U C A G U

UUU

Phenylalanine

(Phe) UUC Phe UUA

Leucine

(Leu) UUG Leu CUU

Leucine

(Leu) CUC Leu

C

CUA Leu UCU

Serine

(Ser) UCC Ser UCA Ser UCG Ser CCU

Proline

(Pro) CCC Pro CCA Pro

A

CUG Leu AUU

Isoleucine

(Ile) AUC Ile AUA Ile AUG

Methionine

(Met) or

START

CCG Pro ACU

Threonine

(Thr) ACC Thr ACA Thr ACG Thr GUU

Valine

Val

G

GUC (Val) GUA Val GUG Val GCU

Alanine

(Ala) GCC Ala GCA Ala GCG Ala UAU

Tyrosine

(Tyr) UGU

Cysteine

(Cys) UAC Tyr UAA UAG

STOP STOP

CAU

Histidine

(His) CAC His CAA

Glutamine

(Gln) CAG Gln AAU

Asparagine

(Asn) AAC Asn AAA

Lysine

(Lys) UGC Cys UGA

STOP

UGG

Tryptophan

(Trp) CGU

Arginine

(Arg) CGC Arg CGA Arg CGG Arg AGU

Serine

(Ser) AGC Ser AGA

Arginine

(Arg) AAG Lys AGG Arg GAU

Aspartic acid

(Asp) GAC Asp GAA

Glutamic acid

(Glu) GAG Glu GGU

Glycine

(Gly) GGC Gly GGA Gly GGG Gly

U C A G U C A G U C A G U C A G

WARM-UP

• •

Are mutations always detrimental (bad)? Name a possible mutation that has been beneficial. There is increasing scientific evidence which shows that cancer is often an inherited mutation. Does this increasing evidence change the way you would live your life (eating healthy, exercising, smoking, etc)?

Schedule for the Week

• • •

Today

– mutations.

Wed/Thurs

– putting it all together

Friday

– Gene Expression Test (Chapter 12)

29 April 2008 What are Mutations?

Chernobyl Raised Mutations 600%

• Children of the "liquidators" - those drafted in to clear up the Chernobyl disaster - suffer seven times the mutation rate of offspring whose parents were not exposed to radiation, research published today by the Royal Society shows. The "unexpectedly high" mutation rate, discovered by using DNA fingerprinting techniques, means that a significant proportion of the world's population doing jobs where even low-level radiation is present are exposing their unborn children to increased risk, the researchers say. • People exposed to the immediate radioactive clouds often died within a week from radiation poisoning.

People living farther away from the incident suffered immediately from thyroid cancer. Since the accident birth defects have gone up 22%; the live birth rate has decreased immensely.

Chernobyl

Genetic mutation turns tot into superboy

» Somewhere in Germany is a baby Superman, born in Berlin with bulging arm and leg muscles. Not yet 5, he can hold seven-pound weights with arms extended, something many adults cannot do.

their body fat. DNA testing showed why: human case of such a mutation. cells to produce myostatin.

He has muscles twice the size of other kids his age and half The boy has a genetic mutation that boosts muscle growth DNA segment was found to block production of a protein called myostatin that limits muscle growth.

“mighty mice” by “turning off” the gene that directs . The discovery, reported in Thursday’s New England Journal of Medicine, represents the first documented The boy’s mutant The news comes seven years after researchers at Johns Hopkins University in Baltimore created buff

Warm-Up

•

In the back of your lab notebook describe the process of protein synthesis. Include all the steps from DNA to physical trait.

Cigarette Smoke Alters DNA In Sperm, Genetic Damage Could Pass To Offspring

• ScienceDaily (Jun. 1, 2007) — The science has long been clear that smoking causes cancer, but new research shows that children could inherit genetic damage from a father who smokes. Canadian researchers have demonstrated in mice that smoking can cause changes in the DNA sequence of sperm cells, alterations that could potentially be inherited by offspring.

Mutations

Mutation- a change in the DNA nucleotide sequence

Mutations can cause subtle or dramatic effects on observed traits in individuals. Mutations can be an important source of genetic variation in a population.

What Causes Mutations?

•

Mutations can happen for several reasons.

•

DNA fails to copy accurately.

– Most of the DNA

mutations

that we think matter to

evolution

occurring.” For example, when a cell divides, it makes a copy of its —and sometimes the copy is not quite perfect. That small difference from the original DNA sequence is a mutation. are “naturally •

External influences can create mutations.

– Mutations can also be caused by exposure to specific chemicals or radiation. These agents cause the DNA to break down. This is not necessarily unnatural —even in the most isolated and pristine environments, DNA breaks down. – Nevertheless, when the cell repairs the DNA, it might not do a perfect job of the repair. So the cell would end up with DNA slightly different than the original DNA and hence, a mutation.

Mutations in multicellular organisms can be divided into two types

• •

Somatic Mutations

– occur in somatic (body) cells. Passed to daughter cells through mitosis. Not passed to sexually produced offspring.

Germ Line Mutations

– occur in the cells of the germ line (those cells that give rise to gametes). A gamete with the mutation passes it on to a new organism at fertilization

All mutations are alterations in the nucleotide sequence of DNA

– At the molecular level, we can divide mutations into two categories

1. Point Mutations

– are mutations of single base pairs and so are limited to single genes. One allele becomes another allele because of an alteration (gain, loss, or substitution) of a single nucleotide

2. Chromosomal Mutations

– are more extensive alterations. CM’s may change the position or orientation of a DNA segment without actually removing any genetic information, or they may cause a segment of DNA to be irretrievably lost or duplicated.

How does your DNA determine your traits?

DNA mRNA protein Observed trait

Remember: •Traits are determined by the functions of proteins •Protein function is determined by protein shape •Protein shape is determined by amino acid sequence

Mutations can change the amino acid sequences of proteins

DNA sequence: T A C C G A G A T T C A mRNA sequence: A U G G C U C U A A G U amino acid sequence: Met -- Ala -- Leu -- Ser DNA sequence: T A C C G A G A T T C A mRNA sequence: A U G G C U A U A A G U amino acid sequence: Met -- Ala - Iso -- Ser

How does this mutation change the amino acid sequence?

(Original) DNA sequence: A A T G C A T A T G C A mRNA sequence: U U A C G U A U A C G U amino acid sequence: Leu -- Arg -- Ile -- Arg (Mutated) DNA sequence: A A T T C A T A T G C A mRNA sequence: U U A A G U A U A C G U amino acid sequence: Leu - Ser -- Ile -- Arg

Warm-up

1.

We’ve studied transcription, translation, and replication. A mistake in which of these processes would result in a mutation?

The Synthesis of Proteins

• Point mutations can affect protein structure & function – Knowing how genes are translated into proteins, scientists can give a molecular description of heritable changes that occur in organisms •

Mutation, point mutation

(review)

The Synthesis of Proteins

• • Types of point mutations – Two categories:

base-pair substitutions & base-pair insertions or deletions Base-Pair Substitutions

– Depending on how they are translated, can result in little or no change in the protein encoded by the mutated gene • Some result in readily-detectable changes

The Synthesis of Proteins

• Base-pair substitutions are usually

missense

or

nonsense

mutations – Missense mutations alter an amino acid codon to a new codon for a different amino – Nonsense mutations change an amino acid sequence to a chain termination (or v-v) • Can result in premature termination

The Synthesis of Proteins

•

Insertions or deletions

– Usually have a greater negative effect on proteins than substitutions • May alter the reading frame (triplet grouping) if the genetic message –

Frameshift mutation

occurs when insertion or deletion does not occur in 3’s or multiples of 3

The Synthesis of Proteins

• Mutagens –

Mutagenesis

: the creation of mutations • May be spontaneous or caused by exposure to

mutagens

– Physical or chemical agents that interact with genetic material to cause mutations

3 types of point mutations

Substitution Insertion Deletion

Substituting one nucleotide for another.

T A C C G A

Inserting one or more nucleotides

T A C C G A G A T T C A

Deleting one or more nucleotides

Different types of mutations happen

Substitution Insertion T A C C G A Deletion T A C C G A G A T T C A

• •

Frameshift mutations

One or more than one nucleotide can be added or deleted with insertion and deletion mutations.

If the number of nucleotides is not a multiple of 3, it is called a

frameshift

mutation.

1. Why do we call this a frameshift mutation?

2. Can substitution mutations cause frameshifts? Explain why or why not.

Malaria and Sickle Cell Anemia

Bits About Malaria

• • • • •

Four species of protozoan parasite of the plasmodium genus -

P. falciparum

, P. vivax, P. ovale, and P. malariae - cause malaria in humans. There are more than 2,500 known species of mosquitoes worldwide. Out of that, only around 50 to 60 species of Anophelis mosquitoes are capable of transmitting the infection .

Numerous epidemiologic and ecologic factors play a vital role in determining the effect of malaria on human health and in the intensity of disease transmission. The immunological status of a person also has a bearing on the severity of the disease.

The clinical features of malaria vary. The classic symptoms include persistant fever, shivering, joint pains, and headaches and repeated vomiting. Severe and complicated malaria causing renal failure, hypoglycemia, anemia, pulmonary edema, shock and coma can have fatal consequences, leading to death . Malaria can be cured if promptly diagnosed and adequately treated.

Malaria is among the top 10 killer diseases in the world. and 1.5 to 2.7 million deaths worldwide Annual estimates vary between 300 to 500 million clinical episodes of malaria , 90% of which occur in tropical Sahara

• Sickle cell hemoglobin (a PROTEIN) has a

single mutation

that causes the protein to polymerize under certain conditions.

• The amino acid substitution results in a sticky patch that causes the hemoglobin to polymerize into spikes under certain conditions (low pH, low Oxygen) . The parasite causes these conditions to be amplified so that red cells with the sickle trait that are infected, preferentially sickle, leak potassium and become toxic to the plasmodium.

• Those who are

homozygous

in the sickle cell gene will have problems with sickling under milder conditions in the absence of the parasite.

The Sickle Cell Mutation

• • One amino acid out of a total 287 differs in sickle cell haemoglobin compared with normal haemoglobin. In the latter, the triplet GAG (guanine, adenine, guanine) codes for the amino acid glutamic acid (left-hand diagram). In sickle cell haemoglobin, the corresponding three-base sequence is GTG (guanine, thymine, guanine) which codes for the amino acid valine.

The type of mutation exemplified in sickle cell anemia is called a substitution, because one nucleotide base is substituted for another.

• • • • • • • • • • • • • • • •

Genetics of Sickle cell anemia

For some genes, neither allele is completely dominant, so a heterozygous individual differs from either type of individuals that are either

AA

or

aa

are homozygous, whereas individuals that are

Aa

are heterozygous.)

homozygous

individual. (A heterozygous individual has two different alleles for the same gene, whereas a homozygous individual has two identical alleles for the same gene. For example The gene for hemoglobin is an example. One allele codes for normal hemoglobin, while another allele codes for altered hemoglobin, called sickle cell hemoglobin. When a person is homozygous for this sickle cell allele, this causes a serious disease called sickle cell anemia. The sickle cell hemoglobin tends to cause the red blood cells to assume a sickle shape, in contrast to the normal disk-shaped red blood cell shown on the left in the figure below. What problems might be caused by the sickle-shaped red blood cells? A person who is heterozygous for the sickle cell allele often has very few or no symptoms of sickle cell anemia. In addition, people who are heterozygous for the sickle cell allele are more resistant to malaria, an infection of the red blood cells which is transmitted by mosquitoes in many tropical countries. Thus, in areas where malaria is widespread, people who are heterozygous for the sickle cell allele are less likely to become ill and die. Because of this advantage, the sickle cell allele became relatively common in regions like West Africa where malaria is common. Since African Americans are descended from populations in which the sickle cell allele was relatively common, African-Americans have relatively high rates of the sickle cell allele (approximately 8% are heterozygous for this allele and 0.16% are homozygous). Suppose that a person who is heterozygous for the sickle cell allele (

SK/sk

) marries a person who is also heterozygous for this allele (

SK/sk

). Draw a Punnett Square to show the expected genetic makeup of their children, and then answer the following questions. 1. What fraction of their children will suffer from sickle cell anemia? 2. What fraction of their children will inherit the sickle cell allele, but will not suffer from sickle cell anemia? (These children will be resistant to malaria.)

Challenge Question

Shown below is a pedigree chart for the inheritance of achondroplasia (ay-kon-druh-

play

-zhuh), a form of dwarfism. Dark circles or squares indicate individuals with achondroplasia. Examine the pedigree chart, and answer the following questions. Is the gene that causes this form of dwarfism a recessive or dominant trait? How do you know? Using (

D

) to represent the dominant allele and (

d

) to represent the recessive allele, write the genotypes of the indicated individuals. For one of the labeled individuals, there are two possible genotypes. Write both genotypes and indicate which one is more likely. •

Graph of survival curves ("survival function estimates") of children HbAA, HbAS or HbSS. Those who were HbAS had a slight survival advantage over HbAA, with HbSS faring the worst. Sickle cell trait confers protection against mortality between 2-16 months of life in western Kenya.

Consequences of mutations…

• If a mutation in sperm or egg DNA is not repaired, the new sequence of DNA is passed on to offspring.

• Over generations, more mutations accumulate.

• As a result, differences occur between people’s DNA sequences!

How much variation in DNA exists between 2 people?

Hemoglobin (beta) gene sequence from person A

How much variation in DNA exists between 2 people?

Hemoglobin (beta) gene sequence from person B

How much variation in DNA exists between 2 people?

• About 1 in every 1,000 nucleotides is different between 2 people • (0.1% difference means 99.9% identical) • We have about 3 billion nucleotides in all, so that means there are about 3 million nucleotide differences between 2 people

• •

What is the observed effect of mutations?

No Effect

(think about it: are there 3 million differences between 2 people?) – Why?

1. Some mutations code for the same amino acid 2. Most mutations are in sequences of DNA between genes.

Variation

– there are a variety of traits in a population.

Fly Lab – Crossing

Drosophila melanogaster

• Introduction (a little about flies, a little about genetics/genes/traits/alleles) • Materials • Procedure • Data table (raw data from your own flies and class set) • Discussion and Analysis (more about flies, genetics/genes/alleles/assortment/segrega tion [if applicable])

Genetic diseases

• Many alleles are harmless, but some can cause specific diseases. • One disease caused by a specific mutation is

sickle cell anemia

• •

Frameshift mutations

One or more than one nucleotide can be added or deleted with insertion and deletion mutations.

If the number of nucleotides is not a multiple of 3, it is called a

frameshift

mutation.

1. Why do we call this a frameshift mutation?

2. Can substitution mutations cause frameshifts? Explain why or why not.

Genetic diseases

• Many alleles are harmless, but some can cause specific diseases. They can be dominant or recessive. To determine whether a disease is genetic, we trace the family history of a disease by creating a type of family tree called a

pedigree

.

• • Breast Cancer Link Genetic - Activity 5 - Making Decisions in the Face of Uncertainty