all mutations are bad. Mutations also provide a species with the opportunity to adapt to new environments, as well as to protect a species from new pathogens. Mutations are what lie behind the popular saying of "survival of the fittest", the basic theory of evolution proposed by Charles Darwin in 1859. This theory proposes that as new environments arise, individuals carrying certain mutations that enable an evolutionary advantage will survive to pass this mutation on to its offspring. It does not suggest that a mutation is derived from the environment, but that survival in that environment is enhanced by a particular mutation. Some genes, and even some organisms, have evolved to tolerate mutations better than others. For example, some viral genes are known to have high mutation rates. Mutations serve the virus well by enabling adaptive traits, such as changes in the outer protein coat so that it can escape detection and thereby destruction by the host's immune system. Viruses also produce certain enzymes that are necessary for infection of a host cell. A mutation within such an enzyme may result in a new form that still allows the virus to infect its host but that is no longer blocked by an anti-viral drug. This will allow the virus to propagate freely in its environment.

Mendel's Laws—How We Inherit Our Genes In 1866, Gregor Mendel studied the transmission of seven different pea traits by carefully test-crossing many distinct varieties of peas. Studying garden peas might seem trivial to those of us who live in a modern world of cloned sheep and gene transfer, but Mendel's simple approach led to fundamental insights into genetic inheritance, known today as Mendel's Laws. Mendel did not actually know or understand the cellular mechanisms that produced the results he observed. Nonetheless, he correctly surmised the behavior of traits and the mathematical predictions of their transmission, the independent segregation of alleles during gamete production, and the independent assortment of genes. Perhaps as amazing as Mendel's discoveries was the fact that his work was largely ignored by the scientific community for over 30 years!

Mendel's Principles of Genetic Inheritance Law of Segregation: Each of the two inherited factors (alleles) possessed by the parent will segregate and pass into separate gametes (eggs or sperm) during meiosis, which will each carry only one of the factors. Law of Independent Assortment: In the gametes, alleles of one gene separate independently of those of another gene, and thus all possible combinations of alleles are equally probable. Law of Dominance: Each trait is determined by two factors (alleles), inherited one from each parent. These factors each exhibit a characteristic dominant, co-dominant, or recessive expression, and those that are dominant will mask the expression of those that are recessive.

Mechanisms of Genetic Variation and Heredity

Does Everyone Have the Same Genes? When you look at the human species, you see evidence of a process called genetic variation, that is, there are immediately recognizable differences in human traits, such as hair and eye color, skin pigment, and height. Then there are the not so obvious genetic variations, such as blood type. These expressed, or phenotypic, traits are attributable to genotypic variation in a person's DNA sequence. When two individuals display different phenotypes of the same trait, they are said to have two different alleles for the same gene. This means that the gene's sequence is slightly different in the two individuals, and the gene is said to be polymorphic, "poly" meaning many and "morph" meaning shape or form. Therefore, although people generally have the same genes, the genes do not have exactly the same DNA sequence. These polymorphic sites influence gene expression and also serve as markers for genomic research efforts.

Genetic Variation The cell cycle is the process that a cell undergoes to replicate. Most genetic variation occurs during the phases of the cell cycle when DNA is duplicated. Mutations in the new DNA strand can manifest as base substitutions, such as when a single base gets replaced with another; deletions, where one or more bases are left out; or insertions, where one or more bases are added. Mutations can either be synonymous, in which the variation still results in a codon for the same amino acid or non-synonymous, in which the variation results in a codon for a different amino acid. Mutations can also cause a frame shift, which occurs when the variation bumps the reference point for reading the genetic code down a base or two and results in loss of part, or sometimes all, of that gene product. DNA mutations can also be introduced by toxic chemicals and, particularly in skin cells, exposure to ultraviolet radiation.

The manner in which a cell replicates differs with the various classes of life forms, as well as with the end purpose of the cell replication. Cells that compose tissues in multicellular organisms typically replicate by organized duplication and spatial separation of their cellular genetic material, a process called mitosis. Meiosis is the mode of cell replication for the formation of sperm and egg cells in plants, animals, and many other multicellular life forms. Meiosis differs significantly from mitosis in that the cellular progeny have their complement of genetic material reduced to half that of the parent cell.

Mutations that occur in somatic cells—any cell in the body except gametes and their precursors—will not be passed on to the next generation. This does not mean, however, that somatic cell mutations, sometimes called acquired mutations, are benign. For example, as your skin cells prepare to divide and produce new skin cells, errors may be inadvertently introduced when the DNA is duplicated, resulting in a daughter cell that contains the error. Although most defective cells die quickly, some can persist and may even become cancerous if the mutation affects the ability to regulate cell growth.

The Influence of DNA Structure and Binding Domains

Sequences that are important in regulating transcription do not necessarily code for transcription factors or other proteins. Transcription can also be regulated by subtle variations in DNA structure and by chemical changes in the bases to which transcription factors bind. As stated previously, the chemical properties of the four DNA bases differ slightly, providing each base with unique opportunities to chemically react with other molecules. One chemical modification of DNA, called methylation, involves the addition of a methyl group (-CH3). Methylation frequently occurs at cytosine residues that are preceded by guanine bases, oftentimes in the vicinity of promoter sequences. The methylation status of DNA often correlates with its functional activity, where inactive genes tend to be more heavily methylated. This is because the methyl group serves to inhibit transcription by attracting a protein that binds specifically to methylated DNA, thereby interfering with polymerase binding. Methylation also plays an important role in genomic imprinting, which occurs when both maternal and paternal alleles are present but only one allele is expressed while the other remains inactive. Another way to think of genomic imprinting is as "parent of origin differences" in the expression of inherited traits. Considerable intrigue surrounds the effects of DNA methylation, and many researchers are working to unlock the mystery behind this concep

Controlling Transcription

Promoters and Regulatory Sequences Transcription is the process whereby RNA is made from DNA. It is initiated when an enzyme, RNA polymerase, binds to a site on the DNA called a promoter sequence. In most cases, the polymerase is aided by a group of proteins called "transcription factors" that perform specialized functions, such as DNA sequence recognition and regulation of the polymerase's enzyme activity. Other regulatory sequences include activators, repressors, and enhancers. These sequences can be cis-acting (affecting genes that are adjacent to the sequence) or trans-acting (affecting expression of the gene from a distant site), even on another chromosome.

The Globin Genes: An Example of Transcriptional Regulation An example of transcriptional control occurs in the family of genes responsible for the production of globin. Globin is the protein that complexes with the iron-containing heme molecule to make hemoglobin. Hemoglobin transports oxygen to our tissues via red blood cells. In the adult, red blood cells do not contain DNA for making new globin; they are ready-made with all of the hemoglobin they will need. During the first few weeks of life, embryonic globin is expressed in the yolk sac of the egg. By week five of gestation, globin is expressed in early liver cells. By birth, red blood cells are being produced, and globin is expressed in the bone marrow. Yet, the globin found in the yolk is not produced from the same gene as is the globin found in the liver or bone marrow stem cells. In fact, at each stage of development, different globin genes are turned on and off through a process of transcriptional regulation called "switching". To further complicate matters, globin is made from two different protein chains: an alpha-like chain coded for on chromosome 16; and a beta-like chain coded for on chromosome 11. Each chromosome has the embryonic, fetal, and adult form lined up on the chromosome in a sequential order for developmental expression. The developmentally regulated transcription of globin is controlled by a number of cis-acting DNA sequences, and although there remains a lot to be learned about the interaction of these sequences, one known control sequence is an enhancer called the Locus Control Region (LCR). The LCR sits far upstream on the sequence and controls the alpha genes on chromosome 16. It may also interact with other factors to determine which alpha gene is turned on. Thalassemias are a group of diseases characterized by the absence or decreased production of normal globin, and thus hemoglobin, leading to decreased oxygen in the system. There are alpha and beta thalassemias, defined by the defective gene, and there are variations of each of these, depending on whether the embryonic, fetal, or adult forms are affected and/or expressed. Although there is no known cure for the thalassemias, there are medical treatments that have been developed based on our current understanding of both gene regulation and cell differentiation. Treatments include blood transfusions, iron chelators, and bone marrow transplants. With continuing research in the areas of gene regulation and cell differentiation, new and more effective treatments may soon be on the horizon, such as the advent of gene transfer therapies.