What is a gene?

Genes are very small structures inside almost every cell of the body. Genes are the instructions, or blueprints, that tell our body how to grow and develop, build necessary proteins, and thus determine an individual’s characteristics, such as eye color and blood type. It is estimated that there are about 100,000 genes, each of which is an instruction that the cells of the body need to grow and survive. Genes come in pairs and are made of strands of genetic material called deoxyribonucleic acid, or DNA. They line up similar to beads on a string to form larger structures called chromosomes. Genetic disorders are caused when the instruction coded by a particular gene is changed and the gene can no longer perform its proper function.


What is a chromosome?


This diagram, called a karyotype, shows the chromosomes of a male (XY). A karyotype arranges the chromosomes into their 23 pairs. Just as genes come in pairs, chromosomes also come in pairs. Each cell in our body has 23 pairs of chromosomes (for a total of 46); one member of each pair is inherited from the mother and the other from the father. The first 22 pairs (numbered 1 through 22) are called autosomes and they determine most of our features. The last pair is called the sex chromosomes and they determine if we are male or female. Females have two X chromosomes and males have one X chromosome and one Y chromosome.

How are genetic disorders inherited in a family?

There are two patterns of inheritance that involve genes on the autosomes. Genetic disorders that follow this pattern are said to have autosomal dominant or autosomal recessive inheritance. One characteristic of autosomal dominant disorders is that males are affected equally as frequently as females. There are also some disorders that are caused by genes on the sex chromosomes. The genes for these disorders are located on the X chromosome and, therefore, are said to have X-linked inheritance. X-linked disorders can also be dominant or recessive.

Autosomal Dominant

Autosomal dominant means that a person only needs one copy of the changed gene in order to have the disorder. Usually, the changed gene is inherited from a parent who also has the disorder and every generation in the family may have members with the disorder. There are some instances in which a person has the gene that causes the disorder and does not show symptoms of the disorder, but can still pass the gene to his or her children. A person who carriers a gene for an autosomal dominant disorder has a 50% chance of passing the gene to each child.

Autosomal Recessive

Autosomal recessive means that it is necessary to have two copies of the changed gene to have the disorder. Each parent contributes one changed copy of the gene to the child who has the disorder. The parents are called carriers of the disorder because they have one normal copy of the gene and one changed copy of the gene, but they do not show symptoms of the disorder. When both parents are carriers of the changed gene, each of their children has a 25% chance of having the disorder, a 50% chance of being a carrier of the disorder (like their parents), and a 25% chance of neither being a carrier nor having the disorder. These risks are the same for each pregnancy. When there is more than one person in a family who has the disease, these people are often in the same generation.

X-linked Dominant Inheritance

X-linked dominant inheritance follows a pattern similar to autosomal dominant inheritance except that more females are affected than males. However, X-linked dominant disorders are very rare.

X-linked Recessive Disorders

X-linked recessive disorders are usually only seen in males and they are much more common than X-linked dominant disorders. People with an X-linked recessive disorder do not have any normal copies of the gene. Males only have one X chromosome, so if a male inherits a changed gene on his X chromosome (which is always inherited from his mother), then he does not have another copy of the working gene to compensate. Females with one copy of a changed gene on one X chromosome are called carriers of X-linked recessive disorder. It is rare for a female to have the changed gene on both her X chromosomes. In most cases, females who are carriers do not show symptoms because the working copy of the gene compensates for the non-working copy of the gene. Carrier females have a 25% of having a son with the disorder, a 25% chance of having a son without the disorder, a 25% chance of having a carrier daughter and a 25% chance of having a daughter who is not a carrier. Males with an X-linked recessive disorder cannot pass the disorder to their sons, but 100% of their daughters will be carriers.

The Genetics of Complex Disorders

Some disorders, however, are determined by changes in more than one gene. These disorders, known as complex disorders, do not follow the same predicted pattern of inheritance seen in autosomal or X-linked dominant and recessive disorders. Sometimes changes in these genes must be in combination with certain environmental factors, such as exposure to certain chemicals or medications or maybe even diet. This type of inheritance is often referred to as multifactorial because many different factors, genetic and/or environmental, are involved. A person will have a complex disorder if he or she has the right combination of changed genes and environmental exposures. Sometimes these disorders are caused by changes in one or more genes that make a person susceptible to developing the disorder after exposure to specific environmental factors. The close relatives of someone with a complex disorder have a higher chance of later developing the disorder than the close relatives of someone who does not have the disorder. Diabetes, heart disease, neural tube defects, autism, Alzheimer disease, and many cancer syndromes are examples of disorders that can be caused by multifactorial, or complex, inheritance.

How do scientists search for genes?

Scientists use maps of the chromosomes (similar to a road map) in order to look for genes. However, these maps are still somewhat incomplete. Thus, looking for a gene is a difficult task and often takes years to accomplish. Searching for genes that cause a specific disorder is somewhat like trying to find a street on a city map that lists the city’s major landmarks, but not the streets.
What do scientists use as “genetic” landmarks?

Just as gas stations or restaurants can be used as landmarks when locating a friend’s house, scientists use markers to find a gene. The instructions encoded in genes are written in a special genetic alphabet consisting of four letters — A, T, C, and G (called nucleotide bases). These bases are the critical chemicals from which DNA is made. Markers are areas of DNA along the chromosomes which have differences in the string of genetic letters so that the “message” on each member of a chromosome pair is slightly different. These differences (called polymorphisms) do not usually affect a person’s health; they act as “flags” that can be tested in individuals. Scientists can track which marker came from a person’s mother and which came from a person’s father.

Scientists have maps of the markers on each chromosome, just like people have maps that tell them where streets are. These maps have been developed by scientists all over the world. One of the major goals of the Human Genome Project, which is funded, in part, by the U.S. Department of Energy and the National Institutes of Health, is to develop a detailed map of markers evenly spread throughout the entire human genome, or the whole human DNA (like a landmark found on every other street block). Each year this map becomes more dense, providing researchers with more markers to test when looking for genes that cause disorders. In fact, there are so many markers on the genetic map that the scientists’ ability to find genes responsible for disorders has progressed rapidly.

How do markers help find genes that cause disorders?

Scientists test many different markers on all the chromosomes, trying to find markers that are consistently found in family members who have a particular disorder, but not in family members without the disorder. These markers are landmarks that identify which chromosome a disorder gene is located on (like which street a house is on). Certain statistical methods can tell a scientist how close these landmarks are to a gene. Testing more markers will narrow the search area of the gene (like which block a friend’s house is on). Markers that are very close to a gene are said to be linked because the marker is rarely inherited without that gene also being inherited (the marker and gene “travel together”). Once scientists find a set of markers that are linked to a gene, then scientists say that they have found linkage.

What happens after linkage is found?
What is a candidate gene?

Linkage tells us approximately where on a chromosome a gene is located. Scientists still need to determine the exact location of the gene (like which house on the street). One common method uses “candidate” genes, which are genes known to be localized to the region. A gene is called a “candidate” if the function of it relates in some way to the effect the disorder has on the individuals who have the disorder. This laboratory technique is like knocking on the door of every house on a block until you find the one your friend lives in. Similarly, scientists test the candidate genes for changes that might cause the disorder. If there are not any changes in the gene of a person who has the disorder, then that candidate gene could not have caused the disorder. If after all the candidate genes are tested and none are found to be responsible for the disorder, then the researcher studies genes whose functions are not yet known. Many genes may be tested until the right gene is found. Then comes the long process of understanding how the gene works and why it causes the problems that it does.

— Abstracted in part from publications distributed by the NCHGR Office of Communications.

How does one participate in a genetic study?

We usually start with a family history. We also need a small amount of blood (for DNA), and a brief clinical evaluation specific for the disorder being studied. Most of the time this is done outside of the medical center at a place and time convenient to the family. Today many families are spread across the country or world. These members can still participate as we can often obtain samples by mail or through the cooperation of fellow researchers who are near the family members.

All information provided to the researchers at the Center for Human Genetics is considered medical information, including family histories. Therefore, all information on individuals, as well as on the family, is kept confidential.

The Center for Human Genetics and Families

The Center for Human Genetics is a research organization. The Center for Human Genetic’s policy is one of long-term commitment to families participating in research studies. To this end, we remain in contact with members through update letters or newsletters. If requested by family members or an attending physician, recommendations for formal referral for genetic counseling or for clinical and laboratory evaluation man be made. While information on inherited disorders and suggestions for further evaluation may be provided, routine medical care must remain with the primary physician.