Genetic Inheritance

Genetic inheritance is the transmission of genetic material from parent to offspring. Almost all physical traits and many personality traits and unique abilities are found in the genes. A gene is the basic unit of heredity and consists of a specific sequence of nucleotide bases that carries information needed to make the proteins required for the body's structure and function. The genes are arranged on chromosomes. Humans have thousands of genes encoded in their DNA, each of which plays an important role in life. Some traits have relatively simple genetics, while others are complex, involving many different genes.

How It Works

When a genetic disorder is diagnosed, family members often want to know the likelihood that they or their children will develop the condition. This can be difficult to predict in some cases because many factors influence a person’s chances of developing a genetic condition. One important factor is how the condition is inherited. For example:

• Autosomal dominant inheritance: A person affected by an autosomal dominant disorder has a 50% chance of passing the mutated gene to each child. The chance that a child will not inherit the mutated gene is also 50%. Examples of autosomal dominant disorders include Huntington disease and neurofibromatosis.
• Autosomal recessive inheritance: Two unaffected people who each carry one copy of the mutated gene for an autosomal recessive disorder (carriers) have a 25%chance with each pregnancy of having a child affected by the disorder. The chance with each pregnancy of having an unaffected child who is a carrier of the disorder is 50%, and the chance that a child will not have the disorder and will not be a carrier is 25%. Diseases inherited through autosomal recessive inheritance include cystic fibrosis and sickle cell anemia.
• X-linked dominant inheritance: The chance of passing on an X-linked dominant condition differs between men and women because men have one X chromosome and one Y chromosome, while women have two X chromosomes. A man passes on his Y chromosome to all of his sons and his X chromosome to all of his daughters. Therefore, the sons of a man with an X-linked dominant disorder will not be affected, but all of his daughters will inherit the condition. A woman passes on one or the other of her X chromosomes to each child. Therefore, a woman with an X-linked dominant disorder has a 50%chance of having an affected daughter or son with each pregnancy. Fragile X Syndrome is a disease with X-linked dominant inheritance.
• X-linked recessive inheritance: Because of the difference in sex chromosomes, the probability of passing on an X-linked recessive disorder also differs between men and women. The sons of a man with an X-linked recessive disorder will not be affected, while the daughters will carry one copy of the mutated gene. With each pregnancy, a woman who carries an X-linked recessive disorder has a 50% chance of having sons who are affected and a 50% chance of having daughters who carry one copy of the mutated gene. Two examples of X-linked recessive diseases are hemophilia and Fabry disease

In this example, a man with an X-linked recessive condition has two unaffected daughters who each carry one copy of the gene mutation, and two unaffected sons who do not have the mutation., Source:NIH ^[1]

In this example, an unaffected woman carries one copy of a gene mutation for an X-linked recessive disorder. She has an affected son, an unaffected daughter who carries one copy of the mutation, and two unaffected children who do not have the mutation.Source:NIH ^[2]

• Codominant inheritance: In codominant inheritance, each parent contributes a different version of a particular gene, and both versions influence the resulting genetic trait. The chance of developing a genetic condition with codominant inheritance, and the characteristic features of that condition, depend on which versions of the gene are passed from parents to their child. The ABO blood group types and alpha-1 antitrypsin deficiency are passed on through codominant inheritance.
• Mitochondrial inheritance: Mitochondria, which are the energy-producing centers inside cells, each contain a small amount of DNA. Disorders with mitochondrial inheritance result from mutations in DNA. Although mitochondrial disorders can affect both males and females, only females can pass mutations in mitochondrial DNA to their children. A woman with a disorder caused by changes in mitochondrial DNA will pass the mutation to all of her daughters and sons, but the children of a man with such a disorder will not inherit the mutation. Leber hereditary optic neuropathy (LHON) is a condition inherited through mitochondrial inheritance.

It is important to note that the chance of passing on a genetic condition applies equally to each pregnancy. For example, if a couple has a child with an autosomal recessive disorder, the chance of having another child with the disorder is still 25% (or 1 in 4). Having one child with a disorder does not “protect” future children from inheriting the condition. Conversely, having a child without the condition does not mean that future children will definitely be affected.

Although the chances of inheriting a genetic condition appear straightforward, factors such as a person’s family history and the results of genetic testing can sometimes modify those chances. In addition, some people with a disease-causing mutation never develop any health problems or may experience only mild symptoms of the disorder. If a disease that runs in a family does not have a clear-cut inheritance pattern, predicting the likelihood that a person will develop the condition can be particularly difficult.

Estimating the chance of developing or passing on a genetic disorder can be complex. Genetics professionals can help people understand these chances and help them make informed decisions about their health.

Family History

A condition can affect several generations of a family. Source: Genetics Home Reference, U.S. National Library of Medicine

A family medical history is a record of health information about a person and their close relatives. A complete record includes information from three generations of relatives, including children, brothers and sisters, parents, aunts and uncles, nieces and nephews, grandparents, and cousins. Some relevant terms used in a family history:

• First-degree relatives are parents, children, brothers, and sisters
• Second-degree relatives are grandparents, aunts and uncles, nieces and nephews, and grandchildren
• Third-degree relatives are first cousins

Families have many factors in common, including genes, environment, and lifestyle. Together, these factors can provide clues to medical conditions that may run in a family. By noticing patterns of disorders among relatives, healthcare professionals can determine whether an individual, other family members, or future generations may be at an increased risk of developing a particular condition.

A family medical history can identify people with a higher-than-usual chance of having common disorders, such as heart disease, high blood pressure, stroke, certain cancers, and diabetes. These complex disorders are influenced by a combination of genetic factors, environmental conditions, and lifestyle choices. A family history also can provide information about the risk of rarer conditions caused by mutations in a single gene, such as cystic fibrosis and sickle cell anemia.

While a family medical history provides information about the risk of specific health concerns, having relatives with a medical condition does not mean that an individual will definitely develop that condition. On the other hand, a person with no family history of a disorder may still be at risk of developing that disorder.

Knowing one’s family medical history allows a person to take steps to reduce his or her risk. For people at an increased risk of certain cancers, healthcare professionals may recommend more frequent screening (such as mammography or colonoscopy) starting at an earlier age. Healthcare providers may also encourage regular checkups or testing for people with a medical condition that runs in their family. Additionally, lifestyle changes such as adopting a healthier diet, getting regular exercise, and quitting smoking help many people lower their chances of developing heart disease and other common illnesses.

It is not always easy to determine whether a condition in a family is inherited. A genetics professional can use a family history (a record of health information about a person’s immediate and extended family) to help determine whether a disorder has a genetic component.

Other Factors

Reduced penetrance and variable expressivity are factors that influence the effects of particular genetic changes. These factors usually affect disorders that have an autosomal dominant pattern of inheritance, although they are occasionally seen in disorders with an autosomal recessive inheritance pattern.

Reduced penetrance

Penetrance refers to the proportion of people with a particular genetic change (such as a mutation in a specific gene) who exhibit signs and symptoms of a genetic disorder. If some people with the mutation do not develop features of the disorder, the condition is said to have reduced (or incomplete) penetrance. Reduced penetrance often occurs with familial cancer syndromes. For example, many people with a mutation in the BRCA1 or BRCA2 gene ^[3] will develop cancer during their lifetime, but some people will not. Doctors cannot predict which people with these mutations will develop cancer or when the tumors will develop.

Reduced penetrance probably results from a combination of genetic, environmental, and lifestyle factors, many of which are unknown. This phenomenon can make it challenging for genetics professionals to interpret a person’s family medical history and predict the risk of passing a genetic condition to future generations.

Variable expressivity

Although some genetic disorders exhibit little variation, most have signs and symptoms that differ among affected individuals. Variable expressivity refers to the range of signs and symptoms that can occur in different people with the same genetic condition. For example, the features of Marfan syndrome vary widely; some people have only mild symptoms (such as being tall and thin with long, slender fingers), while others also experience life-threatening complications involving the heart and blood vessels. Although the features are highly variable, most people with this disorder have a mutation in the same gene (FBN1).

As with reduced penetrance, variable expressivity is probably caused by a combination of genetic, environmental, and lifestyle factors, most of which have not been identified.

Genomic imprinting

People inherit two copies of their genes—one from their mother and one from their father. Usually both copies of each gene are active, or “turned on,” in cells. In some cases, however, only one of the two copies is normally turned on. Which copy is active depends on the parent of origin: some genes are normally active only when they are inherited from a person’s father; others are active only when inherited from a person’s mother. This phenomenon is known as genomic imprinting.

In genes that undergo genomic imprinting, the parent of origin is often marked, or “stamped,” on the gene during the formation of egg and sperm cells. This stamping process, called methylation, is a chemical reaction that attaches small molecules called methyl groups to certain segments of DNA. These molecules identify which copy of a gene was inherited from the mother and which was inherited from the father. The addition and removal of methyl groups can be used to control the activity of genes.

Only a small percentage of all human genes undergo genomic imprinting. Researchers are not yet certain why some genes are imprinted and others are not. They do know that imprinted genes tend to cluster together in the same regions of chromosomes. Two major clusters of imprinted genes have been identified in humans, one on the short (p) arm of chromosome 11 (at position 11p15) and another on the long (q) arm of chromosome 15 (in the region 15q11 to 15q13).

Uniparental disomy

Uniparental disomy (UPD) occurs when a person receives two copies of a chromosome, or part of a chromosome, from one parent and no copies from the other parent. UPD can occur as a random event during the formation of egg or sperm cells or may happen in early fetal development.

In many cases, UPD likely has no effect on health or development. Because most genes are not imprinted, it doesn’t matter if a person inherits both copies from one parent instead of one copy from each parent. In some cases, however, it does make a difference whether a gene is inherited from a person’s mother or father. A person with UPD may lack any active copies of essential genes that undergo genomic imprinting. This loss of gene function can lead to delayed development, mental retardation, or other medical problems.

Several genetic disorders can result from UPD or a disruption of normal genomic imprinting. The most well-known conditions include Prader-Willi syndrome, which is characterized by uncontrolled eating and obesity, and Angelman syndrome, which causes mental retardation and impaired speech. Both of these disorders can be caused by UPD or other errors in imprinting involving genes on the long arm of chromosome 15. Other conditions, such as Beckwith-Wiedemann syndrome (a disorder characterized by accelerated growth and an increased risk of cancerous tumors), are associated with abnormalities of imprinted genes on the short arm of chromosome 11.

Diseases of Genetic Inheritance

Errors in DNA are called mutations. Mutations can be inherited or can arise spontaneously during development. Some disorders that affect multiple family members are caused by gene mutations, which can be inherited (passed down from parent to child). Other conditions that appear to run in families are not caused by mutations in single genes. Instead, environmental factors such as dietary habits or a combination of genetic and environmental factors are responsible for these disorders.

Some of the most frequently encountered disorders and diseases that are primarily due to gene mutations include:

• Cystic Fibrosis
• Down Syndrome
• Fragile X Syndrome
• Inherited Thrombophilias (Factor V Leiden, Factor II)
• Gaucher Disease
• Tay-Sachs Disease
• Klinefelter Syndrome
• Open neural tube defects
• Sickle Cell Disease
• Triple X Syndrome
• Thalassemia
• Trisomy 13
• Trisomy 18
• Turner Syndrome

Chromosomal disorders

Although it is possible to inherit some types of chromosomal abnormalities, most chromosomal disorders (such as Down Syndrome and Turner syndrome) are not passed from one generation to the next.

Some chromosomal conditions are caused by changes in the number of chromosomes. These changes are not inherited, but occur as random events during the formation of reproductive cells (eggs and sperm). An error in cell division called nondisjunction results in reproductive cells with an abnormal number of chromosomes. For example, a reproductive cell may accidentally gain or lose one copy of a chromosome. If one of these atypical reproductive cells contributes to the genetic makeup of a child, the child will have an extra or missing chromosome in each of the body’s cells.

Changes in chromosome structure can also cause chromosomal disorders. Some changes in chromosome structure can be inherited, while others occur as random accidents during the formation of reproductive cells or in early fetal development. Because the inheritance of these changes can be complex, people concerned about this type of chromosomal abnormality may want to talk with a genetics professional.

Complex or multifactorial disorders

Many disorders result from mutations in multiple genes, and often have environmental causes as well. These complex diseases are difficult to study and to treat. Heart Disease, diabetes, schizophrenia, and cancer are examples of diseases which have a complex genetic component, but also environmental or behavioral components.

Cancer

The defects that cause cancerous growth of cells are accumulated over time. In general, any one defect is not enough to cause cancer on its own. However, when enough defects accumulate, either through inheritance of mutations or acquisition of new mutations during the life of an organism (for example, due to environmental causes such as exposure to UV light, infection by certain viruses, spontaneous mutations, changes in copying the DNA during the aging process), cancer results.

Some cancer cells also have changes in the number or structure of their chromosomes. Because these changes occur in somatic cells (cells other than eggs and sperm), they cannot be passed from one generation to the next.

Keys to the genetic basis of cancer can be inferred from examining cancer symptoms, including:

• Cancer cells divide at inappropriate times. These cells either do not receive signals to stop dividing, or may not require outside signals to start dividing.
• Cancer cells lose their normal awareness of their position with respect to other cells. When cancer cells encounter neighbors, they do not stop dividing as normal cells do, but pile up and form a tumor.
• Cancer cells sometimes gain an abnormal ability to invade healthy tissue, leading to the spread of cancer to other sites in the body (metastasis).

The genes that control the processes listed above for normal cells are the genes that are mutant in cancerous cells. Genes mutant in cancerous cells include those whose normal function is to prevent cell division, to help cells sense their environment and respond properly to it, and to help cells in their normal process of adhering to other cells.

Genetic scientists are studying the mechanics of cancer --- how cells receive start and stop signals for cell division, what genes control these processes, and what can be done to control this abnormal state. Understanding the normal situation as well as the cancerous state will lead to better methods of prevention and treatment.

Anticipation

The signs and symptoms of some genetic conditions tend to become more severe and appear at an earlier age as the disorder is passed from one generation to the next. This phenomenon is called anticipation. Anticipation is most often seen with certain genetic disorders of the nervous system, such as Huntington disease, myotonic dystrophy, and fragile X syndrome.

Anticipation typically occurs with disorders that are caused by an unusual type of mutation called a trinucleotide repeat expansion. A trinucleotide repeat is a sequence of three DNA building blocks (nucleotides) that is repeated a number of times in a row. DNA segments with an abnormal number of these repeats are unstable and prone to errors during cell division. The number of repeats can change as the gene is passed from parent to child. If the number of repeats increases, it is known as a trinucleotide repeat expansion. In some cases, the trinucleotide repeat may expand until the gene stops functioning normally. This expansion causes the features of some disorders to become more severe with each successive generation.

Most genetic disorders have signs and symptoms that differ among affected individuals, including affected people in the same family. Not all of these differences can be explained by anticipation. A combination of genetic, environmental, and lifestyle factors is probably responsible for the variability, although many of these factors have not been identified. Researchers study multiple generations of affected family members and consider the genetic cause of a disorder before determining that it shows anticipation.

Ethnicity and Genetics

The genetic material in all humans is 99.9% identical. However, since the human genome is made up of 3 billion chemical units strung together, the one-tenth of 1% of DNA that is different among people can add up to a few million tiny differences. The average differences between individuals are larger than those between groups. People who belong to groups that share the same ancestry are likely to have genes that are more similar than do people who are not so closely related. Studying the DNA from family members—or from populations in which people share a common ancestry—makes it easier for scientists to pick out the genetic differences linked with disease. Researchers study genes from people in different population groups to find the genetic differences that are unique to certain diseases, not to particular ethnic and racial groups. Occasionally, however, scientists do study members of certain groups because a disease is much more common in that group. The gene linked to Tay-Sachs disease, for example, was identified in Ashkenazi Jews.

Some genetic disorders are more likely to occur among people who trace their ancestry to a particular geographic area. People in an ethnic group often share certain versions of their genes, which have been passed down from common ancestors. If one of these shared genes contains a disease-causing mutation, a particular genetic disorder may be more frequently seen in the group.

Examples of genetic conditions that are more common in particular ethnic groups are sickle cell anemia, which is more common in people of African, African-American, or Mediterranean heritage; and Tay-Sachs disease, which is more likely to occur among people of Ashkenazi (eastern and central European) Jewish or French Canadian ancestry. It is important to note, however, that these disorders can occur in any ethnic group.

Related Professions

A geneticist is a scientist who studies genetics (the science of heredity and the way that traits are passed from one person to another). Geneticists may be physicians, teachers and researchers. There are several professions related to genetics:

• A genetic counselor speaks with people at risk of developing an inherited disorder about the nature of the disorder and the chances of transmitting or inheriting the disorder as well as ways to decrease the risk of transmission.
• A laboratory geneticist generally has special training in laboratory medicine. These scientists apply the study of genetics to a variety of fields, including agriculture, police or legal investigation (DNA fingerprinting, paternity testing, forensics), pharmaceutical research, and clinical medicine.
• Genetic medicine applies the science of genetics to the field of medicine to prevent or manage inherited conditions, to provide prenatal diagnosis of genetic disorders or birth defects and to research the causes and potential treatments of birth defects and genetic disorders. ^[4]

History

How Genetic Inheritance was discovered

Gregor Mendel (1822-1884), an Augustinian monk and scientist, studied the patterns of the inheritance of traits in pea plants. He discovered that the passing down of traits followed certain laws (later named Mendel's laws), that genetic material is passed intact to the offspring from both parents, and that traits can be dominant or recessive. Mendel's discoveries were initially not understood. His work was re-examined by scientists in the early 20th century and the study of genetics was born. Mendel is known as the father of genetics.

Clinical Trials

There are a number of clinical trials involving the inheritance of specific diseases. These trials can be accessed at ClinicalTrials.gov: genetic inheritance trials.

The National Institutes of Health is recruiting participants for a study to identify the genes responsible for several inherited disorders commonly seen in the Amish and Mennonite populations. More information is available at Genetic Studies in the Amish and Mennonites.

Research

Recent discoveries

There has been a significant amount of ongoing research regarding the genetics of common diseases. Some recent studies include:

• Using common genes thought to be linked to the development of breast cancer to determine the risk of developing the disease. ^{[5] [6]}
• Genetic testing for a subset of Parkinson disease associated with a genetic mutation. This type of the disease is associated with a better outcome than idiopathic disease. ^[7]
• There may be a role for genetic testing and counseling in early onset Alzheimer disease. ^[8]

Controversy

Now that genetic testing is becoming available for certain diseases, such as breast cancer and Huntington's Disease, there is some debate over whether it is better to know about the risk of developing the disease ahead of time.

• The risk of breast cancer, as well as ovarian cancer, colon cancer, and prostate cancer, is increased in families that have mutations in the genes BRCA-1 and BRCA-2. BRCA-2 mutations may also be associated with an increased risk of developing melanoma, lymphoma, and cancers of the gallbladder, panceas, bile duct and stomach. ^[9] Testing a family member affected with a BRCA-related cancer and receiving a positive can then lead to testing other family members to determine risk. If the test is negative, the individual may be reassured that the chance of developing one of the relevant cancers is decreased. If the test is positive, prophylactic surgery or more frequent screening may be helpful in detecting disease at an earlier stage or preventing disease.
• Whether to have genetic testing for Huntington disease can be a more difficult decision. Huntington disease is an adult-onset disease which has autosomal dominant inheritance. Because symptoms do not generally present until the 40s, persons with Huntington's disease may have children before they know about the disease. Huntington disease has no cure and no preventive measures that can delay disease progression. The concern about genetic testing involves the psychological impact of a diagnosis of Huntington disease when nothing can be done to prevent or mitigate the disease. ^[10]

Controversy may arise when testing impacts a person's emotional state (depression or excessive worry when a test is positive). There is also a possibility of discrimination by insurance companies or employers if a positive test result is revealed. There are laws in place that are designed to prevent discrimination. Many people choose to pay for the test themselves in an attempt to keep the results private. A genetic counselor may be helpful in determining the risks and benefits of genetic testing.

References

1. ↑ http://ghr.nlm.nih.gov/handbook/illustrations/patterns?show=xlinkrecessivefather
2. ↑ http://ghr.nlm.nih.gov/handbook/illustrations/patterns?show=xlinkrecessivemother
3. ↑ Breastcancer.org web site. Cancer Risk and Abnormal Breast Cancer Genes
4. ↑ Cedars-Sinai Medical Genetics Institute web site. Applying the Latest in Medical Genetics to Patient Care and Research
5. ↑ Pharoah PD, Antoniou AC, Easton DF, Ponder BA. Polygenes, risk prediction, and targeted prevention of breast cancer. N Engl J Med. 2008 Jun 26;358(26):2796-803. Abstract | Full Text
6. ↑ Bradbury AR, Olopade OI. Genetic susceptibility to breast cancer. Rev Endocr Metab Disord. 2007 Sep;8(3):255-67. Epub 2007 May 17. Abstract
7. ↑ Healy DG, Falchi M, O'Sullivan SS, et al. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurol. 2008 Jul;7(7):583-590. Epub 2008 Jun 6. Abstract
8. ↑ Filley CM, Rollins YD, Anderson CA, et al. The genetics of very early onset Alzheimer disease. Cogn Behav Neurol. 2007 Sep;20(3):149-56. Abstract
9. ↑ National Cancer Institute web site. Genetic Testing for BRCA1 and BRCA2: It's Your Choice.
10. ↑ Meiser B, Dunn S. Psychological impact of genetic testing for Huntington's disease: an update of the literature. J Neurol Neurosurg Psychiatry. 2000 November; 69(5): 574–578. Abstract | PDF

External Links

National Human Genome Research Institute

Genetics and Public Policy Center

American College of Medical Genetics

U.S. National Library of Medicine: Genetics Home Reference

The Wellcome Trust (UK): The Human Genome

AccessDNA.com