Biology 105                                            Mendelian Genetics

I. Introduction
   A. The concepts of  genetics are some of the most important and interesting in biology.  They help us answer questions like 
        1. Why are offspring similar to their parents?
        2. How do living things get their traits and characteristics, including genetic diseases? 
        3. How are different species related to one another?
        4. How do our bodies work at the cellular level?
   B. Genetics is also the basis for understanding advances in cloning, genetically modified organisms, genetic medicine, and reproductive technologies.  

II. The Basics of Inheritance
   A. To answer these questions we need to understand the principles of inheritance, which were discovered by the monk Gregor Mendel, in the late 1800's.  Mendel studied the transmission of traits, like flower color, from one generation to the next in peas.  Incredibly, the rules that apply to pea inheritance also apply to dog, bacteria, and human inheritance!!
   B. Others had studied inheritance before Mendel, but he was the first to be successful because he was organized and designed his experiments well.  He used the scientific method!   
        1. He used simple traits that were easy to classify (flower color rather than yield, for example).
        2. He analyzed his data mathematically.
        3. Most people before Mendel believed that inheritance occurred by a process of blending maternal and paternal traits.  This often seems correct: in humans, for example, children with a dark-skinned parent and a light-skinned parent usually have an intermediate skin tone.  
            a. Mendel's experiments carefully examined this hypothesis and he was able to reject it.  (We will see later why this idea often seems to be true.)     
   C. To talk about genetics, we need the terminology
        1. Phenotype: an organism's traits (like blue eyes, bushy eyebrows)
        2. Genotype: an organism's genes, which help give it its traits  
        3. DNA: the chemical within cells which carries the genetic information. 
        4. Gene: a section of DNA responsible for a particular trait (like blue eyes).  Each gene contains  instructions to build a small piece of a cell called a protein. 
        5. Chromosome: a single very long DNA molecule (and associated proteins), containing many different genes.  Chromosomes are inherited from one's parents.  Analogy: a page in an instruction book on how to build a human.
        6. Genome: all of the genetic material of an organism or species (the goal of the human genome project is to study all of the genetic material, or DNA, of a human being)   Analogy: the entire instruction book on how to build a human.
        7. Allele: alternate forms of a gene that give different traits (there are blue eye alleles, brown eye alleles, etc).  These alleles come about due to mutation: changes in the DNA of a gene so its instructions are different.
            a. Example: There is a gene that determines the pattern of hair growth at the hairline.  This gene is a piece of DNA in the human genome.  This gene has two alleles: one gives a straight hairline, the other causes a widow's peak. 
        8. People, like most other organisms, have two copies of each gene.   So we have two eye color genes and two hair pattern genes.  Since there are two, the alleles corresponding to these two copies of the gene can be the same or they can be different. 
            a. Homozygous: having two of the same alleles for a gene
            b. Heterozygous: having two different alleles for the same gene. 
            c. Example: the gene for widow's peak is abbreviated W.  Each person has two hairline genes.  WW and ww are homozygous.  Ww is heterozygous. 
        9. Dominant alleles are always expressed, and are represented by a capital letter.  A widow's peak is dominant over a straight hairline, so both WW and Ww people have widow's peaks. 
            a. For most genes, a heterozygous person is  indistinguishable from a homozygous dominant. 
        10. The trait which is only expressed when homozygous is called recessive.
            a. Note: Dominant is NOT THE SAME as common, and recessive is NOT THE SAME as rare. 
            b. For example, blue eyes are recessive, but very common in certain countries. Huntington's disease and 6 fingers are dominant but rare conditions. 
        11. Sometimes, a heterozygote shows a trait intermediate to both homozygotes.  This is called incomplete dominance.  Example: snapdragon color.  If a red flowered plant is crossed with a white flowered plant, the offspring have pink flowers.

III. Single factor crosses: inheritance of a single trait
   A. Steps in doing a single factor cross
        1. Determine the genotypes of the parents.  Each genotype will consist of two letters corresponding to the 2 alleles for the gene being crossed. 
        2. Gametes are the egg and sperm cells which will be used to produce the offspring.  To know what the offspring will be like, we need to know the genes that will be found in the gametes produced by each parent.  While each parent has two alleles for each gene, a gamete will contain only ONE of the two alleles. 
            a. if the parent is homozygous; there will be only one type of gamete; all will contain the same allele. 
            b. if the parent is heterozygous, there will be two types of gametes.  Half of the gametes will contain one allele and half will contain the other. 
        3. Make offspring by pairing gametes from both parents together.  Pairing will occur randomly, so a Punnett square is the best way to do that. 
            a. Example: a person homozygous for freckles marries a person homozygous for no freckles.    This is the starting point for our genetic crosses and is called the F1 generation.  

                   parental genotypes                    FF        X          ff
                   gametes produced               100% F            100% f
                   offspring genotypes                             all Ff                                      

   The phenotype of Ff is freckles  because freckles are dominant. So all of the children of this couple would have freckles.  All of the children are the same with regard to this particular trait, because each parent only produces one type of gamete.
        4. Some people studying inheritance before Mendel stopped with this observation and concluded that the gene for no freckles had blended with the freckles gene and was now gone from this family.    
        5. Mendel, however, carried his studies into the next generation, called the F2 generation. 
            a. If one of these heterozygous children marries another heterozygous person, what types of children will they have? 
                parental genotypes             Ff           X            Ff
                gametes produced       1/2 F, 1/2f              1/2F, 1/2 f        

            b. Now each parent produces two different types of gametes, and they can pair up randomly; F from one parent can end up with F or f from the other parent.     
            c. To figure out genotypes of offspring use a Punnett square:
                       One parent's gamete types go across the top.
                       The other parent's gamete types go down the side.   
                        Then fill the correct allele combinations into each box.   

   F     f
 F  FF Ff
 f  Ff ff

            d. This shows that 3/4 of the children will be expected to have freckles and 1/4 will not.  Note: These are statistical expectations only; individual families will differ.  
            e. Of the children with freckles, 2/3 will be heterozygous (Ff) and 1/3 homozygous (FF).
            f. Obviously, the no freckles allele, f,  which seemed to disappear in the F1 generation, was actually still there and reappears, unchanged, in the F2 generation.  Thus the concept of blending inheritance cannot be true. 

   Let's try some crosses.    
     Amanda's mother has a straight hairline and her father has a widow's peak.  Amanda has a widow's peak.  Her husband, Harry has a straight hairline.  What types of children will they be likely to have, and in what proportions?  

    Steps in carrying out a cross
            1. Determine the genotypes of the parents.  Each genotype will consist of two letters corresponding to the 2 alleles for the gene being crossed. 

        Amanda: Ww

        Harry: ww

            2. Determine the gametes formed by each parent. Each gamete will contain only ONE of the two alleles. 
                a. if the parent is homozygous; there will be only one type of gamete
                b. if the parent is heterozygous, there will be two types of gametes.

        Amanda: 1/2W, 1/2w

        Harry: all w

            3. Make offspring by pairing gametes from both parents together.  Pairing will occur randomly, so a Punnett square is the best way to do that. 

   W     w
 W  WW Ww
 w  Ww ww

Answer: On average, half of their children would have a widow's peak and half would not. 

2. Caroline has freckles, but her daughter from a previous marriage does not.  She is going to marry Josh, whose Dad has a lot of freckles but he does not.  What are the chances that Caroline and Josh's first child will have freckles?    Answer: 50% chance

IV. Two factor crosses: inheritance of two separate traits
   A. These are done like the single factor crosses, but the two genes are inherited separately. 
   B. Example: a person homozygous for dimples and widows peak (WWDD) marries a person homozygous for no dimples and straight hairline (wwdd)

Parental genotypes:                    WWDD       x         wwdd
each gamete gets one
    copy of each gene                   all WD                  all wd

offspring genotype                                   all WwDd
    phenotype of WwDd children: widows peak, dimples

    or you can make a tiny Punnett square:

wd WwDd

       1. Remember the essential difference between gametes and people: gametes have one copy of each type of gene, and people have two.  
   C. Now if a doubly heterozygous child marries another like himself, the situation gets more complex.
    Parental genotypes                          WwDd              x                WwDd
 Each person can now form
4 different types of gametes:       WD, Wd, wD, wd                WD, Wd, wD, wd

       1. Each gamete must get  ONE and ONLY ONE copy of each gene.  A gamete  must never have two of the same type of letter.  To make gametes, eyeball it or use the FOIL (First, Outside, Inside, Last) technique.
       2. Since each person can form 4 different types of gametes, you need a 4X4 Punnett square to figure out the possible combinations of offspring.                                                                       

          WD         Wd         wD        wd   
widows peak
widows peak
widows peak
widows peak
 Wd WWDd
widows peak
widows peak
no dimples
widows peak
widows peak
no dimples
 wD WwDD
widows peak
straight hairline
straight hairline
widows peak
 wd   WwDd
widows peak
widows peak
no dimples
straight hairline
straight hairline
no dimples

       3. This shows a 9:3:3:1 offspring phenotype ratio which Mendel found over and over in his two factor crosses.   9/16 of the offspring will have both dominant traits: 3/16 will have one dominant and one recessive: 3/16 will have the other dominant and other recessive: 1/16 will have both recessive traits.
      4. This is because a pair of genes that came to a parent from his or her own parent do not have to be passed on together to the next generation.  Each gene is transmitted to the offspring separately from the others.  Grandchildren carry any mixture of traits from their grandparents. 

Practice Problems.  
1. What gametes would the following individuals make?
a) FFWWDd  (hint: only two different kinds)  50% FWD   50% FWd

b) FfwwDd   (4 different kinds)   25% FwD, 25% fwD, 25% Fwd, 25% fwd

2. Figure out the expected proportions of children in the following crosses
a) A woman  with no dimples and straight hairline marries a man heterozygous for both dimples and Widows peak. 

1/4 dimples, widows peak; 1/4 dimples straight hairline; 1/4 no dimples, widows peak; 1/4 no dimples straight hairline

b) A man heterozygous for dimples, with a straight hairline marries a woman heterozygous for both dimples and Widows peak.

3/8 dimples, widows peak, 3/8 dimples, straight hairline, 1/8 no dimples, widows peak, 1/8 no dimples, straight hairline. 

V. Human Genetic Diseases
   A. Most of the known human genetic traits are diseases.  Since genes carry information needed to make cells and organs of the body, if the instructions are changed, or mutated, the cells and organs may not function correctly and a disease may result.
       1. Inborn errors of metabolism are genetic diseases caused by lack of a necessary enzyme, a protein which carries out a cellular reaction. The enzyme isn't made, or isn't made properly, because of a mutation in the DNA instructions for making it.  Without the enzyme, certain cellular products can't be made, or used, or broken down correctly. 
       2. Rare human genetic diseases are sometimes more common in certain ethnic groups than in others, because as members of the ethnic group intermarry they pass the gene around among themselves. 
   B. Recessive disorders
        1. Most human genetic diseases are recessive disorders, because people who have either one or both correct copies of the gene can correctly carry out the cellular function; only those lacking any correct copies become ill.    
                        Aa or AA: healthy
                        aa: sick
            a. In phenylketonuria or PKU , a cellular waste product can't be broken down because a necessary enzyme is lacking, so the waste material accumulates in tissues.  This causes mental retardation, hyperactive muscle movements, and reduced life span, but the symptoms are preventable by controlling the diet. All newborns are given a blood test for this condition, and parents are counseled on how to feed their child if he or she tests positive.
            b. Tay-Sachs disease is the most common genetic disease of the American and European Jewish populations.  It also results from the lack of an enzyme to remove a cellular byproduct; however, buildup of this product poisons nerve cells in the brain.  It cannot be treated, and is invariably fatal by 3-5 years of age. 
                i. Newborns are not tested for this condition, since it can't be cured.  People can be tested to see if they are carriers, and fetuses of carrier parents can be tested before birth to see if they have the disease. 
           c. Cystic fibrosis is the most common genetic disease of white Americans and western Europeans.  A protein which should remove chloride from cells doesn't function.  This results in extra thick, sticky mucus in the lung which traps bacteria, resulting in debilitating lung infections.  Ability to digest food is also impacted.  Management of the disease has increased life expectancy over the last few decades, however, it is still often fatal by young adulthood.   CF is a good candidate for a genetic cure, as we will discuss later, and progress is being made on cure by lung transplant.
            d. These are all recessive diseases because both parents must contribute a disease gene in order for the child to get the disease.  Parents are heterozygotes, or carriers, and show no symptoms themselves.  Recessive disorders are more common among offspring of relatives, such as cousins, because relatives tend to carry the same disease alleles. 
        2.  Codominant disorders
            a. In a codominant condition, neither allele is dominant or recessive, and both are expressed in heterozygotes. 
            b. Sickle cell disease is the most common genetic disease of Africans and African Americans, and it shows codominant inheritance. The sickle allele was caused by a mutation of the hemoglobin gene, which forms the hemoglobin that carries oxygen in the blood. 
              i. SS is homozygous normal, normal hemoglobin, no disease
              ii. ss has sickle cell disease.  These people have only mutated hemoglobin in their blood, which causes sickle cell disease
              iii. Ss has sickle cell trait.  These people have half normal and half altered hemoglobin, hence the codominance, but are rarely ill with sickle cell disease.  In fact, the trait seems to help protect them from the blood disease malaria.  
              iv. Sickle cell disease occurs when the altered hemoglobin starts to bind together, deforming blood cells and causing them to be broken, reducing oxygen delivery and causing a painful sickle crisis.  The disease can be fatal but can frequently be managed with access to good health care. 
             v. Sickle cell was the first genetic disease understood at the molecular level and we will talk about it more later in that context.  

        Problem:  If two parents both carry the allele for Tay-Sachs, what types of children, in what proportions, could they expect to have?

            Parents genotypes: Tt X Tt    

            Gametes: 1/2 T, 1/2 t for both parents 

            Making a Punnett square shows that 1/4 of the children would be expected to have the disease and 1/2 would be carriers. 

        Problem: If a man has sickle cell disease but his wife does not and is not a carrier, what percentage of their children would be expected to have the disease?  What percentage would be carriers? 

            Parental genotypes SS X ss.  All children would be carriers. 

        3. Dominant disease conditions
            a. Huntington's disease is a neurological disease with gradual onset between 40 and 50 years old. Victims slowly lose muscular and mental abilities.  It is invariably fatal.   By definition, since it is dominant a person needs to inherit only one disease allele to get the disease, and everyone with an allele gets it.

           Problem: If a person has the (dominant) allele for Huntington's disease, what is the probability that his child will inherit the disease?  (Since this is a rare condition, assume that the affected parent is heterozygous). 

Parents genotypes: Hh x hh

Gametes: 1/2 H, 1/2 h for first parent; all h for second parent.  Half of the children would be expected to have the disease.

VI. Quantitative inheritance
   A. So far we have dealt with discontinuous traits, but traits with continuous variation are also important in genetics. 
   B. Discontinuous traits are either present or absent, with no intermediate possibilities. Examples include gender, presence of diseases such as cystic fibrosis, etc.  People are easy to categorize. 
   C. Traits with continuous variation do not fall into a few discrete categories; instead, the characteristic has a broad range of possible expression.  A population often shows a normal, or bell-shaped, distribution of traits with continuous variation. Examples: height, intelligence, skin and hair color.  
       1. Continuous traits are controlled by several genes, each contributing to the final phenotype, and are called polygenic or quantitative traits.  
            a. The range in variation is due to the presence of several independent genes all contributing to the same final phenotype.
       2. Example: skin color.  There are at least 3 genes responsible for melanin formation in the skin, which makes skin dark.  Each gene has 2 alleles: one for making more melanin and one for making less melanin, signified by A or a.  Therefore, people can range from AAAAAA (darkest) to aaaaaa (lightest).  Intermediate skin tones result from having some A alleles and some a alleles.
            a. Depending on how the alleles are inherited, people with intermediate skin tones can have children who vary widely in skin tone, or children who are all very similar.
       3. Another example: intelligence. Intelligence is due to many genes acting together, but these genes do different things.  Some control the shape or structure of the brain, some work on the activities of nerve cells, production of neurotransmitters, etc.  
            a. So polygenic traits can come about either due to several genes doing the same thing, or different genes which affect the same organ in different ways. 
            b. Traits can also have continuous variation if there is a significant environmental effect on the expression of the trait. 

VII. The Effect of the Environment
   A. Organisms are not just the sum of their genes.  A person's genotype interacts with the environment to produce the observed phenotype.  The environment begins in the womb before birth.  Even if you have the genes to be Mozart or Einstein, if your mother is a severe alcoholic you will be born with fetal alcohol syndrome (FAS), which causes mental retardation. 
       1. It is difficult to know, in a complex trait such as intelligence for example, how much of the trait is genetic and how much is due to the environment.  Twin studies can be used to help determine to what degree a trait is determined genetically as opposed to environmentally.  
            a. Identical twins share the same genotype because they come from a single fertilized egg that has been split in two; fraternal twins come from two different eggs fertilized by two sperm and are no more similar than any pair of siblings. 
            b. If identical twins share a trait more often than fraternal (non-identical) twins do, that is evidence that the trait has a genetic component.  Twin studies like this have estimated the heritable component of human intelligence to be about 52%.  
       2. There is a database of identical twins which were given up for adoption and raised separately, not knowing about each other's existence.  This has been the source of some interesting findings on the role of genetics vs. upbringing in human characteristics, because these twins have 100% similar genes but entirely different upbringing.  These studies have indicated a heritability of intelligence of up to 72%. 
            a. These separated twins sometimes show weirdly similar patterns to their lives.