Genes at Work in the Brain 

B r a i n B a s i c s 
Introduction 

Our Genes Make Us Human 

Genes do more than just determine the color of our eyes or whether we are tall 

or short. Genes are at the center of everything that makes us human. 

Genes are responsible for producing the proteins that run everything in our bodies. 

Some proteins are visible, such as the ones that compose our hair and skin. Others work out 

of sight, coordinating our basic biological functions. 

For the most part, every cell in our body contains exactly the same genes, but inside individual cel

some genes are active while others are not. When genes are active, they are capable of 

producing proteins. This process is called gene expression. When genes are inactive, 

they are silent or inaccessible for protein production. 

At least a third of the approximately 20,000 different genes that make up the human 

genome are active (expressed) primarily in the brain. This is the highest proportion of genes 

expressed in any part of the body. These genes influence the development and function of 

the brain, and ultimately control how we move, think, feel, and behave. Combined with 

the effects of our environment, changes in these genes can also determine whether 

we are at risk for a particular disease and if we are, the course it might follow. 

This brochure is an introduction to genes, how they work in the brain, 

and how genomic research is helping lead to new therapies 

for neurological disorders. 

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DNA is made of four different chemical 

bases (nucleotides) bound together in 

pairs across the double helix. 

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From DNA 

In order to understand how genes work in the brain, we have to understand how genes 

make proteins. This begins with DNA (deoxyribonucleic acid). 

DNA is a long molecule packaged into structures called chromosomes. Humans have 

23 pairs of chromosomes, including a single pair of sex chromosomes (XX in females 

and XY in males). Within each pair, one chromosome comes from an individual’s 

mother and the other comes from the father. In other words, we inherit half of our DNA 

from each of our parents. 

DNA consists of two strands wound together to form a double helix. Within each 

strand, chemicals called nucleotides are used as a code for making proteins. DNA 

contains only four nucleotides – adenine (A), thymine (T), cytosine (C), and guanine (G) – 

but this simple genetic alphabet is the starting point for making all of the proteins in 

the human body, estimated to be as many as one million. 

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To Gene 

A gene is a stretch of DNA that contains the 

instructions for making or regulating a specific protein. 

Genes that make proteins are called protein-coding 

genes. In order to make a protein, a molecule 

closely related to DNA called ribonucleic acid (RNA) 

first copies the code within DNA. Then, proteinmanufacturing machinery within the cell scans the 

RNA, reading the nucleotides in groups of three. 

These triplets encode 20 distinct amino acids, which 

are the building blocks for proteins. The largest 

known human protein is a muscle protein called titin, 

which consists of about 27,000 amino acids. 

Some genes encode small bits of RNA that are not 

used to make proteins, but are instead used to tell 

proteins what to do and where to go. These are 

called non-coding or RNA genes. There are many 

more RNA genes than protein-coding genes. 

A gene is a stretch of DNA code that 

makes or regulates a protein. When it is time to make a protein, 

the section of DNA that contains 

the code unzips. 

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Messenger RNA (mRNA) 

copies the code. 

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The cell’s protein-making machinery 

reads the mRNA and produces a 

chain of amino acids. 

To Protein 

Proteins form the internal machinery within brain cells 

and the connective tissue between brain cells. They 

also control the chemical reactions that allow brain 

cells to communicate with each other. 

Some genes make proteins that are important for the 

early development and growth of the infant brain. 

For example, the ASPM gene makes a protein that 

is needed for producing new nerve cells (or neurons) 

in the developing brain. Alterations in this gene can 

cause microcephaly, a condition in which the brain 

fails to grow to its normal size. 

Certain genes make proteins that in turn make 

neurotransmitters, which are chemicals that transmit 

information from one neuron to the next. Other 

proteins are important for establishing physical 

connections that link various neurons together in 

networks. 

Still other genes make proteins that act as housekeepers 

in the brain, keeping neurons and their networks in 

good working order. 

For example, the SOD1 gene makes a protein that 

fights DNA damage in neurons. Alterations in this 

gene are one cause of the disease amyotrophic lateral 

sclerosis (ALS), in which a progressive loss of musclecontrolling neurons leads to eventual paralysis and 

death. The SOD1 gene is believed to hold important 

clues about why neurons die in the common “sporadic” 

form of ALS, which has no known cause. 

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A protein’s amino 

acid sequence helps 

determine its unique 

3-D structure and 

function. 

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DNA Binding Proteins 

About 10 percent of the genes in the human genome encode 

DNA binding proteins. Some of these proteins recognize and 

attach to specific bits of DNA to activate gene expression. 

Another type of DNA binding protein, called a histone, acts as 

a spool that can keep DNA in tight coils and thus suppress gene 

expression. 

sRNA 

Scattered throughout the genome are many types of small RNA 

(sRNA) that actively regulate gene expression. Because of their 

short length, they are able to target, match, and deactivate small 

bits of genetic code. 

Epigenetic Factors 

The word epigenetics comes from the Greek word epi, meaning 

above or beside. In a broad sense, epigenetics refers to longlasting changes in gene expression without any changes to the 

genetic code. Epigenetic factors include chemical marks or tags 

on DNA or on histones that can affect gene expression. 

We know which protein a gene will make by looking at its 

code, also called its DNA sequence. What we cannot predict is 

the amount of protein that will be made, when it will be made, 

or what cell will make it. 

Each cell turns on only a fraction of its genes, while it silences 

the rest. For example, genes that are expressed in brain cells 

may be silenced in liver cells or heart cells. Some genes are 

only turned on during the early months of human development 

and then are silenced later. 

What determines these unique patterns of gene expression? 

Like people, cells have a unique lineage, and they tend to 

inherit traits from their parents. So, a cell’s origins influence the 

genes it turns on to make proteins. The cell’s environment – its 

exposure to surrounding cells and to hormones and other signals 

– also helps determine which proteins the cell makes. 

These cues from a cell’s past and from its environment act 

through many regulatory factors inside the cell, some of which 

are described in the following sections. 

How Gene Expression Is Regulated 

When DNA is coiled tightly around 

histones, the genes within it tend 

to be inaccessible and silent. 

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Variations In Genetic Code 

A genetic variation is a permanent change in the DNA sequence 

that makes up a gene. Most variations are harmless or have no 

effect at all. However, other variations can have harmful effects 

leading to disease. Still others can be beneficial in the long run, 

helping a species adapt to change. 

Single Nucleotide Polymorphism (SNP) 

SNPs are variations that involve a change in just one nucleotide. 

It is estimated that the human genome contains more than 10 

million different SNPs. Because SNPs are such small changes 

within DNA, most of them have no effect upon gene expression. 

Some SNPs, however, are responsible for giving us unique 

traits, such as our hair and eye color. Other SNPs may have 

subtle effects on our risk of developing common diseases, such 

as heart disease, diabetes, or stroke. 

Copy Number Variation (CNV) 

At least 10 percent of the human genome is made up of CNVs, 

which are large chunks of DNA that are deleted, copied, flipped 

or otherwise rearranged in combinations that can be unique for 

each individual. These chunks of DNA often involve proteincoding genes. This means that CNVs are likely to change how 

a gene makes its protein. 

Since genes usually occur in two copies, one inherited from 

each parent, a CNV that involves a single missing gene could 

lower the production of a protein below the amount needed. 

Having too many copies of a gene can be harmful, too. 

Although most cases of Parkinson’s disease are sporadic 

(without a known cause), some cases have been linked to 

having two or more copies of the SNCA gene, which encodes 

a protein called alpha-synuclein. The excess alpha-synuclein 

accumulates in clumps inside brain cells, and appears to jam the 

cells’ machinery. For reasons that are not clear, similar clumps 

are associated with sporadic Parkinson’s disease. 

Single Gene Mutation 

Some genetic variations are small and affect only a single gene. 

These single gene mutations can have large consequences, 

however, because they affect a gene’s instructions for making 

a protein. Single gene mutations are responsible for many rare 

inherited neurological diseases. 

For example, Huntington’s disease is the result of what is called 

an expanded “triplet repeat” in the huntingtin gene. Normal 

genes often have triplet repeats, in which the same triplet amino 

acid code occurs multiple times like a stutter. These repeats are 

usually harmless. 

In the huntingtin gene, triplet repeats of 20 to 30 times are 

normal. But in people with Huntington’s disease, the number 

of repeats reaches 40 or more. The mutation creates an 

abnormally shaped protein that is toxic to neurons. As cells 

start to die, the symptoms of Huntington’s disease appear – 

uncontrollable writhing movements of the legs and arms, 

a loss of muscle coordination, and changes in personality 

and thinking. 

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The Role Of Genes In Neurological Disease 

Most of the single gene mutations that cause rare neurological 

disorders such as Huntington’s disease have been identified. 

In contrast, there is still much to learn about the role of genetic 

variations in common neurological disorders and conditions, 

like Alzheimer’s disease and stroke. A few things are clear. 

First, for most people, a complex interplay between genes and 

environment influences the risk of developing these diseases. 

Second, where specific genetic variations such as SNPs are 

known to affect disease risk, the impact of any single variation 

is usually very small. In other words, most people affected by 

stroke or Alzheimer’s disease have experienced an unfortunate 

combination of many “hits” in the genome and in the 

environment. Finally, beyond changes in the DNA sequence, 

changes in gene regulation – for example, by sRNAs and 

epigenetic factors – can play a key role in disease. 

Scientists search for connections between genes and disease 

risk by performing two kinds of studies. In a genome-wide 

association (GWA) study, scientists search for SNPs or other 

changes in the DNA sequence, comparing the genomes of subjects 

(people, laboratory animals or cells) that have a disease and 

subjects that do not have the disease. In another type of study 

called gene expression profiling, scientists look for changes in 

gene expression and regulation that are associated with a disease. 

Both kinds of studies often use a device called a DNA 

microarray, which is a small chip, sometimes called a gene chip, 

coated with row upon row of DNA fragments. The fragments 

act as probes for DNA (in a GWA study) or RNA (in gene 

expression profiling) isolated from a sample of blood or tissue. 

Increasingly, scientists are conducting these studies by direct 

sequencing, which involves reading DNA or RNA sequences 

nucleotide by nucleotide. Sequencing was once a timeconsuming and expensive procedure, but a new set of techniques 

called next-generation sequencing has emerged as an efficient, 

cost-effective way to get a detailed readout of the genome. 

A microarray is a device used to study individual 

differences in the genetic code and in gene expression. 

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DNA probe attached to the microarray (yellow) 

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DNA isolated from tissue sample (orange) 

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Genes At Work For Better Treatments And Cures
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Doctors can prescribe DNA-based tests to look for the mutations

that cause single gene mutation disorders such as Duchenne 

muscular dystrophy, neurofibromatosis type 1, and Huntington’s

disease. Genetic tests are often used to confirm the diagnosis 

of disease in people who already have symptoms, but they 

can also be used to establish the presence of a mutation in 

individuals who are at risk for the disease but who have not 

yet developed any symptoms. 

In the laboratory, GWA studies and gene expression profiling 

studies are leading to insights into new possibilities for disease 

prevention, diagnosis and treatment. When scientists identify 

a gene or gene regulatory pathway associated with a disease, 

they uncover potential new targets for therapy. 

Understanding the relationships between genes and complex 

diseases also is expected to play an important part in 

personalized medicine. One day, microarray-based genome 

scanning could become a routine way to estimate a person’s 

genetic risk of developing diseases like stroke, Alzheimer’s 

disease, Parkinson’s disease and certain brain cancers. 

Also, researchers hope to develop customized drug “cocktails” 

that are matched to a person’s unique genetic profile. 

Researchers believe that these customized drugs will be much 

less likely than current medicines to cause side effects. 

RNA interference (RNAi) is a technique that takes advantage 

of the ability of small RNAs to modify gene expression. In the 

future, RNAi could be used therapeutically to power up a gene 

that has been abnormally silenced, or to turn down one that is 

overactive. There are still many technical hurdles to overcome 

before these kinds of treatments become a reality. For example, 

researchers do not yet know how to best deliver these molecules 

to the nervous system. 

These are just a few of the ways scientists are using newfound 

knowledge about gene expression to make life better for people 

with neurological disorders. 

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The National Institute of 

Neurological Disorders and Stroke 

Since its creation by Congress in 1950, the National Institute 

of Neurological Disorders and Stroke (NINDS) has grown to 

become the nation’s leading supporter of biomedical research 

on the brain and nervous system. Most research funded by 

the NINDS is conducted by scientists in public and private 

institutions such as universities, medical schools, and hospitals. 

Government scientists also conduct a wide array of 

neurological research in the more than 20 laboratories and 

branches of the NINDS itself. This research ranges from 

studies on the structure and function of single brain cells to 

tests of new diagnostic tools and treatments for those with 

neurological disorders. For more information, write or call the 

Institute’s Brain Resources and Information Network (BRAIN) at: 

BRAIN 

P.O. Box 5801 

Bethesda, Maryland 20824 

1-800-352-9424 

braininfo@ninds.nih.gov 

Prepared by 

Office of Communications 

and Public Liaison 

National Institute of Neurological 

Disorders and Stroke 

National Institutes of Health 

Bethesda, Maryland 20892 

U.S. Department of Health 

and Human Services 

Public Health Service 

NIH Publication No. 10-5475 

July 2010 

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