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The New Genetics

U.S. DEPARTMENT OF

HEALTH AND HUMAN SERVICES

National Institutes of Health

National Institute of General Medical Sciences

W H AT I S N I G M S? The National Institute of General Medical Sciences (NIGMS) supports basic research on genes, proteins and cells. It also funds studies on fundamental processes such as how cells communicate, how our bodies use energy and how we

respond to medicines. The results of this research increase our understanding of life and lay the foundation for advances in the diagnosis, treatment and prevention of disease. The Institute’s research training programs produce the next generation of scientists, and NIGMS has programs to increase the diversity of the biomedical and behavioral research workforce. NIGMS supported the research of most of the scientists mentioned in this booklet.

Produced by the Office of Communications and Public Liaison National Institute of General Medical Sciences

National Institutes of Health

U.S. Department of Health and Human Services

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The New Genetics

NIH Publication No.10 662

Revised April 2010

http:// www.nigms.nih.gov

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Contents

F O R E W O R D

2

C H A P T E R 1 : H O W G E N E S W O R K

4

Beautiful DNA

5

Copycat

8

Let’s Call It Even

9

Getting the Message

11

Nature’s CutandPaste Job

14

All Together Now

16

Genetics and You: Nursery Genetics

17

Found in Translation

18

RNA Surprises

19

An Interesting Development

20

The Tools of Genetics: Mighty Microarrays

22

C H A P T E R 2 : R N A A N D D N A R E V E A L E D : N E W R O L E S , N E W R U L E S

2 4

RNA World

25

Molecular Editor

26

Healthy Interference

29

Dynamic DNA

30

Secret Code

30

Genetics and You: The Genetics of Anticipation 32

Battle of the Sexes

33

Starting at the End

34

The Other Human Genome

36

The Tools of Genetics: Recombinant DNA and Cloning 38

C H A P T E R 3 : L I F E ’ S G E N E T I C T R E E

4 0

Everything Evolves

40

Selective Study

42

Clues from Variation

43

Living Laboratories

46

The Genome Zoo

52

Genes Meet Environment

53

Genetics and You: You’ve Got Rhythm!

56

Animals Helping People

58

My Collaborator Is a Computer

58

The Tools of Genetics: Unlimited DNA

60

C H A P T E R 4 : G E N E S A R E U S

6 2

Individualized Prescriptions

64

The Healing Power of DNA

65

Cause and Effect

67

Us vs. Them

68

Genetics and You: Eat Less, Live Longer?

69

Gang Warfare

70

The Tools of Genetics: Mathematics and Medicine 72

C H A P T E R 5 : 2 1 S T C E N T U RY G E N E T I C S

7 4

No Lab? No Problem!

76

Hard Questions

78

Good Advice

80

Genetics and You: CrimeFighting DNA

81

Genetics, Business, and the Law

82

Careers in Genetics

85

The Tools of Genetics: Informatics and Databases 86

G LO S SA RY

8 8

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Foreword

Consider

And every living thing

just three of Earth’s inhabitants:

does one thing the same

a bright yellow daffodil that greets the

way: To make more of

itself, it first copies its

spring, the singlecelled creature called

molecular instruction

Thermococcus

manual — its genes — and then passes this inforthat lives in boiling hot mation on to its offspring. This cycle has been

springs, and you. Even a sciencefiction

repeated for three and a half billion years.

But how did we and our very distant relawriter inventing a story set on a distant tives come to look so different and develop so

planet

many different ways of getting along in the

could hardly imagine three more difworld? A century ago, researchers began to answer ferent forms of life. Yet you, Thermococcus

that question with the help of a science called

genetics. Get a refresher course on the basics in

and the daffodil are related! Indeed, all of

Chapter 1, “How Genes Work.”

the

It’s likely that when you think of heredity

Earth’s billions of living things are kin

you think first of DNA, but in the past few years,

to each other.

researchers have made surprising findings about

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The New Genetics I Foreword 3

another molecular actor that plays a starring role.

Can DNA and RNA help doctors predict

Check out the modern view of RNA in Chapter 2,

whether we’ll get diseases like cancer, diabetes or

“RNA and DNA Revealed: New Roles, New Rules.”

asthma? What other mysteries are locked within

When genetics first started, scientists didn’t

the 6 feet of DNA inside nearly every cell in our

have the tools they have today. They could only

bodies? Chapter 4, “Genes Are Us,” explains what look at one gene, or a few genes, at a time. Now,

researchers know, and what they are still learning,

researchers can examine all of the genes in a livabout the role of genes in health and disease.

ing organism— its genome — at once. They are

Finally, in Chapter 5, “21stCentury

doing this for organisms on every branch of the

Genetics,” see a preview of things to come. Learn tree of life and finding that the genomes of mice,

how medicine and science are changing in big

frogs, fish and a slew of other creatures have

ways, and how these changes influence society.

many genes similar to our own.

From metabolism to medicines to agriculture,

So why doesn’t your brother look like your

the science of genetics affects us every day. It is

dog or the fish in your aquarium? It’s because of

part of life … part of your life!

evolution. In Chapter 3, “Life’s Genetic Tree,”

find out how evolution works and how it relates

to genetics and medical research.

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C H A P T E R 1

How Genes Work

People have known for many years that

Proteins do many other things, too. They

living things inherit traits from their parents.

provide the body’s main building materials,

That commonsense observation led to agriculforming the cell’s architecture and structural ture, the purposeful breeding and cultivation of

components. But one thing proteins can’t do is

animals and plants for desirable characteristics.

make copies of themselves. When a cell needs

Firming up the details took quite some time,

more proteins, it uses the manufacturing instructhough. Researchers did not understand exactly tions coded in DNA.

how traits were passed to the next generation

The DNA code of a gene—the sequence of

until the middle of the 20th century.

its individual DNA building blocks, labeled A

Now it is clear that genes are what carry our

(adenine), T (thymine), C (cytosine) and G

traits through generations and that genes are

(guanine) and collectively called nucleotides

made of deoxyribonucleic acid (DNA). But

spells out the exact order of a protein’s building

genes themselves don’t do the actual work.

blocks, amino acids.

Rather, they serve as instruction books for mak

Occasionally, there is a kind of typographical

ing functional molecules such as ribonucleic

error in a gene’s DNA sequence. This mistake—

acid (RNA) and proteins, which perform the

which can be a change, gap or duplication— is

chemical reactions in our bodies.

called a mutation.

Genetics in the Garden

In 1900, three European scientists inde

The monk Gregor

Mendel first described

pendently discovered an obscure research

how traits are inherited

paper that had been published nearly 35

from one generation to

years before. Written by Gregor Mendel,

the next.

an Austrian monk who was also a scientist, the report described a series of offspring and learned that these characteristics

breeding experiments performed with pea

were passed on to the next generation in orderly,

plants growing in his abbey garden.

predictable ratios.

Mendel had studied how pea plants

When he crossbred purpleflowered pea plants

inherited the two variant forms of easytosee

with whiteflowered ones, the next generation had

traits. These included flower color (white or purple)

only purple flowers. But directions for making white

and the texture of the peas (smooth or wrinkled).

flowers were hidden somewhere in the peas of that

Mendel counted many generations of pea plant

generation, because when those purpleflowered

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The New Genetics I How Genes Work 5

A mutation can cause a gene to encode a

Beautiful DNA

protein that works incorrectly or that doesn’t

Up until the 1950s, scientists knew a good deal

work at all. Sometimes, the error means that no

about heredity, but they didn’t have a clue what

protein is made.

DNA looked like. In order to learn more about

But not all DNA changes are harmful. Some

DNA and its structure, some scientists experimutations have no effect, and others produce mented with using X rays as a form of molecular

new versions of proteins that may give a survival

photography.

advantage to the organisms that have them. Over

Rosalind Franklin, a physical chemist worktime, mutations supply the raw material from ing with Maurice Wilkins at King’s College in

which new life forms evolve (see Chapter 3,

London, was among the first to use this method

“Life’s Genetic Tree”).

to analyze genetic material. Her experiments

plants were bred to each other, some of their offfactors, whatever they were, must be physical spring had white flowers. What’s more, the

material because they passed from parent to

secondgeneration plants displayed the colors in a

offspring in a mathematically orderly way. It wasn’t

predictable pattern. On average, 75 percent of the

until many years later, when the other scientists

secondgeneration plants had purple flowers and

unearthed Mendel’s report, that the factors were

25 percent of the plants had white flowers. Those

named genes.

same ratios persisted, and were reproduced when

Early geneticists quickly discovered that

the experiment was repeated many times over.

Mendel’s mathematical rules of inheritance applied

Trying to solve the mystery of the missing color

not just to peas, but also to all plants, animals and

blooms, Mendel imagined that the reproductive

people. The discovery of a quantitative rule for

cells of his pea plants might contain discrete

inheritance was momentous. It revealed that a

“factors,” each of which specified a particular trait,

common, general principle governed the growth

such as white flowers. Mendel reasoned that the

and development of all life on Earth.

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6 National Institute of General Medical Sciences

produced what were referred to at the time as

“the most beautiful Xray photographs of any

COLD SPR

substance ever taken.”

ING HAR

Other scientists, including zoologist James

BOR LAB

Watson and physicist Francis Crick, both work

ORATORY

ing at Cambridge University in the United

ARCHIV

Kingdom, were trying to determine the shape

ES

. In 1953, Watson and Crick created their historic of DNA too. Ultimately, this line of research

model of the shape of DNA: the double helix.

revealed one of the most profound scientific

discoveries of the 20th century: that DNA exists

handrails —were complementary to each other,

as a double helix.

and this unlocked the secret of how genetic

The 1962 Nobel Prize in physiology or mediinformation is stored, transferred and copied.

cine was awarded to Watson, Crick and Wilkins

In genetics, complementary means that if

for this work. Although Franklin did not earn a

you know the sequence of nucleotide building

share of the prize due to her untimely death at age

blocks on one strand, you know the sequence of

38, she is widely recognized as having played a

nucleotide building blocks on the other strand:

significant role in the discovery.

A always matches up with T and C always links

The spiral staircaseshaped double

to G (see drawing, page 7).

helix has attained global status as

Long strings of nucleotides form genes,

the symbol for DNA. But what

and groups of genes are packaged tightly into

is so beautiful about the

structures called chromosomes. Every cell in your

discovery of the twisting

body except for eggs, sperm and red blood cells

ladder structure isn’t just

contains a full set of chromosomes in its nucleus.

its good looks. Rather, the

If the chromosomes in one of your cells were

structure of DNA taught

uncoiled and placed end to end, the DNA would

researchers a fundamental

be about 6 feet long. If all the DNA in your body

lesson about genetics. It taught

were connected in this way, it would stretch

them that the two connected

approximately 67 billion miles! That’s nearly

strands —winding together like parallel

150,000 round trips to the Moon.

. Rosalind Franklin’s

original Xray diffraction

photo revealed the physical

structure of DNA.

OREGON STATE UNIVERSITY LIBRARIES

SPECIAL COLLECTIONS

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The New Genetics I How Genes Work 7

DNA Structure

The long, stringy DNA that makes up genes is

spooled within chromosomes inside the nucleus

of a cell. (Note that a gene would actually be a much

Chromosome

longer stretch of DNA than what is shown here.)

Nucleus

G

C

Bases

Cell

C

G

A

T

G

C

DNA

Guanine

G

C

Cytosine

A

T

C

G

Thymine

T

A

Adenine

Gene

A

T

Sugar

G

C

phosphate

backbone

C

G

A

T

DNA consists of two long, twisted chains made up

of nucleotides. Each nucleotide contains one base,

one phosphate molecule and the sugar molecule

deoxyribose. The bases in DNA nucleotides are

adenine, thymine, cytosine and guanine.

P

Nucleotide

S

C

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8 National Institute of General Medical Sciences

Copycat

It’s astounding to think that

your body consists of trillions

of cells. But what’s most

amazing is that it all starts

with one cell. How does this

massive expansion take place?

As an embryo progresses

. Humans have 23 pairs of chromosomes. Male DNA (pictured here) through development, its cells

contains an X and a Y chromosome, whereas female DNA contains two X chromosomes.

must reproduce. But before

CYTOGENETICS LABORATORY, BRIGHAM AND WOMEN’S HOSPITAL

a cell divides into two new,

nearly identical cells, it must

copy its DNA so there will be a complete set of

the complementary new strand. The process,

genes to pass on to each of the new cells.

called replication, is astonishingly fast and

To make a copy of itself, the twisted, comaccurate, although occasional mistakes, such as pacted double helix of DNA has to unwind and

deletions or duplications, occur. Fortunately, a

separate its two strands. Each strand becomes

cellular spellchecker catches and corrects nearly

a pattern, or template, for making a new strand,

all of these errors.

so the two new DNA molecules have one new

Mistakes that are not corrected can lead to

strand and one old strand.

diseases such as cancer and certain genetic disor

The copy is courtesy of a cellular protein

ders. Some of these include Fanconi anemia, early

machine called DNA polymerase, which reads

aging diseases and other conditions in which

the template DNA strand and stitches together

people are extremely sensitive to sunlight and

some chemicals.

DNA copying is not the only time when DNA

damage can happen. Prolonged, unprotected sun

exposure can cause DNA changes that lead to

skin cancer, and toxins in cigarette smoke can

cause lung cancer.

. When DNA polymerase makes an error while copying a gene’s DNA sequence, the mistake is called a mutation. In this example, the nucleotide G has been changed to an A.

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The New Genetics I How Genes Work 9

C G

A

T

C

G

It may seem ironic, then, that many drugs

A

T

used to treat cancer work by attacking DNA. That’s

T

A

because these chemotherapy drugs disrupt the

DNA copying process, which goes on much faster

C

G

in rapidly dividing cancer cells than in other

T

A

cells of the body. The trouble is that most of these

G

C

T

A

drugs do affect normal cells that grow and

T

A

divide frequently, such as cells of the immune

system and hair cells.

G

C

A

A

T

Understanding DNA replication better could

T

A

be a key to limiting a drug’s action to cancer

G

C

G

C

cells only.

A

T

A

T T

G

C

Let’s Call It Even

G

C

After copying its DNA, a cell’s next challenge is

New strand

getting just the right amount of genetic material

G

C

G

C

into each of its two offspring.

A

T

A

T

G

C

Most of your cells are called diploid

G

C

A

T

(“di” means two, and “ploid” refers to sets of

A

T

chromosomes) because they have two sets of

chromosomes (23 pairs). Eggs and sperm are

A

T

A

T

different; these are known as haploid cells. Each

G

C

G

C

haploid cell has only one set of 23 chromosomes

C

G

C

G

so that at fertilization the math will work out:

A

T

A

T

A haploid egg cell will combine with a haploid

sperm cell to form a diploid cell with the right

A

T

number of chromosomes: 46.

A

T

Chromosomes are numbered 1 to 22,

according to size, with 1 being the largest

chromosome. The 23rd pair, known as the sex

. During DNA replication, each strand of the

original molecule acts as a template for

chromosomes, are called X and Y. In humans,

the synthesis of a new, complementary

DNA strand.

abnormalities of chromosome number usually

occur during meiosis, the time when a cell

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10 National Institute of General Medical Sciences Meiosis

Chromosomes

Cell nucleus

from parents

During meiosis, chromosomes

from both parents are copied

Chromosomes

and paired to exchange portions

replicate

of DNA.

Matching

chromosomes

pair up

This creates a mix of new genetic

Chromosomes swap

material in the offspring’s cells.

sections of DNA

Nucleus divides into

Chromosome pairs divide

daughter nuclei

Daughter nuclei

Chromosomes divide;

divide again

daughter nuclei have

single chromosomes

and a new mix of

genetic material

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The New Genetics I How Genes Work 11

reduces its chromosomes from diploid to haploid

Amon has made major progress in underin creating eggs or sperm.

standing the details of meiosis. Her research shows

What happens if an egg or a sperm cell gets

how, in healthy cells, gluelike protein complexes

the wrong number of chromosomes, and how

called cohesins release pairs of chromosomes at

often does this happen?

exactly the right time. This allows the chromo

Molecular biologist Angelika Amon of

somes to separate properly.

the Massachusetts Institute of Technology in

These findings have important implications

Cambridge says that mistakes in dividing DNA

for understanding and treating infertility, birth

between daughter cells during meiosis are the

defects and cancer.

leading cause of human birth defects and mis

Getting the Message

carriages. Current estimates are that 10 percent

So, we’ve described DNA — its basic properties

of all embryos have an incorrect chromosome

and how our bodies make more of it. But how

number. Most of these don’t go to full term and

does DNA serve as the language of life? How do

are miscarried.

you get a protein from a gene?

In women, the likelihood that chromosomes

won’t be apportioned properly increases with age.

One of every 18 babies born to women over 45

has three copies of chromosome 13, 18 or 21

instead of the normal two, and this improper

balancing can cause trouble. For example, three

copies of chromosome 21 lead to Down

syndrome.

To make her work easier, Amon—like many

other basic scientists —studies yeast cells, which

separate their chromosomes almost exactly the

same way human cells do, except that yeast do it

much faster. A yeast cell copies its DNA and

produces daughter cells in about 11/2 hours,

compared

.

to a whole day for human cells.

Trisomy, the hallmark of Down syndrome, results

when a baby is born with three copies of chromo

The yeast cells she uses are the same kind

some 21 instead of the usual two.

bakeries use to make bread and breweries use

to make beer!

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12 National Institute of General Medical Sciences There are two major steps in making a

You’d think that for a process so essential to

protein. The first is transcription, where the

life, researchers would know a lot about how

information coded in DNA is copied into RNA.

transcription works. While it’s true that the

The RNA nucleotides are complementary to

basics are clear— biologists have been studying

those on the DNA: a C on the RNA strand

gene transcribing by RNA polymerases since

matches a G on the DNA strand.

these proteins were first discovered in 1960—

The only difference is that RNA pairs a

some of the details are actually still murky.

nucleotide called uracil (U), instead of a T, with

an A on the DNA.

A protein machine called RNA polymerase

1

reads the DNA and makes the RNA copy. This

copy is called messenger RNA, or mRNA, because

A

T

C

G

it delivers the gene’s message to the protein

A

T

producing

A

machinery.

T

At this point you may be wondering why all

of the cells in the human body aren’t exactly

alike, since they all contain the same DNA. What

makes a liver cell different from a brain cell? How

do the cells in the heart make the organ contract,

but those in skin allow us to sweat?

Cells can look and act differently, and do

entirely different jobs, because each cell “turns

on,” or expresses, only the genes appropriate for

what it needs to do.

That’s because RNA polymerase does not

work alone, but rather functions with the aid of

many helper proteins. While the core part of

RNA polymerase is the same in all cells, the

helpers vary in different cell types throughout

the body.

DNA

. RNA polymerase transcribes DNA to

make messenger RNA (mRNA).

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The New Genetics I How Genes Work 13

The biggest obstacle to learning more

But our understanding is improving fast,

has been a lack of tools. Until fairly recently,

thanks to spectacular technological advances.

researchers were unable to get a picture at the

We have new Xray pictures that are far more

atomic level of the giant RNA polymerase prosophisticated than those that revealed the structure tein assemblies inside cells to understand how

of DNA. Roger Kornberg of Stanford University in

the many pieces of this amazing, living machine

California used such methods to determine the

do what they do, and do it so well.

structure of RNA polymerase. This work earned

Threonine

Arginine

2

3

4

Amino acids

DNA strand

Tyrosine

Threonine

RNA strand

. Amino acids link up to

make a protein.

A

A T

tRNA

C

C G

A

A T

Ribosome

T

U A

G

G C

C

C G

T

U A

A

A T

T

U A

G

C

G

A

C

G

U

A

U

C

G

U

A

C

A

C

G

C

A

T

A

Codon 1

Codon 2

Codon 3

Codon 4

mRNA

. The mRNA sequence (dark red strand) is com

. On ribosomes, transfer RNA (tRNA) helps

plementary to the DNA sequence (blue strand).

convert mRNA into protein.

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14 National Institute of General Medical Sciences him the 2006 Nobel

Nature’s CutandPaste Job

Prize in chemistry. In

Several types of RNA play key roles in making

addition, very powerful

a protein. The gene transcript (the mRNA)

microscopes and other

transfers information from DNA in the nucleus to

tools that allow us to

the ribosomes that make protein. Ribosomal RNA

watch one molecule

forms about 60 percent of the ribosomes. Lastly,

at a time provide a

transfer RNA carries amino acids to the ribonew look at RNA polysomes. As you can see, all three types of cellular merase while it’s at work

RNAs come together to produce new proteins.

reading DNA and pro

But the journey from gene to protein isn’t

ducing RNA.

quite as simple as we’ve just made it out to be.

For example, Steven

After transcription, several things need to hap

Block, also of Stanford,

pen to mRNA before a protein can be made. For

has used a physics techexample, the genetic material of humans and nique called optical

other eukaryotes (organisms that have a

trapping to track RNA

nucleus) includes a lot of DNA that doesn’t

polymerase as it inches

encode proteins. Some of this DNA is stuck right

. RNA polymerase (green) and one end of a DNA

strand (blue) are attached to clear beads pinned

along DNA. Block and

in the middle of genes.

down in two optical traps. As RNA polymerase

moves along the DNA, it creates an RNA copy of

his team performed

To distinguish the two types of DNA, sciena gene, shown here as a pink strand.

this work by designing

tists call the coding sequences of genes exons and STEVEN BLOCK

a specialized microscope

the pieces in between introns (for intervening

sensitive enough to watch the realtime motion of

sequences).

a single polymerase traveling down a gene on

If RNA polymerase were to transcribe DNA

one chromosome.

from the start of an introncontaining gene to

The researchers discovered that molecules of

the end, the RNA would be complementary to

RNA polymerase behave like batterypowered

the introns as well as the exons.

spiders as they crawl along the DNA ladder,

To get an mRNA molecule that yields a workadding nucleotides one at a time to the growing ing protein, the cell needs to trim out the intron

RNA strand. The enzyme works much like a

sections and then stitch only the exon pieces

motor, Block believes, powered by energy released

together (see drawing, page 15). This process is

during the chemical synthesis of RNA.

called RNA splicing.

The New Genetics I How Genes Work 15

RNA Splicing

Gene

Genes are often interrupted

DNA

Exon 1

Intron 1

Exon 2

Intron 2

Exon 3

by stretches of DNA

(introns, blue) that do not

contain instructions for

making a protein. The DNA

Transcription

segments that do contain

(RNA synthesis)

protein making instructions

are known as exons (green).

Nuclear RNA

Exon 1

Intron 1

Exon 2

Intron 2

Exon 3

RNA splicing

Messenger RNA

Exon 1

Exon 2

Exon 3

Translation

(protein synthesis)

Protein

Gene

Arranging exons in different

DNA

Exon 1

Exon 2

Exon 3

Exon 4

patterns, called alternative

splicing, enables cells to

make different proteins

from a single gene.

Exon 1

Exon 2

Exon 3

Exon 4

Alternative splicing

Exon 1

Exon 2

Exon 3

Exon 1

Exon 2

Exon 4

Translation

Protein A

Protein B

16 National Institute of General Medical Sciences Splicing has to be extremely accurate. An

By cutting and pasting the exons in different

error in the splicing process, even one that results

patterns, which scientists call alternative splicing,

in the deletion of just one nucleotide in an exon

a cell can create different proteins from a single

or the addition of just one nucleotide in an

gene. Alternative splicing is one of the reasons

intron, will throw the whole sequence out of

why human cells, which have about 20,000

alignment. The result is usually an abnormal

genes, can make hundreds of thousands of

protein—or no protein at all. One form of

different proteins.

Alzheimer’s disease, for example, is caused by

All Together Now

this kind of splicing error.

Until recently, researchers looked at genes, and

Molecular biologist Christine Guthrie of the

the proteins they encode, one at a time. Now, they

University of California, San Francisco, wants

can look at how large numbers of genes and proto understand more fully the mechanism for teins act, as well as how they interact. This gives

removing intron RNA and find out how it stays

them a much better picture of what goes on in a

so accurate.

living organism.

She uses yeast cells for these experiments.

Already, scientists can identify all of the genes

Just like human DNA, yeast DNA has introns,

that are transcribed in a cell — or in an organ, like

but they are fewer and simpler in structure and

the heart. And although researchers can’t tell you,

are therefore easier to study. Guthrie can identify

right now, what’s going on in every cell of your

which genes are required for splicing by finding

body while you read a book or walk down the

abnormal yeast cells that mangle splicing.

street, they can do this sort of “wholebody” scan

So why do introns exist, if they’re just going to

for simpler, singlecelled organisms like yeast.

be chopped out? Without introns, cells wouldn’t

Using a technique called genomewide

need to go through the splicing process and keep

location analysis, Richard Young of the

monitoring it to be sure it’s working right.

Massachusetts Institute of Technology unraveled

As it turns out, splicing also makes it possible

a “regulatory code” of living yeast cells, which

for cells to create more proteins.

have more than 6,000 genes in their genome.

Think about all the exons in a gene. If a cell

Young’s technique enabled him to determine

stitches together exons 1, 2 and 4, leaving out

the exact places where RNA polymerase’s helper

exon 3, the mRNA will specify the production

proteins sit on DNA and tell RNA polymerase

of a particular protein. But instead, if the cell

to begin transcribing a gene.

stitches together exons 1, 2 and 3, this time leav

Since he did the experiment with the yeast

ing out exon 4, then the mRNA will be translated

exposed to a variety of different conditions,

into a different protein (see drawing, page 15).

index-21_1.jpg

index-21_2.jpg

index-21_3.jpg

The New Genetics I How Genes Work 17

GENETICS AND YOU: Nursery Genetics W hile most genetic research Newborn screening is governed by uses lab organisms, test

individual states. This means that the

tubes and petri dishes,

state in which a baby

the results have real consequences for

is born determines the

people. Your first encounter with

genetic conditions for

genetic analysis probably happened

which he or she will be

shortly after you were born, when a

screened. Currently,

doctor or nurse took a drop of blood

states test for between

from the heel of your tiny foot.

28 and 54 conditions. All states test

Lab tests performed with that single

for PKU.

drop of blood can diagnose certain rare

Although expanded screening for

genetic disorders as well as metabolic

genetic diseases in newborns is advoproblems like phenylketonuria (PKU).

cated by some, others question the

Screening newborns in this way

value of screening for conditions that

began in the 1960s in Massachusetts

are currently untreatable. Another

with testing for PKU, a disease affecting

issue is that some children with mild

1 in 14,000 people. PKU is caused by an

versions of certain genetic diseases

enzyme that doesn’t work properly due

may be treated needlessly.

to a genetic muta

In 2006, the Advisory Committee

tion. Those born

on Heritable Disorders in Newborns

with this disorder

and Children, which assists the Secretary

cannot metabolize

of the U.S. Department of Health and

the amino acid

Human Services, recommended a

phenylalanine,

standard, national set of newborn

which is present

tests for 29 conditions, ranging from

in many foods. Left untreated, PKU can

relatively common hearing problems

lead to mental retardation and neurologto very rare metabolic diseases.

ical damage, but a special diet can

prevent these outcomes. Testing for this

condition has made a huge difference in

many lives.

index-22_1.jpg

18 National Institute of General Medical Sciences Young was able to figure out how transcription

method to scan the entire human genome in

patterns differ when the yeast cell is under stress

small samples of cells taken from the pancreases

(say, in a dry environment) or thriving in a sugaryand livers of people with type 2 diabetes. He rich nutrient solution. Done one gene at a time,

used the results to identify genes that aren’t tranusing methods considered stateoftheart just a scribed correctly in people with the disease.

few years ago, this kind of analysis would have

This information provides researchers with

taken hundreds of years.

an important tool for understanding how dia

After demonstrating that his technique

betes and other diseases are influenced by

worked in yeast, Young then took his research

defective genes. By building models to predict

a step forward. He used a variation of the yeast

how genes respond in diverse situations,

researchers may be able to learn how to stop or

jumpstart genes on demand, change the course

of a disease or prevent it from ever happening.

Found in Translation

After a gene has been read by RNA polymerase

and the RNA is spliced, what happens next in

the journey from gene to protein? The next step

is reading the RNA information and fitting the

building blocks of a protein together. This is

called translation, and its principal actors are

the ribosome and amino acids.

Ribosomes are among the biggest and most

intricate structures in the cell. The ribosomes of

bacteria contain not only huge amounts of RNA,

but also more than 50 different proteins. Human

ribosomes have even more RNA and between 70

and 80 different proteins!

Harry Noller of the University of California,

. A ribosome consists of large and small

Santa Cruz, has found that a ribosome performs

protein subunits with transfer RNAs

nestled in the middle.

several key jobs when it translates the genetic

RIBOSOME STRUCTURE COURTESY OF JAMIE CATE, MARAT YUSUPOV, code of mRNA. As the messenger RNA threads

GULNARA YUSUPOVA, THOMAS EARNEST AND HARRY NOLLER. GRAPHIC

COURTESY OF ALBION BAUCOM, UNIVERSITY OF CALIFORNIA, SANTA CRUZ.

through the ribosome protein machine, the

index-23_1.jpg

The New Genetics I How Genes Work 19

ribosome reads the mRNA sequence and helps

recognize and recruit the correct amino acidcarrying transfer RNA to match the mRNA code.

The ribosome also links each additional amino

acid into a growing protein chain (see drawing,

page 13).

For many years, researchers believed that even

though RNAs formed a part of the ribosome, the

protein portion of the ribosome did all of the

work. Noller thought, instead, that maybe RNA,

. Some firstaid ointments contain the antibiotic neomycin, not proteins, performed the ribosome’s job. His

which treats infections by attacking ribosomes in bacteria.

idea was not popular at first, because at that time

it was thought that RNA could not perform such

RNA Surprises

complex functions.

But which ribosomal RNAs are doing the work?

Some time later, however, the consensus

Most scientists assumed that RNA nucleotides

changed. Sidney Altman of Yale University in

buried deep within the ribosome complex—the

New Haven, Connecticut, and Thomas Cech,

ones that have the same sequence in every species

who was then at the University of Colorado in

from bacteria to people—were the important

Boulder, each discovered that RNA can perform

ones for piecing the growing protein together.

work as complex as that done by protein enzymes.

However, recent research by Rachel Green,

Their “RNAasanenzyme” discovery turned the

who worked with Noller before moving

research world on its head and earned Cech and

to Johns Hopkins University in Baltimore,

Altman the 1989 Nobel Prize in chemistry.

Maryland, showed that this is not the case.

Noller and other researchers have continued

Green discovered that those RNA nucleotides

the painstaking work of understanding riboare not needed for assembling a protein. Instead, somes. In 1999, he showed how different parts

she found, the nucleotides do something else

of a bacterial ribosome interact with one

entirely: They help the growing protein slip off

another and how the ribosome interacts with

the ribosome once it’s finished.

molecules involved in protein synthesis.

Noller, Green and hundreds of other scientists

These studies provided near proof that the

work with the ribosomes of bacteria. Why should

fundamental mechanism of translation is

you care about how bacteria create proteins from

performed by RNA, not by the proteins of

their genes?

the ribosome.

20 National Institute of General Medical Sciences One reason is that this knowledge is impor

An Interesting Development

tant for learning how to disrupt the actions of

In the human body, one of the most important

diseasecausing microorganisms. For example,

jobs for proteins is to control how embryos

antibiotics like erythromycin and neomycin work

develop. Scientists discovered a hugely important

by attacking the ribosomes of bacteria, which are

set of proteins involved in development by studydifferent enough from human ribosomes that our ing mutations that cause bizarre malformations

cells are not affected by these drugs.

in fruit flies.

As researchers gain new information about

The most famous such abnormality is a fruit

bacterial translation, the knowledge may lead to

fly with a leg, rather than the usual antenna,

more antibiotics for people.

growing out of its head (see page 21). According

New antibiotics are urgently needed because

to Thomas C. Kaufman of Indiana University

many bacteria have developed resistance to the

in Bloomington, the leg is perfectly normal—it’s

current arsenal. This resistance is sometimes the

just growing in the wrong place.

result of changes in the bacteria’s ribosomal RNA.

In this type of mutation and many others,

It can be difficult to find those small, but critical,

something goes wrong with the genetic program

changes that may lead to resistance, so it is

that directs some of the cells in an embryo to

important to find completely new ways to block

follow developmental pathways, which are

bacterial translation.

a series of chemical reactions that occur in a

Green is working on that problem too. Her

specific order. In the antennaintoleg problem,

strategy is to make random mutations to the

it is as if the cells growing from the fly’s head,

genes in a bacterium that affect its ribosomes.

which normally would become an antenna,

But what if the mutation disables the ribosome