Biology

Genetics: Smoking out BRCA2

Doctors have known for years that smoking causes lung cancer, but scientists have recently stumbled on to a specific genetic "spelling error" – in a gene already famous for causing breast cancer – that adds to the riskof developing the disease.

In this lesson you will investigate the following:

• What are bases and how do they help make you, you?

• When are mutations harmful?

• What is bioinformatics?

Are you ready to untangle your understanding of DNA, genes and chromosomes?

This is a print version of an interactive online lesson. To sign up for the real thing or for curriculum details about the lesson go to http://www.cosmosforschools.com

Introduction: Genetics

When you're tuning a guitar, the smallest of tweaks can make a big difference to the way the instrument sounds. And inbooks, small changes in the way the words are put together can change how the story unfolds – little changes can have big effects.

The same applies to DNA – the molecule that carries the genetic information you inherited from your parents. Your DNA directlyaffects how your body is built and functions, and small changes in the information it contains – mutations – can have a big impact.

Often these mutations occur because the processes used to copy DNA are imperfect. Very occasionally the misspellings originate inyour own body, but most often they are inherited from parents, who in turn likely inherited them from their parents. The mutationscan alter the construction of proteins vital to our bodies, with significant harmful results. On the other hand, many mutations haveno noticeable effects at all.

BRCA2 is a very well studied gene because it has a mutation that increases a woman's chance of breast cancer five to ten times. Infact, the gene's name stands for Breast Cancer 2. But recently scientists found a new mutation on the same gene. It also increasesthe risk of breast cancer but is dangerous in a different way as well – it significantly increases the risk of lung cancer in smokers.Which goes to show how two small tweaks in the same gene can carry two very different – and dangerous – tunes.

Read the full Cosmos Magazine article here.

Children often look similar to their parents with family resemblances that can run for generations.

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class before answering.

Question 1

If you look more like one parent then you have inherited moreof that parent’s genes.

True

False

Question 2

Boys get all their traits from their fathers and girls get theirtraits from their mothers.

True

False

Question 3

The genetic information passed on to you from your parentscame from their sex cells – that is, from your father's sperm andyour mother's egg cells.

True

False

Question 4

Your genes determine all your characteristics.

True

False

To finish the section, a quick poll to check your understanding...

A mutation to any part of your DNA is:

  This poll is currently closed, so you can't vote

Poll 1

always harmful

sometimes harmful and sometimes harmless

always harmless

Just to warm you up, here are some questions to find out what you already know about genes. Perhaps you can discuss them in

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Gather: Genetics

Left: DNA samples are often taken by lightly scraping the inside of the mouth. Some of our cells, containing DNA, are inthe saliva. Right: Testing DNA in a lab.

Gregor Mendel showed in 1865 that both parents pass traits on to offspring. But no-one knew how. It wasn’t until 1944 that thechemical substance that carried these traits was discovered. It was a molecule called deoxyribonucleic acid, or DNA.

DNA, chromosomes and genes

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Question 1

Match: Which of the following statements apply best to DNA, gene or chromosome.

Statement applies to...

Shaped like a twisted ladder called a double helix

Contains many genes

Unit of instruction inherited from parents

Constructed from sugar and phosphate molecules and four bases

Long DNA molecule packaged tightly into a coil

Provides a particular cellular instruction (to make a protein)

Each DNA molecule is a double helix. You can easily see the twostrands in the diagram (right) where the double comes from, andhelix just means that the strands are twisted around each other.

If you straighten out the molecule, DNA looks like a ladder. Each"step" is made up of two bases – also called nucleobases. Theselink together, joining the two strands of the molecule together.

There are four types of base and each one links to only oneother type, forming base pairs:

adenine (A) and thymine (T) link together – A-T

guanine (G) and cytosine (C) link together – G-C

When all the bases on two DNA strands align in their A-T and G-C pairings a stable DNA molecule forms.

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Question 2

Label: In the sketchpad below:

1. Drag the text to correctly label the diagram.

2. Drag and position the coloured bases to fill in the gaps in the DNA strands. You will need to rotate some of them.

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Did you know?

In humans, each DNA molecule is from 3.5 cm to 5 cm long. Putall the DNA from the 46 chromosomes – in just one cell – end-to-end, and it comes to 1.8 m. That's probably taller than you! 

Sometimes, for example when a cell is dividing, the DNAmolecules coil themselves up to form the H-shaped chromosomes you sometimes see pictures of. They endup about 2.5 µm long – 1/16,000 of their original length.th

The sequence of bases in each gene provides instructions for building proteins.

Proteins are molecules. They are often very large, made up of many thousands of atoms, and they are critical to all livingorganisms. They make up most of the tissue in the organisms' bodies and help control all of the chemical reactions that occur in theorganisms. 

Codons, amino acids and proteins

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is called a codon. Codons "code" for amino acids – the building blocks of proteins.

So, to summarize:

genes are made up of sequences of bases,

bases are grouped into codons,

codons code for amino acids,

amino acids make up proteins.

With the essential roles that proteins play, you can see how important our genes are!

There are 4 bases – adenine, thymine, guanine and cytosine – and 3 each of these per codon. All possible codon permutationsoccur in nature, for example, ATG, GTA, TTT, and so on. How many are there in total?

To answer this we'll start with a simpler example...

Mathematical interlude

Question 3

List: Let's begin with just 3 letters (a, b, c) and 2 positions. How many permutations does this give?

One way to answer is to write down every permutation and then count them. Do that below – write down all the possiblepermutations of 3 letters with 2 positions, and then count how many permutations there are.

Hint: One way to be sure you get every permutation is to start by putting the first letter in the first position and then going through all the

possible letters in the second position – aa, ab, ac. Then move to the second letter in the first position and again go through all the

possibilities for the second position. And so on.

Question 4

Deduce: Listing all the permutations gets harder if you addmore letters and positions, but you can use a formula instead. 

One of the formulas below is the correct one for working outthe number of permutations (P). Use your answer from the lastquestion to choose which one. Remember, for that example:

the total number of letters (L) = 3

the number of positions (S) = 2

P = S × L

P = LS

P = S + L

P = S L

Question 5

Calculate: Returning to the original question, how manycodon permutations are there? In this case:

the total number of letters (L) = 4 (the 4 bases)

the number of positions (S) = 3 (3 bases per codon)

Using the formula you selected in the previous question,calculate the number of permutations.

When the machinery in a cell reads the bases that make up a gene it interprets them in groups of three. Each group of three

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End of the mathematical interlude

Human proteins are made from 20 amino acids. Your answer above should have told you that there are more codonpermutations than that, so some amino acids are coded for by more than one codon. 

Which codons code for which amino acids can be shown in a codon wheel, like the one below.

To use it, find the first letter of your codon in the inner circle and work outwards to the second letter and finally to the third letter.The outermost ring shows the amino acid coded for. 

Hint: To double-check your answer for the number of codon permutations above, you can count the number of sections in the third ring of

the codon wheel.

Here are some examples using the wheel: 

1. ATG = methionine – this amino acid is found at the start of every gene

2. GTA = valine

3. TGA, TAA and TAG do not code for amino acids. They each stop protein creation.

Note: You can download a PDF of the codon wheel below to print.

codon_wheel_A4_.pdf

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Question 6

Identify: Identify one amino acid that is coded for by more than one codon. Write two 3-letter codon sequences associated withyour chosen amino acid.

Question 7

Interpret: In the sketchpad below:

1. Use the codon wheel to find the amino acids that the bases code for (the first one is done for you).

2. Drag the text labels to their correct positions.

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Question 8

Determine: Two of the following DNA sequences code for the same small protein. Determine the amino acid sequence of thatprotein.

1. ATG   TTA   ACG   AGA   AGT

2. ATG   CTA   AGG   AGT   TCG

3. ATG   CTC   ACT   CGT   AGC

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Process: Genetics

Left: People with Marfan syndrome are very often tall with long, thin arms, legs and fingers. The condition is caused by asingle point mutation to the FBN1 gene. Right: Distichiasis causes people to grow additional eyelashes. It is caused by a

point mutation in the FOXC2 gene.

The Introduction tells how small changes in genes can have big consequences. Scientists use the term mutation to refer to anysuch changes that persist, passing down to new generations. There are many different types of mutations, but some involve achange to just a single base. These are called point mutations.

Point mutations

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Question 1

Define: A point mutation is a change in a single

amino acid

base

gene

protein

Question 2

Consider: If a point mutation causes a frameshift, the resultingprotein is likely nonfunctional. This is because:

frameshifts only change a single amino acid, but

that is enough to disable the resulting protein.

frameshifts always replace many bases, changing

the sequence of amino acids in the protein.

all the amino acids after the changed base are

likely to be different.

Question 3

Identify: The sketchpad below has an original base sequence and three mutations of it, each one caused by a different pointmutation.

1. Drag the text to the appropriate text boxes to identify and explain each type of point mutation.

2. Drag the arrows to show which base changed in each mutation, or where a base was removed.

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Question 4

Deduce: The sketchpad below has the same original sequence and point mutations as the question above. This time:

1. Use the codon wheel to work out the amino acids produced in each case, and write them in.

2. Put ticks or crosses in the appropriate boxes to indicate if the point mutations have changed the amino acid sequences, and ifthere has been a frameshift.

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Question 5

Summarize: For each of the two point mutations below:

Drag an arrow to identify where the mutation occurred

Use the DNA codon wheel to find the mutated sequence

Name the type of point mutation

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Question 6

Reason: A single-base substitution can occur in the first, second or third position of a codon. In which position is the point mutationmost likely to go unnoticed?

Why? Use examples from the DNA codon wheel to support your answer.

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Question 7

Relate: People faced with haemochromatosis, either because they have or carry the condition or someone in their family does, canmeet with a genetic counsellor to discuss the disorder and seek advice. You can find some of the information they might be given inthis booklet. 

Working with a partner, jot down three or four questions that someone with haemochromatosis in their family might want to ask,and the answers. Work these into a short dialogue between the person and a counsellor.

Act out your dialogue in front of your class peers. If you have time, switch roles.

HaemochromatosisHaemochromatosis, or inherited iron overload, is a treatable metabolic disorder caused by DNA mutations. 

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Apply: Genetics

Project: Bioinformatics investigation or haemochromatosispresentation

Scientists now have powerful technologies for reading the bases in your DNA.

For this Apply you have a choice – you can:

investigate an online bioinformatics database, or

create a presentation to explain the haemochromatosis point mutation.

If you have time, do both!

Bioinformatics investigation

You may have seen the movie “GATTACA”. Set in the future, a character provides a hair sample and receives a complete DNAanalysis in a matter of minutes. 

In reality, no machines can do this yet, but there is steady progress. Since 2003 when the entire human genetic sequence – thehuman genome – was first determined, DNA sequencing technologies have been getting cheaper and faster.

But even once all of your A’s, T’s, C’s and G’s are known it is not possible to simply look at the data and know what proteins orcharacteristics it codes for – that is far more complex. To help sort out those questions scientists use enormous databases and thetechniques of bioinformatics.

The National Center for Biotechnology Information (NCBI) houses a collection of more than 40 bioinformatics databases, allfreely available to scientists and the public. 

Background

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in the NCBI databases.

Hint: If you have a computer or laptop, open two browser windows so you can keep the instructions below open alongside the NCBI site. If

you are on a tablet it could be helpful to use two devices, e.g. your phone and the tablet.

1. Open the NCBI homepage here.

2. In the search fields at the top of the page:a. select Gene in the left field,

b. type “BRCA2[SYMBOL]” into the text search field, and

c. click Search.

Results from the search are presented in a table.

Note that the second column has a briefdescription of the gene and identifies the organismsin which is has been found. Column 3 indicates whichchromosome the gene is found on.

Gene search

Question 1

Identify: Name four organisms that have the BRCA2 gene. 

Question 2

Observe: Is the BRCA2 gene found on the same numberchromosome in each of these organisms?

No

Yes

Question 3

Consider: Why do you think scientists are interested in studying the BRCA2 gene in organisms other than humans?

AimThe aim of this task is to locate information about the human BRCA2 gene and in so doing show the extensive range of information

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page under the heading Symbol. Can you see HFE, thehaemochromatosis gene? Scroll to the bottom of the page. How many genes arethere on chromosome 6? (Answer below).

4. Go back to the previous page and now open chromosome13.Can you see BRCA2 listed?Scroll to the bottom of the page. How many genes arethere on chromosome 13? (Answer below).

Question 4

Research: How many genes are there on chromosome 6?

Question 5

Research: How many genes are there on chromosome 13?

1. The NCBI site has a tool called the Map Viewer, forbrowsing the genetic sequences of organisms. Click hereto open it.The home page opens with the sequenceVertebrates/Mammals/Primates expanded.

2. Find the row for Homo sapiens and click on the latestAnnotation Release.You see representations of all the humanchromosomes. Most are numbered, but three are not. Theabbreviations “X” and “Y” refer to the sex chromosomes.“MT” is for the DNA in human mitochondria – our cellnuclei are not the only place we have DNA.

3. Click on the number under chromosome 6.On the left is a diagram of the chromosome, and some ofthe genes on it are listed down the middle of the

Map viewer

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Question 6

What is the official full name for the BRCA2 gene?

Question 7

Complete: Use the information in the Summary to completethe following statement:Inherited _______ in BRCA1 and this gene, BRCA2, confer

_______ lifetime risk of developing _______ or ovarian _______.

Still in the Map Viewer with chromosome 13 open, click on thelink for the BRCA2 gene.

A full description of the human BRCA2 gene opens.

Full description of human BRCA2 gene

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the ORIGIN section, to a section labelled /translation.This list of letters is the amino acids that make up theBRCA2 protein. There are 3,418.

Question 8

Extract: How many bases are there in the BRCA2 gene? What isthe maximum number of amino acids these could code for?

Question 9

Observe: What is the first amino acid in the gene? Why shouldthis not be a surprise?

Haemochromatosis presentationYou are a specialist in genetics. A colleague from your research institute was invited to explain haemochromatosis to interestedmembers of the public, but she has come down with a severe cold and can't attend. She has asked you to do the presentation forher.

She jotted down some of the main points she wanted to cover but, although she says they are fairly complete, they are still jumbledup in the order that she thought of them. As well, she has made a start on slides for a presentation, with some images and textready.

1. In the sketchpad below, organize the images and text your colleague prepared on the slides in the order you want to presentthe material. You can add or edit labels if you want.

2. In the text question that follows, write what you will say as you present each slide.

1. Click NCBI Reference Sequences (RefSeq) in the Table ofContents on the right side of the page.This takes you down the page where you should see asmall section labelled Genomic.

2. In the Download row of the Genomic section clickGenBank.The page that opens shows DNA information about BRCA2.

3. Scroll down the page to a section titled ORIGIN, and thenscroll through this. This is all the bases that make up thegene. How would you like to decode all those codons!?

4. How many bases are there in the gene? (Answer below. Inorder to answer there is a count row beside the ORIGINlist, but the answer is also given in the first line of the page,as "bp" for "base pairs".)

5. Usually, not all the codons in a gene are translated intoamino acids. What is the maximum number of amino acidsthat the BRCA2 gene could code for? (Answer below).

6. Scroll to roughly half way between the top of the page and

Base sequence of BRCA2

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early symptoms: tiredness, joint pain, stomach pain

TGC codon mutated to TAC

later symptoms: liver disease, irregular heart beat, arthritis, diabetes (affects the pancreas)

HFE protein has 348 amino acids – mutation affects no. 282

Question 10

Present: Now it's over to you. You have to make this presentation your own so you you will probably want to add some of yourown text and maybe some arrows. If you have the time you could even draw diagrams or find new images to add, though yourcolleague says that there should be enough with what she has prepared. The meeting organizer says you can use up to 6 slides.

Hint: You can resize any of the images if you need.

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Question 11

Speak: Write down what you will say for each of the slides in your presentation.

Your colleague's notes

HFE protein sits in cell membrane, helps control the flow of iron into the cell

Haemochromatosis due to point mutation on gene HFE

mutant HFE protein lets too much iron into the cell

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Career: Genetics

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Question 1

Relate: Nancy's role requires a) a strong understanding of her area of science, b) an ability to "translate" the science so thatmembers of the public can understand it, and c) the ability to provide emotional support to people faced with serious illness. 

For each of these three elements of the job name one personal quality that would help someone carry out this part of the role. 

Do you think you have any of these qualities? Would you want a career where you would exercise one or more of them? If so,explain what qualities and what sort of job. If not, what qualities do you have that you would like to take advantage of in yourcareer? 

Cosmos Lessons team

Lesson author: Hayley BridgwoodProfile author: Megan ToomeyEditor: Jim RountreeArt director: Wendy JohnsEducation director: Daniel Pikler

Image credits: iStock Photos, Timothy D. Joyce/National MarfanFoundation, Reddit, DNA codon wheel, Genome ResearchLimitedVideo credits: Genome BC, Teachers Pet,HaemochromatosisAust, NWHospital, YouTube

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