Term	Definition
Allele	An alternative form of a gene. Each person receives two alleles of a gene, one from each biologic parent. Different alleles produce variations in inherited traits such as eye color and blood type.
Autosome	Any chromosome that is not a sex chromosome. Humans have 22 pairs of autosomes.
Carrier	Individual who carries a copy of a mutated gene for a recessive disorder.
Chromosome	A compact structure containing DNA and proteins present in nearly all cells of the body. Normally each cell has 46 chromosomes in 23 pairs. Each biologic parent contributes one of each pair of chromosomes.
Codominance	Two dominant versions of a trait that are both expressed in the same individual.
Congenital disorder	Condition present at birth.
Dominant allele	Gene that is expressed in the phenotype of a heterozygous individual.
Familial disorder	Condition that affects more than one person in a family.
Gene	The basic unit of heredity information located on a specific part of a chromosome. Genes direct cells to make proteins and guide almost every aspect of operation and repair of cells.
Genetic risk factor	A change in a gene that increases a person’s risk of developing a disease.
Genetics	Study of genes and their role in inheritance.
Genome	All the DNA contained in an individual.
Genome-wide association study (GWAS)	A study approach that involves scanning complete sets of DNA (genomes) of many individuals to find genetic variations associated with a particular disease.
Genomics	Study of how genes interact and influence people’s biologic and physical characteristics.
Genotype	Genetic identity of an individual. This identity does not show as outward characteristics.
Hereditary	Transmission of a disease, condition, or trait from parent to children.
Heterozygous	Having two different alleles for one given gene, one inherited from each parent.
Homozygous	Having two identical alleles for one given gene, one inherited from each parent.
Locus	Position of a gene on a chromosome.
Mutation	A change in DNA or a gene. Sometimes these changes are passed from parent to children.
Oncogene	Gene that is able to initiate and contribute to the conversion of normal cells to cancer cells.
Pedigree	Family tree that contains the genetic characteristics and disorders of that particular family.
Pharmacogenetics	Study of variability of responses to drugs related to variations in single genes.
Pharmacogenomics	Study of variability of responses to drugs related to variations in and interactions of multiple genes.
Phenotype	Observable traits or characteristics of an individual (e.g., hair color).
Protooncogene	Normal cellular genes that are important regulators of normal cellular processes. Mutations can activate them to become oncogenes.
Recessive allele	Allele that has no noticeable effect on the phenotype in a heterozygous individual.
Trait	Physical characteristic that one inherits, such as hair or eye color.
X-linked gene	Gene located on the X chromosome. In general, sex-linked disorders are only seen in males.

A person’s genes can have a profound impact on health and disease. More than 4000 diseases are thought to be related to altered genes. Genomic factors play a role in 9 of the 10 leading causes of death in the United States, including heart disease, cancer, diabetes, stroke, and Alzheimer’s disease.¹

Genomics may help us understand why some people who eat healthy diets and exercise regularly still die at a young age of cancer, whereas some people eat unhealthy diets and never exercise, and yet live to an old age.

The identification of a genetic basis for many human diseases has the potential to strongly influence the care of patients at risk for or diagnosed with a disease that has a genetic link. You need to know the basic principles of genetics, be familiar with the impact that genetics and genomics have on health and disease, and be prepared to assist the patient and family with genetic issues.

Basic Principles of Genetics

Genes.

Genes are the basic units of heredity. There are approximately 20,000 to 25,000 genes in each person’s genetic makeup, or genome. Genes encode (carry the instructions) for proteins that direct the activities of cells and functions of the body. Genes control how a cell functions, including how quickly it grows, how often it divides, and how long it lives. To control these functions, genes produce proteins that perform specific tasks and act as messengers for the cell. Therefore it is essential that each gene have the correct instructions or “code” for making its protein so that the protein can perform the proper function for the cell.²

Genes are arranged in a specific linear formation along a chromosome (Fig. 13-1). Each gene has a specific location on a chromosome, termed a locus. An allele is one of two or more alternative forms of a gene that occupy corresponding loci on homologous chromosomes (a pair of chromosomes having corresponding deoxyribonucleic acid [DNA] sequences, with one coming from the mother and the other from the father). Each allele codes for a specific inherited characteristic.

When there are two different alleles, the allele that is fully expressed is the dominant allele. The other allele that lacks the ability to express itself in the presence of a dominant allele is the recessive allele. Physical traits expressed by an individual are termed the phenotype, and the actual genetic makeup of the individual is termed the genotype.

Chromosomes.

Chromosomes are contained in the nucleus of a cell and occur in pairs. Humans have 23 pairs of chromosomes; 22 of the 23 pairs of chromosomes are homologous and are termed autosomes. Autosomes are the same in both males and females. The sex chromosomes make up the twenty-third pair of chromosomes. A female has two X chromosomes, and a male has one X and one Y chromosome. One chromosome of each pair is inherited from the mother and one from the father. One half of each child’s chromosomes (and therefore the genetic makeup) comes from his or her father and one half from his or her mother.

DNA.

Genes are made up of a nucleic acid called deoxyribonucleic acid (DNA). DNA stores genetic information and encodes the instructions for synthesizing specific proteins needed to maintain life. DNA also dictates the rate at which proteins are made. Every somatic cell in a person’s body has the same DNA.

The information in DNA is stored as a code made up of four nitrogenous bases: adenine (A), guanine (G), cytosine (C), and thymine (T). Human DNA consists of about 3 billion bases, and more than 99% of those bases are the same in all people. The order (or sequence) of these bases determines the information for building and maintaining an organism. This is similar to the way letters of the alphabet are used to create words and sentences.

DNA bases pair up with each other, A with T and C with G, to form units called base pairs. Each base is also attached to a sugar molecule and a phosphate molecule (Fig. 13-2). Together, a base, sugar, and phosphate are called a nucleotide. Nucleotides are arranged in two long strands that form a spiral called a double helix. The structure of the double helix is somewhat like a ladder, with the base pairs forming the ladder’s rungs and the sugar and phosphate molecules forming the ladder’s vertical sidepieces.

FIG. 13-2 DNA consists of two long, twisted chains made up of nucleotides. Each nucleotide contains one base, one phosphate molecule *(P),* and the sugar molecule deoxyribose *(S).* The bases in DNA nucleotides are adenine *(A),* thymine *(T),* cytosine *(C),* and guanine *(G).*

DNA can replicate (make copies of itself). Each strand of DNA in the double helix can serve as a pattern for duplicating the sequence of bases. When cells divide, each new cell needs to have an exact copy of the DNA that was in the parent (original) cell.

If the chromosomes in one of your cells were uncoiled and placed end-to-end, the DNA would be about 6 feet long. If all of the DNA in your body were connected, it would stretch about 67 billion miles.³

Inheritance Patterns

Genetic disorders can be categorized into autosomal dominant, autosomal recessive, or X-linked (sex-linked) recessive disorders (Table 13-2). If the mutant gene is located on an autosome, the genetic disorder is called autosomal. If the mutant gene is on the X chromosome, the genetic disorder is called X-linked.

TABLE 13-2

COMPARISON OF GENETIC DISORDERS

Characteristics	Examples
Autosomal Dominant
Males and females are affected * equally. More common than recessive disorders and usually less severe. Affected individuals show variable expression. Affected individuals may have an affected parent. Children of a heterozygous (affected) parent have a 50% chance of being affected. Individuals are affected in successive generations.	Breast and ovarian cancer related to BRCA genes Familial hypercholesterolemia Hereditary nonpolyposis colorectal cancer Huntington’s disease Neurofibromatosis Marfan’s syndrome
Autosomal Recessive
Males and females are affected equally. Heterozygotes are carriers and usually asymptomatic. Affected individuals may have unaffected † parents who are heterozygous for trait. Children of two heterozygous parents have 25% chance of being affected and 50% chance of being carriers (see Fig. 13-9). Frequently there is a no family history of disease.	Cystic fibrosis Phenylketonuria Sickle cell disease Tay-Sachs disease Thalassemia
X-Linked Recessive
Most affected individuals have unaffected parents. Affected individuals are usually males. Daughters of affected male are carriers. Sons of affected male are unaffected (unless mother is a carrier).	Duchenne muscular dystrophy Hemophilia Wiskott-Aldrich syndrome

^*Have the disease.

^†Do not have the disease.

Family pedigrees for autosomal recessive and dominant disorders and X-linked recessive disorders are shown in Figs. 13-4 and 13-5.

FIG. 13-4 Examples of family pedigrees showing inheritance of **(A)** autosomal dominant, **(B)** autosomal recessive, and **(C)** X-linked recessive disorders.

Autosomal dominant disorders are caused by a mutation of a single gene pair (heterozygous) on a chromosome. A dominant allele prevails over a normal allele. Autosomal dominant disorders show variable expression. Variable expression means that the symptoms expressed by the individuals with the mutated gene vary from person to person even though they have the same mutated gene. Although autosomal dominant disorders have a high probability of occurring in families, sometimes these disorders cause a new mutation or skip a generation. This is termed incomplete penetrance.

Autosomal recessive disorders are caused by mutations of two gene pairs (homozygous) on a chromosome. A person who inherits one copy of the recessive allele does not develop the disease because the normal allele predominates. However, this person is a carrier.

X-linked recessive disorders are caused by a mutation on the X chromosome. Usually only men are affected by this disorder because women who carry the mutated gene on one X chromosome have another X chromosome to compensate for the mutation. However, women who carry the mutated gene can transmit it to their offspring. It is possible for women to have X-linked recessive disorders, and this can occur when an affected male mates with an unaffected female carrier. This points to the importance of testing the carrier status of the female partner of affected males. X-linked dominant disorders do exist but are rare.

Multifactorial inherited conditions are caused by a combination of genetic and environmental factors. These disorders run in families but do not show the same inherited characteristics as the single gene mutation conditions. Multifactorial conditions include diabetes mellitus, obesity, hypertension, cancer, and coronary artery disease.

Human Genome Project

The Human Genome Project (HGP), which was completed in 2003, mapped the entire human genome.⁵ Analysis of the data will continue for many years. The knowledge gained through the HGP will (1) help improve the diagnosis of diseases, (2) allow for earlier detection of genetic predisposition to diseases, and (3) play a critical role in determining risk assessment for genetic-related diseases. In addition, the results of the HGP assist in matching organ donors with transplant recipients.

Genetic Disorders

A genetic disorder is caused in whole or in part by an alteration in the DNA sequence. As discussed in the section on genetic mutations (pp. 192-193), genetic disorders can be inherited (person born with altered genetic code) or they can be acquired (e.g., replication errors, damage to DNA from toxins). Genetic disorders can be caused by (1) a mutation in one gene (single gene disorder); (2) mutations in multiple genes (multifactorial inheritance disorder), which are often related to environmental factors; or (3) damage to chromosomes (changes in the number or structure of entire chromosomes).

Classification of Genetic Disorders

Single Gene Disorders.

Some genetic disorders result from a single gene mutation (Fig. 13-6, A). Examples of these diseases include cystic fibrosis, sickle cell disease, and polycystic kidney disease. The pattern of inheritance for single gene disorders can be autosomal dominant, autosomal recessive, or X-linked. Single gene disorders are relatively rare compared with more commonly occurring multifactorial genetic disorders such as diabetes mellitus and heart disease.