Genetics

Gregor Mendel:

Austrian monk who studied the inheritance pattern in pea plants in 1857.

He is known as the father of genetics.

Character: detectable feature in an organism

Trait: variant of an inheritable character

Ex: eye color is a character, blue and brown are traits of that character

Mendel chose characters in pea plants that differed clearly. He chose 7 characters, with 2 traits each.

1. Flower color (purple or white)

2. Flower position (axial or terminal)

3. Seed color (yellow or green)

4. Pod shape (inflated or constricted)

5. Pod color (green or yellow)

6. Seed shape (round or wrinkled)

7. Stem length (tall or short)

Mendel chose plants that were true breeding.

True breeding plants only produce the same kind of plant when they are self fertilized.

He started with true breeders, and then performed crosses.

P generation- the parent generation

F 1 – the first generation (P x P)

F 2 – the second generation (F 1x F 1)

Figure 14.1 A genetic cross

Purple x white flowered plant

P gen: PP x pp

Gametes P p

F 1 gen: Pp (appear purple)

F 2 generation: F 1 x F 1

Pp x Pp

Mendel’s Laws:

Law of Segregation : two alleles for a character are packaged into separate gametes.

- an allele is an alternative form of a gene

- segregation of alleles is a direct result of the separation of homologous chromosomes during meiosis

Law of Segregation:

A. Alternative forms of genes are responsible for variation in inherited characters.

Ex: the gene for flower color in pea plants exists in two alternative forms; purple and white

These alternative forms are called alleles.

Law of Segregation:

B. For each character, an organism inherits two alleles, one from each parent.

C. If the two alleles differ, one is fully expressed (dominant) and the other is completely hidden (recessive).

- dominant alleles have a capital letter

- recessive alleles have a lower case letter

Law of Segregation:

D. The two alleles segregate during gamete production.

Without any knowledge of meiosis, Mendel concluded that each sperm or egg only has one copy of each allele!

Homozygous: having two identical alleles for a given trait.

Can be homozygous dominant (PP or AA)

Can be homozygous recessive (bb or tt)

All gametes are identical

Homozygotes are true breeding

Heterozygous: Having two different alleles for a trait. Ex: Aa Bb etc.

50% of gametes carry the dominant allele

50% of gametes carry the recessive allele

They are not true breeding.

Genotype: what the genes (alleles) look like.

Ex: If Aa, then the genotype is heterozygous.

If AA the genotype is homozygous dominant.

Phenotype: what the organism physically looks like. Ex: Blue, brown, purple etc.

The genotype may not be apparent form the phenotype.

If brown eyes are dominant, then having brown eyes could be the genotype BB or Bb.

In order to determine the genotype of an organism that has the dominant phenotype, a test cross must be done.

Test cross: where you cross the organism with the dominant phenotype with another organism you know the genotype of (a homozygous recessive).

Mendels law of independent assortment:

Used dihybrid crosses to show that not only did alleles segregate, they did so independently of each other.

He used true breeding plants that differed in two characters.

He crossed plants homozygous for round and yellow seeds (RRYY) with plants homozygous for green and wrinkled seeds (rryy).

The F 1 generation were all heterozygotes (RrYy).

From the F 1 generation, he couldn’t tell if the two characters were inherited together or separate. He then self pollinated the F 1 plants for the F 2 generation.

Hypothesis 1: If the 2 characters segregate together, F 1 hybrids can only produce the same two classes of gametes (RY and ry) that they received from their parents. Therefore the F 2 generation would show a 3:1 phenotypic ratio.

Hypothesis 2: If the two characters segregate independently, F 1 will produce 4 types of gametes (RY, Ry, rY and ry).

Therefore the F 2 generation would show a 9:3:3:1 phenotypic ratio.

Try crossing a Cat who is heterozygous for long whiskers and big ears with a cat who is homozygous recessive for short whiskers and small ears.

L = long whiskers

l = short whiskers

E = big ears

e = small ears

LlEe x llee

Mendel’s 3 rd Law:

Law of Probability: Gametes have a probability of the way the will fuse for fertilization.

Both are random events.

Examples:

Tossing heads on a quarter ½ = .50 = 50%

Tossing tails on a quarter ½ = .50 = 50%

The sum of all probabilities must add up to 1.0 (or 100%).

Rolling a 1 on a die: 1/6

Rolling any # but 1: 5/6

1/6 + 5/6 = 1.0

Random events are independent of each other:

The outcome of a random event is unaffected by the outcome of previous such events.

EX: you toss a coin 2 times and get tails twice.

What is the probability that the next coin toss will be tails?

.50 or 50%

A. The Rule of Multiplication:

The probability that independent events will occur simultaneously is the product of their individual probabilities.

Ex: You have 2 coins. What is the probability that they will both be heads?

Chance of 1 coin having heads = ½

Chance of the other coin having heads = ½

Chance of BOTH having heads when they are tossed at the same time: ?

½ x ½ = ¼ or 25%

B. The Rule of Addition:

The probability of an event that can occur in two or more independent ways is the sum of the separate probabilities of the separate ways.

Example:

You have two pea plants: Pp x Pp. What is the probability that the offspring will be a heterozygote?

Probability that the dominant allele will be in the egg and the recessive allele in the sperm: ½ x ½ = ¼

Probability that the dominant allele will be in the sperm and the recessive allele in the egg is: ½ x ½ = ¼

Therefore there are 2 ways to get a heterozygote. ¼ + ¼ = ½ or 50%

Another example:

A couple wants to have 3 kids. They want two boys and a girl in that order. What is the chance of this happening?

½ x ½ x ½ = 1/8 = .125

What is the chance they will have two boys and one girl in any order?

B (1/2) B (1/2) G (1/2) = 1/8

B G B = 1/8

G B B = 1/8

1/8 + 1/8 + 1/8 =.375 or 37.5%

Ex: A Trihybrid Cross

What is the probability of getting an offspring with the genotype of aabbcc when you cross two heterozygotes?

AaBbCc x AaBbCc

Because segregation of each allele pair is an independent event, treat this as three separate monohybrid crosses.

AaBbCc x AaBbCc

Aa x Aa: probability of aa = ¼

Bb x Bb: probability of bb = ¼

Cc x Cc: probability of cc = ¼

Probability of these independent events occurring simultaneously:

¼ aa x ¼ bb x ¼ cc = 1/64

Incomplete Dominance:

Where one allele is not completely dominant over the other.

The heterozygote has a phenotype intermediate between the phenotypes of the parents.

Ex: snapdragons

R = red and r = white

P gen = RR x rr

All F 1 offspring are heterozygotes (Rr)

But instead of being Red, they are pink.

When you cross the F 1 for the F 2: Rr x Rr

Both the phenotypic and genotypic ratio is 1:2:1

Codominance:

Inheritance characterized by full expression of both alleles in the heterozygote.

Seen in:

Chickens

Tay Sacs disease

Blood Types

You have a black chicken and a white chicken. You cross them and get checkered chickens.

B = black feathers & W = white feathers

BB = Black chicken

WW = white chicken

BW = checkered chicken

The clue for codominance taking place is that the phenotype is both characters being expressed from both parents.

Both alleles are evenly expressed.

Codominance: Tay Sacs

A recessively inherited disorder; only children who are homozygous recessive have the disease.

Brain cells lack a crucial lipid-metabolizing enzyme. Lipids accumulate in the brain and it leads to death (by age 5).

At the organismal level, heterozygotes are symptom free. It “looks” like a case of complete dominance.

At the biochemical level it seems to be incomplete dominance because there is an intermediate phenotype: heterozygotes have an enzyme activity level that is an intermediate between homozygotes.

But at the molecular level, the normal allele & the Tay Sacs allele are actually codominant.

Heterozygotes produce EQUAL numbers of normal and dysfunctional enzymes. They lack symptoms, because having ½ the normal amount of enzymes is sufficient to break down lipids.

Multiple Alleles:

Some genes have more than 2 alleles controlling the characteristic.

Ex: ABO blood groups in humans

There are 3 possible alleles, but each individual can only have 2 alleles.

Blood types:

There are 4: A, B, AB and O

A & B refer to 2 genetically inherited A and B antigens on the surface of red blood cells.

I A – codes for A

I B – codes for B

i - codes for no antigen = type O blood

I A and I B are codominant to each other.

I A and I B are both completely dominant to i.

Pleiotropy:

The ability of a single gene to have multiple phenotypic effects.

Sickle cell anemia

Fur pigmentation & blue eyes in Siamese cats.

Epistasis:

Different genes can interact to control a single phenotypic character.

Ex: fur color in rodents

Polygenic Inheritance:

Many genes have an additive effect on one phenotypic characteristic.

Phenotype varies by degree.

Skin color

Height

Weight

Sex-linked genes:

Some traits are linked to the gender of the organism.

The gene is located on a sex-chromosome rather than an autosome.

Most sex-linked genes are on the X because:

The human X is much larger than the Y.

X linked genes have no homologous loci on the Y.

Most genes on the Y only encode for traits found in males.

Sex-linked genes:

Hemophilia

Colorblindness

Duchenne Muscular Dystrophy

Testicular feminization syndrome

Duchenne MD:

Individuals die ~ 20 yrs.

All males who have the trait are sterile

Female carries ~ 5% of population

Female homozygous are not possible

~ 1 in 4,000 males have disease

Testicular Feminization Syndrome:

~ 1 in 65,000 male births

All individuals are 44 + XY (normal chromosomal males)

Develop as females because there is malfunction in the androgen receptor.

All are sterile, but live as normal behaving females.

Y linked:

There have been no proven genes that are linked to phenotype in humans.

“Hairy ear rims” has been suggested.

X-Inactivation in Females:

“Designed” to compensate for the fact that females have a double dosage of sex-linked genes while males have only one.

In female mammals, most diploid cells only have one active X chromosome.

X-Inactivation in Females:

Proposed by Mary Lyons

In females, each of the embryonic cells inactivates one of the X chromosomes.

The inactive X condenses into an object called a Barr Body. It lies on the nuclear envelope.

Barr bodies are reactivated in a cell that undergoes Meiosis.

X-Inactivation in Females:

Females are a mosaic of two types of cells: those with an active maternal X and those with an active paternal X.

Which X is inactivated is random.

Inactivation occurs by methylation.

X-Inactivation in Females:

After an X is inactivated, all mitotic descendants will have the same inactivated X.

If a female is heterozygous for a sex-linked trait, about ½ the cells will express one allele and ½ will express the other allele.

Ex: Calico Cats- all are female.

Pedigree:

A family tree that represents the relationships among parents and offspring across generations.

They also show the inheritance pattern of a particular phenotypic character.

= represents a male who shows a trait

= represents an unaffected male

= represents a female who shows a trait

= represents a female who is unaffected.

Examples of human traits:

Widow’s Peak vs. absence

Free earlobes vs. attached

Tongue rolling vs. inability to tongue roll

Humans are very difficult to study because:

Long generation time

Few offspring in most cases

Well-planned breeding experiments are impossible.

Recessively Inherited Disorders:

Cystic Fibrosis:

~ 4% of Caucasians are carriers

1/2500 have the disease

The dominant allele codes for a membrane protein that controls chloride traffic into and out of the cell membrane.

Cystic Fibrosis:

Chloride channels are defective or absent in individuals that are homozygous recessive.

Result: accumulation of mucous in the lungs and pancreas.

Individual usually dead ~ 20 yrs.

Sickle Cell Anemia (SCA):

Found more in African Americans, Hispanics from central America.

One amino acid is different from the normal hemoglobin molecule.

Results in ‘sickle-shaped’ cells.

Many phenotypic changes occur.

Sickle Cell Anemia:

Shows “Hybrid Vigor:

People who are heterozygotes (hybrids) have an advantage over homozygotes.

Why? Malaria

People with SCA can not get Malaria.

People who are hybrids have no bad effects from being hybrids, and their chances of getting Malaria are greatly reduced.

Dominantly Inherited Disorders:

Achondroplasia affects 1/10,000 people who are heterozygotes.

Homozygous dominant condition results in spontaneous abortion of the fetus.

Homozygote recessives are normal (~99.99% of the population).

Dominantly Inherited Disorders:

Alzheimer’s

Hypercholesterolemia (1/500 are heterozygous)

Huntington’s Disease

Marfan’s Syndrome

Huntington’s Disease:

Is the degenerative disease of the nervous system.

Near the tip of chromosome # 4.

Effects do not show up until 25- early 40’s

Marfan syndrome is a connective tissue disorder, so affects many structures, including the skeleton, lungs, eyes, heart and blood vessels. The disease is characterized by unusually long limbs, and is believed to have affected Abraham Lincoln.

Is an autosomal dominant disorder that has been linked to the FBN1 gene on chromosome 15. FBN1 encodes a protein called fibrillin, which is essential for the formation of elastic fibres found in connective tissue. Without the structural support provided by fibrillin, many tissues are weakened, which can have severe consequences, for example, ruptures in the walls of major arteries.

A young man with Marfan syndrome, showing characteristically long limbs and narrow face.

The hand at the left is that of a young woman with Marfan's syndrome, while the hand at the right is a normal male. Both persons were of the same height, 188 cm. However, note that the hand at the left demonstrates arachnodactyly.

This is a patient who has albinism.

Aneuploidy:

Having an abnormal number of chromosomes.

Results from a process called nondisjunction.

Sister chromatids do not separate properly in meiosis I or meiosis II.

Ex:

Down’s Syndrome (trisomy 21).

Klinefelter Syndrome (XXY)

Meta-female (XXX)

Super-male (XYY)

Turner Syndrome (XO)

Patau Syndrome (Trisomy 13)

The way to detect aneuploidy is to perform a karyotype on the fetus.

A female with Turner syndrome (45,X).  Note the characteristically broad, "webbed" neck.  Stature is reduced, and swelling (edema) is seen in the ankles and wrists.

The "streak ovaries" of Turner's syndrome are shown here. Bilaterally below the fallopian tubes at the top of the photograph are long thin bands of tan ovarian tissue in this 55 year old female. No ova were ever present.

A feature of many chromosomal abnormalities is fetal hydrops (hydrops fetalis) in which the soft tissues are markedly edematous and body cavities filled with effusions. This is particularly true of monosomy X.

The fetus shown here died in utero (intrauterine fetal demise) and shows signs of maceration (autolysis) such as the slippage of the skin and the reddened color.

One very characteristic feature of a fetus with monosomy X is the "cystic hygroma" of the neck. This is not a true neoplasm, but represents failure of lymphatics to form and drain properly.

It is this structure that eventually forms the "web neck" feature of women with Turner's syndrome. Note the grey coloration from prolonged intrauterine demise.

Triploidy

One characteristic feature of triploidy is syndactyly involving the third and fourth digits of the fetal hand as shown here.

Patau Syndrome (Trisomy 13)

A newborn male with full trisomy 13 (Patau syndrome).  this baby has a cleft palate, atrial septal defect, inguinal hernia, and postaxial polydactyly of the left hand.

An individual with full trisomy 13 at age 7 years (survival beyond the first year is uncommon).  He is deaf and legally blind.

This baby with trisomy 13 has cyclopia (single eye) with a proboscis (the projecting tissue just above the eye).

Polydactyly, particularly of all extremities, strongly suggests trisomy 13. Extra toes are seen here on each foot.

Cri du chat Syndrome

Cri du chat is a rare syndrome (1 in 50,000 live births) caused by a deletion on the short arm of chromosome 5. The name of this syndrome is French for "cry of the cat," referring to the distinctive cry of children with this disorder.

The cry is caused by abnormal larynx development, which becomes normal within a few weeks of birth.

Infants have low birth weight and may have respiratory problems. Some people with this disorder have a shortened lifespan, but most have a normal life expectancy.

In 80 percent of the cases, the chromosome carrying the deletion comes from the father's sperm.

Williams Syndrome

Williams Syndrome is caused by a very small chromosomal deletion on the long arm of chromosome 7.

Because of the lack of the elastin protein, people with Williams Syndrome have disorders of the circulatory system, also known as vascular disorders.

Angelman’s Syndrome

A deleted portion of chromosome 15.

Medical and Development Problems 
    Seizures 
    Gait and Movement Disorders 
    Hyperactivity  
    Laughter and Happiness  
    Speech and Language  
    Mental Retardation and Developmental Testing  
    Hypopigmentation  
    Strabismus and Ocular Albinism  
    CNS Structure 
    Sleep Disorders 
    Feeding Problems and Oral-Motor Behaviors  

Inheritance of the deletion from the mother on chromosome 15 produces Angelman syndrome (note the characteristic posture).

~ 1 in 15 to 30K individuals

Prader-Willi syndrome

Characterized by mental retardation, decreased muscle tone, short stature, emotional lability and an insatiable appetite which can lead to life-threatening obesity. The syndrome was first described in 1956 by Drs. Prader, Labhart, and Willi.

PWS is caused by the absence of segment 11-13 on the long arm of the paternally derived chromosome 15.

1 in 10,000 individuals

Inheritance of the deletion from the father produces Prader-Willi syndrome (note the inverted V-shaped upper lip, small hands, and truncal obesity).

This translocation, which is found only in tumor cells, indicates that a patient has chronic myelogenous leukemia (CML). In CML, the cells that produce blood cells for the body (the hematopoietic cells) grow uncontrollably, leading to cancer.

Duplication: Fragile X syndrome

Fragile X syndrome is the most common cause of inherited mental retardation, seen in approximately one in 1,200 males and one in 2,500 females

The number of CGG repeats in the FMR1 genes of the normal population varies from six to approximately 50. There are two main categories of mutation, premutations of approximately 50 to 200 repeats and full mutations of more than approximately 200 repeats.

A boy with fragile X syndrome.  Note the prominent and elongated ears and long face. Children from different ethnic groups have similar characteristics.   This picture shows a Caucasian boy.

Linked Genes:

Genes located closely together on the same chromosome are said to be “linked’ because they do not assort independently.

Thomas Hunt Morgan perform experiments in the early 1900’s that proved Mendel’s inheritable factors are located on chromosomes.

Found that some genes are linked together.

But the linkage is not a total one; some recombination does occur.

Morgan performed a testcross.

b = black body

b + = gray body

vg = vestigial wings

vg + = normal wings

b +b vg + vg x bb vgvg

Gray, normal wings x black, vestigial wings

If the genes did assort independently, then Mendel’s ratio should be expected.

If the genes did not assort at all, then there would be 100% linkage.

Morgan defined one map unit as 1% recombination frequency.

Map units are now called centimorgans.