Patterns of Inheritance

We know that a gene is a region of a chromosome (piece of DNA) that contains a set of instructions for synthesizing a protein (polypeptide). We know, too that these instructions are passed from cell to cell and from generation to generation as inheritable traits or characteristics.

We know that the chromosomes of diploid organisms come in pairs, the homologous chromosomes, so that each cell of a diploid organism has two genes for each inheritable trait, one on each of the homologous chromosome pairs.

The alternative forms (variants) a gene can have on the homologous chromosomes are called alleles. The precise location where a gene is found on a chromosome is known as the locus.

A gamete has one of each "gene pair" (or one of each homologous chromosome) but not both, and that the diploid number of chromosomes with homologous chromosome pairs, is restored at fertilization, when two gametes fuse.

At this time we will look at how genes interact and are expressed in individuals, and how genes are transmitted from generation to generation.

We did not always know that genes were located on chromosomes. We did not even know that inheritable traits, or genes, came in pairs. Gregor Mendel in 1865 was the first to state that inheritable traits (genes) came in pairs. His work went unappreciated for several decades because no one seemed to understand what it meant. In the early 1900's other researchers independently made the same conclusions about inheritance and Mendel's papers were "rediscovered". Soon after, Walter Sutton showed that Mendel's principles of inheritance applied to chromosomes and that chromosomes are the units of heredity.

Prior to Mendel, the subject of inheritance was mostly guesswork. Although the practice of selective animal and plant breeding was well established, virtually nothing was known of the mechanisms of inheritance beyond the presence of an egg and a sperm in animals, and pollen and carpel in plants.

It was generally believed at that time that characteristics of parents were "blended" in offspring since offspring generally had features of both parents. No one went so far as to question why, after several generations, variations still were present, since differences over time should have been thoroughly blended.

The subject of variation among individuals and how different variants were passed on (or apparently not passed on) from generation to generation was very important to science in the 1800's. Mendel's work coincided with the publications of Darwin and Wallace, who addressed variation among the individuals of populations as the foundation for which selective agents could act through time, in the process of evolution.
Gregor Mendel's Contribution to the Subject of Inheritance
Mendel observed how specific traits of the garden pea were transmitted from generation to generation. Mendel kept precise records of the thousands of offspring (and their characteristics) produced in his crosses. He then established mathematical probabilities and explanations to validate his observations.

Although others had studied inheritance, Mendel's educational experiences in math and observing plant variation helped him design and analyze his experiments carefully. Mendel:


Mendel's research led to the following conclusions, two of which are presented as Mendel's Principles:

Mendel's Statements about Inheritance
  1. There are alternative forms (or variations) of genes, the "units" that determine inherited traits. The alternative forms of a gene are now called alleles. To relate this to what we know about homologous chromosomes, the alleles are located at the same locus on homologous chromosomes. (Specifically, we inherit the alleles for a gene, not the gene).

  2. An individual will have 2 alleles for each inherited trait. The 2 alleles may be the same, or they may be different. If the two alleles are the same, the individual will be homozygous for that trait. If the two alleles are different, the individual will be heterozygous for the trait.

    When the two alleles for a gene pair are different from each other, one will be expressed, and the second will not affect the organism's appearance. The allele always expressed is said to be dominant, and the one that may not be expressed is recessive.

    Note: These statements are true for the traits tested in Mendel's peas and for many genes, but are not universally true. Many genes have alleles that are equally expressed, as we shall see, and there are genes that have more than 2 alleles within the population.

  3. Gametes have just one allele for each trait, because the allele (gene) pairs are separated (or segregated) during meiosis I when homologous chromosomes pair and then separate. 50% of the gametes receive one allele and 50% of the gametes receive the alternative allele when the alleles are heterozygous. (And as Mendel proposed, fertilization results in restoring the pairs of alleles for the next generation).

    This statement ultimately resulted in Mendel's Principle of Segregation: Pairs of genes segregate during the formation of gametes (Meiosis), so that each gamete has one of each gene pair (one allele) but not both. Fertilization restores the gene pairs (on the homologous chromosomes).

    Mendel demonstrated his Principle of Segregation with many monohybrid crosses, looking at one characteristic at a time. He could further validate his Principle of Segregation with the test cross, a cross in which the F1 generation, which appeared dominant, was crossed to the recessive parent. Their offspring would exhibit equal proportions of both dominant and recessive forms.

  4. Mendel's experiments with crossing two traits at one time, a dihybrid cross, resulted in his Principle of Independent Assortment. Each gene pair is distributed (assorts) independently of other gene pairs into gametes during meiosis.

    We observed this during meiosis when the homologous pairs of chromosomes align along the equator at metaphase I. Maternal chromosomes of some pairs align towards one pole some of the time, and the other pole some of the time. Each meiosis event has a different alignment pattern.

    We know today that each homologous chromosome pair assorts independently, not specific genes. A gene on one chromosome will be inherited independently of a gene on a non-homologous chromosome, but all genes located on one chromosome are inherited as a linkage unit. That is two genes that are located on the same chromosome will be inherited together, and not assort independently during meiosis.

Many human traits follow Mendelian inheritance predictions. You will look at some of those in the laboratory as well as reading about them in your text.

We will not discuss in lecture the specific crosses or predictions which Mendel did which resulted in his conclusions about inheritance. These crosses are thoroughly discussed in your text and in the laboratory exercise.

You will be responsible for knowing the following inheritance patterns and the predicted inheritance ratios for each outside of lecture. (Text references in parentheses). You will also be responsible for other types of inheritance patterns that are in your text or discussed in class.


Note that Mendelian inheritance predictions follow the mathematical laws of probability. Although it is fairly "easy" to diagram a monohybrid test and a dihybrid test using Punnett squares (see figures in text), making predictions and looking at results for increasing numbers of genes or other inheritance observations becomes tedious and time consuming. Applying probability laws is much faster and easier.

Some terms used in Mendelian Inheritance Tests

True Breeding


Cross Breeding
F1 Generation
F2 Generation
Punnett Square
 Gene
Alleles
Locus
 Homozygous Heterozygous Dominant Allele (loosely and incorrectly called a dominant gene) Recessive Allele Phenotype Genotype
You should also review your knowledge of homologous chromosomes and the process of meiosis, since the homologous chromosomes "carry" the alleles, or alternative forms for each gene.

Beyond Mendel
Mendel's research occurred before we had knowledge about chromosomes, molecular genetics, mitosis or meiosis. All of Mendel's genes had dominant and recessive forms, and each of his characteristics was found on different chromosomes. Early on, some inheritance patterns did not match the expectations proposed by Mendel's principles. We shall now turn our attention to some gene actions that go beyond the basic Mendelian predictions.

The Chromosome Theory of Inheritance
Gregor Mendel's work was "rediscovered" in 1900 by three independent geneticists who had done studies which came to the same conclusions that Mendel had made. They had the advantage that the processes of mitosis and meiosis were known explaining how genes could be separated. The next step was accomplished in 1902, when Sutton and Boveri correlated Mendel's conclusions about genes (or inherited traits) to the behavior of chromosomes during mitosis and meiosis. Sutton is credited with first proposing the chromosome theory of inheritance:


Chromosomes and Mendel's Laws

Gene Linkage
Today we know that each cell contains several thousand genes, and that genes are specific regions of chromosomes. Further we know that entire chromosomes, not individual genes, are transmitted by meiosis to the gametes. But the inheritance patterns discussed to date have involved genes located on different chromosomes, so they have followed Mendel's Principle of Independent Assortment.

We can now look at the inheritance of genes which are located on the same chromosome, the subject of gene linkage. This adds some interesting complications to the predicted patterns of inheritance (and also explains why recombination, which we discussed with meiosis, is so important as a source of variation).

In 1908, researchers discovered a dihybrid cross in sweet peas that did not give the predicted Mendelian ratio of 9:3:3:1. They could not explain why their results were closer to 75% and 25% (the 3:1 ratio expected for a monohybrid cross).

Ultimately it was shown that the flower color and pollen length (the genes observed) were on the same chromosome. Since we inherit entire chromosomes rather than independent genes, all genes on one chromosome are inherited together as a single unit (called the linkage group), and we should expect a 3:1 inheritance ratio for the linkage group. This was just the first time someone had seen this.



Crossing over results in the exchange of bits and pieces of DNA between homologous pairs of chromosomes at the chiasmata during prophase I of meiosis. This process of recombination results in gametes (or meiotic products) that are not identical; some of the linkage groups have been changed by the crossing-over. As a result of recombination, new allele combinations are formed, and we have more genetic variation.



Sex-Linkage and Sex-determining Chromosomes
One of the earliest discoveries about gene linkage related to another significant thing about chromosomes and species, especially animal species. By the early 1900's it was known that males and females of most species have one pair of "not-exactly-matching" homologous chromosomes, which determined the gender of the individual. These chromosomes were called the sex chromosomes. (The truly matching chromosomes are the autosomes.)

With the gender-determining chromosomes, one sex, usually female, will have two matching chromosomes (XX) and the other sex will have two unmatched chromosomes (XY). At meiosis, all eggs will contain an X chromosome, but half the sperm gametes will have a Y chromosome and the other half will have an X chromosome.

Some species have the reverse pattern of sex chromosomes (male = XX and female = XY), and some species have one gender (female) with a pair of chromosomes and one gender (male) with a single unmatched chromosome. In all cases the gender with the dissimilar pattern will determine the gender of the offspring.

In 1910, Thomas Hunt Morgan, who spent much of his career studying inheritance patterns of the fruit fly, Drosophila melanogaster, discovered the presence of a white eye in certain individuals. Since this was a distinctive feature, Morgan decided to study the inheritance pattern for this recessive eye color.

Morgan made several crosses using a white-eyed male, expecting the standard Mendelian results. He did not get them. While the ratio of 3:1 was obtained, all of the white-eyed second generation offspring were male flies. All females had red eyes (and 25% of the males also had red eyes).

Morgan did a series of reciprocal crosses of white-eye males with red-eye females and red-eye males with white-eye females. He concluded that the gene for eye color in the fruit fly was located on the X chromosome. Males passed the trait to their daughters (on their solitary X chromosome) and mothers passed the trait to sons. White eyed females could also pass the white eye allele to their daughters, but if the father fly had red eyes, the eye color of the daughters would be red, while the eye color of the sons of white-eyed females would always be white.



Morgan concluded that eye color was related to sex, and that the sex-determining chromosomes also had genes that were unrelated to gender determination. Prior to Morgan's discovery, no one knew that genes unrelated to gender were also located on these chromosomes.

The other traits are said to be sex-linked because they are inherited along with the sex of the individual. Because the X and Y chromosome are not exactly matching, the X chromosome can have genes that are not located on the Y chromosome, and vice-versa. Some of these genes are unrelated to the sexual characteristics, but are inherited with the sex-determination. This is referred to as sex-linkage.

Some human sex-linked traits are


The Barr Body Revisited
Females have two X-chromosomes. In cells, one of them is deactivated during embryonic development and forms a tightly condensed object that lines the nuclear membrane, the so-call Barr body. Transcription does not occur on the Barr body, a form of gene regulation by chromosome inactivation discussed earlier. Which X gets condensed for a given cell line appears to be random. The specific allele for genes carried on the X chromosome that gets expressed in any given cell line depends on which X chromosome is made into a Barr body.

The pattern of the calico cat is an example of Barr body expression. Both orange and black pigment alleles are on the X chromosome. The black patches of fur are from cell lines where the orange X chromosome is a Barr body. Orange patches of fur result when the black X chromosome becomes the Barr body. The patches of white fur are the expression of a different gene.




Gene Interactions – Beyond Mendel
Recall that all of Mendel's genes had dominant and recessive forms, and that each inheritable trait was found on different chromosomes. Early on, some inheritance patterns did not match the expectations proposed by Mendel's principles. We shall now turn our attention to some of the gene interactions that go beyond the basic Mendelian predictions.

Single Gene Variations
Lack of Dominance
Mendel's F1 offspring always resembled the dominant parent, because each of the genes Mendel chose to study showed complete dominance. When there is no dominant allele, the heterozygote will have a phenotype different from either homozygous form. This is sometimes referred to as an intermediate phenotype.

There are a number of variations in lack of dominance, but each results in heterozygous conditions that have a phenotype different from either homozygous phenotype. In other words, when a gene lacks dominance, there will be three different phenotypes, two homozygous phenotypes (AA and A'A') and a third heterozygous phenotype (AA').

A. Incomplete Dominance


B. Co-Dominance


Lack of Dominance is just one of the many different ways that genes are expressed.

Multiple Alleles of One Gene
The "typical" gene has two alleles, one for each of the homologous chromosomes. This is the same for individuals and within the population. For some genes, however, there can be more than two alternative alleles at the single gene locus among members of the species.


One consequence of the inheritance of the ABO blood type is that the A and B coatings are antigens, and can trigger antibody reactions in non-complementary individuals. This is important for blood transfusions, but not in genetics. In reality, there are variant alleles for each of the blood types beyond those discussed in biology classes. (See Table 12-1, p.224 for information on antigen-antibody reactions.)

Interactions Involving More Than One Gene
Controlling Genes - Epistasis (means standing upon)

Epistasis in Corn Pigmentation



Polygenic Inheritance
The traits that we have so far discussed all have phenotypes resulting from the interaction of one gene or, with epistasis, one gene and a second, controlling gene.

Two or more genes can interact to produce greater numbers of phenotypes. When two or more genes interact in ways that result in a number of different phenotypes, we see more variation in the population, with respect to that genetic characteristic. We call this type of inheritance polygenic inheritance. The individual phenotype is the result of the combined interaction of all the alleles at all of the gene loci involved.

Inheritance of Eye Color in Humans
Human eye color involves the polygenic inheritance of two genes each of which lacks dominance. The eye color genes code for the production of a yellow-brown pigment

Polygenic Inheritance can also involve two different genes that result in one phenotype.



Continuous Variation in Polygenic Inheritance
When several copies of a gene interact, continuous variation within the population results. Continuous variation can most easily be demonstrated when population data shows a bell-shaped distribution pattern when graphed. Skin and hair pigmentation and height are two examples of such polygenic inheritance in humans. It is believed that there are at least 3 independent genes, each of which lacks dominance, responsible for producing the melanin pigment in human skin (and in hair).

Genes with More Than One Effect - Pleiotropy (Pleio means "more")
The phenotype conferred by the gene can result in many additional alterations in the individual, many of which seem unrelated to each other. In reality, most genes are probably pleiotropic, but some are dramatically so.

Some Examples

The Influence of the Environment on Gene Expression
Conditions of the environment can often affect the expression of a gene. Or stated differently, the environmental conditions can regulate whether or not a gene gets expressed.

Some examples:

Ultimately each individual is a combination of his/her genetic potential and response to the multitude of environmental factors to which he/she is exposed.

Mendelian Inheritance in Humans
How do we apply Mendelian inheritance to humans? Historically, most of our information about human genetics, which, like all organisms, follow basic rules of chromosome inheritance, has come from careful analysis of family histories, or pedigrees, sometimes over many generations. It is only within the last generation that advances in molecular genetics have led to much better analyses of the inheritance of specific genetic traits.

We have been discussing several different types of gene interactions in this unit, and have given some examples of human inheritance patterns, such as the inheritance of eye color, skin pigmentation and the inheritance of multiple alleles with blood typing, and briefly noted the pleiotropic effects of sickle cell anemia.

At this time, we will look a bit at how and why we study human inheritance and some of the things that are occurring in the field of human genetics today. We will also look at some chromosomal alterations that affect human inheritance. In the next section, we will also address some of the ways in which biotechnology is progressing with gene therapy with human genetic disorders.

Most of our attention focuses on the inheritance of genetic conditions which negatively impact health and well-being; perhaps because these genetic traits are more easily identified, and perhaps because we would like to be able to better treat or prevent these conditions.

Inheritance of Recessive Alleles
Any mutation has the potential to inhibit the formation of a needed enzyme. With diploid organisms, however, a mutation most likely affects just one of the homologues, and the second can still code for the appropriate enzyme with little or no phenotypic effect on the individual. This has been demonstrated in laboratory experiments, and is demonstrated with many single gene inheritance patterns when the heterozygous and homozygous dominant phenotypes are indistinguishable.

Many of our genetic disorders that affect metabolism are the result of the inheritance of recessive alleles that fail to code for the needed enzyme. If this enzyme is critical for survival, affected individuals, those that are homozygous recessive, will die if they can not be treated.

It is difficult to remove recessive alleles from the population since individuals who are heterozygous have the allele but do not exhibit the problem. In human inheritance, individuals who are heterozygous for a genetic "disorder", but do not exhibit symptoms are called carriers. Hence carriers can pass the allele on to the next generation.

In contrast, it is rare to have serious genetic disorders that are caused by dominant alleles. The dominant is always expressed so individuals who inherit the dominant allele express the genetic problem and often succumb to the effects of the disorder before they can reproduce and pass the trait on to their children.


Some Examples of Human Recessive Alleles which cause problems
Galactosemia
Phenylketonuria
Lactose Intolerance
Albinism
Hemophilia (This is also a sex-linked genetic "disorder")
Tay-Sachs Disease
Sickle Cell Anemia
Cystic Fibrosis

Some Dominant Allele Problems
As mentioned, those dominant alleles that negatively impact individuals are rare in the population. The exceptions are dominant alleles that express themselves post-reproductively, such as Huntington's disease, which causes the brain to deteriorate, a disease which affected Woody Guthrie. Although it is possible to identify and screen for the Huntington's dominant allele, many who have the trait in their pedigree may choose not to go through the testing procedure. It may be difficult to decide if one wants to know that he/she will have the symptoms of this brain disease at "mid-life".

A second dominant "disorder", acondroplastic dwarfism, is very rare in the human population. This allele is not lethal.

Chromosome "Abnormalities" and Inheritance
It is fairly easy to observe our 46 human chromosomes and their shapes, because we can obtain a karyotype, or chromosome display during the metaphase stage of cell division. This allows us to see distinct chromosomes, and detect patterns that are not typical.

For reasons not understood, occasionally, a homologous chromosome pair will fail to separate during meiosis, resulting in an egg or sperm with one more or one fewer than the normal complement of chromosomes (trisomy or monosomy). In general, we call this non-disjunction or aneuploidy

Most often, a non-disjunction results in a gamete that does not survive; in some cases, however, some gametes do survive, producing individuals with abnormal chromosome numbers. Most of these non-disjunctions have serious genetic consequences. A non-disjunction can affect either the sex-determining chromosomes or autosomes. We will mention a few human examples.

Non-disjunction of Autosomes
Survival with an autosomal non-disjunction is rare.


Non-disjunction of sex chromosomes


Other Chromosome Abnormalities
Polyploidy


The impacts of these chromosomal alterations vary, depending on when and where. In some cases, the cell will not work, and dies. In gametes, they will be carried in all cell lines, and there is some evidence that some chromosomal alterations may activate oncogenes, or cancer causing genes. One form of leukemia is known to be caused by a translocation.

Extra-nuclear gene expression
And for our final note on transmission of characteristics from generation to generation, Mendelian inheritance addresses the behavior of genes on chromosomes.

Organelles, such as mitochondria and chloroplasts (and all plastids) have small circular pieces of DNA, and that DNA is transcribed and translated within the organelle. Mitochondria and chloroplasts are self-replicating. In sexual reproduction, only the egg cell's cytoplasm is passed to the zygote, so only maternal mitochondrial and chloroplast DNA will be transmitted from generation to generation. Some genetic disorders are traced to mutations in mitochondrial DNA that codes for proteins in the electron transport chain. Mutations in mitochondrial DNA may be one reason cells age.

Current Research in Genetic Treatments
Before we leave our section on human genetics, it's good to reinforce where we are in research. Although this topic overlaps our material on Biotechnology, it makes sense to discuss what we are doing in research today. Much research takes place in trying to treat and "cure" genetic abnormalities; for the benefit of the individual and for humans in general. However, some problems do come up.

A first step in developing treatments for gene disorders is to know the gene sequence and location of genes. This has been accomplished with the 12-year Human Genome project, completed summer, 2000. We can now go forward.

We still have no permanent cures for genetic diseases. We can treat many genetic diseases and many research projects are seeking ways to alter the genetic code to repair faulty genes in affected individuals using cell transplants that carry the "correct" code.

But most of our treatments of genetic disorders are much less glamorous than transplanting cells that may survive and produce the needed substances for survival.

In the past, the genes for many genetic disorders, which normally would be transmitted to the gametes, were not passed on, because the genetic "disease" resulted in premature death; the "afflicted" person never had the opportunity to pass on the problem. As discussed, today, with better treatment, many such individuals reach maturity. For those individuals who have genetic disorders, or who carry these traits we need to be better able to deal with the consequences of the potential to pass on certain harmful human traits. There are a number of ways to do this today.

Genetic Screening for early detection of disorders when treatment can be most helpful


How do we deal with the results when they indicate a genetic problem?
Phenotypic treatments


Gene Therapy
Gene therapy involves transplanting cells that contain the "normal" gene into tissues of the affected individual. To be effective, transplanted cells must:

All of these things are difficult. There are serious risks when trying to use vectors to splice genes into the chromosomes. Viral DNA may itself cause problems in the chromosome and negatively affect gene expression.

We previously mentioned the success with treating some respiratory symptoms of cystic fibrosis using genetically altered cold viruses which contain the normal gene.

There has also been success with transplants of umbilical cord stem cells (a type of white blood cell) into which the desired DNA has been inserted. Promising, but controversial, research uses cells of very young embryos and fetal cells, because such cells often retain their genetic competence and do not trigger immune rejection in the hosts is ongoing. Some diseases that we hope to treat with such cells are Parkinson's (transplants into brain tissue) and Diabetes (cells transplanted into the pancreas). This will be discussed further in our biotechnology chapter.

Each of us, in our lifetimes, as citizens, may be making decisions about the use of DNA technology for medicine, food production and crime, the use of embryonic tissues in research and treatment of diseases, gene experimentation on humans, and even cloning. These are social, political and ethical issues. The more knowledge we have about molecular genetics, the better able each of us will be to make the necessary informed decisions.


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