Genetic Control of Cell Function

Genetic information is stored in the structure of deoxyribonucleic acid (DNA). DNA is an extremely stable macromolecule found in the nucleus of each cell. Because of the stable structure of DNA, the genetic information can survive the many processes of reduction division, in which the gametes (i.e., ovum and sperm) are formed, and the fertilization process. This stability is also maintained throughout the many mitotic cell divisions involved in the formation of a new organism from the single-celled fertilized ovum called the zygote. The term gene is used to describe a part of the DNA molecule that contains the information needed to code for the types of proteins and enzymes needed for the day-to-day function of the cells in the body. Genetic Control of Cell Function The genetic information needed for protein synthesis is encoded in the DNA contained in the cell nucleus. A second type of nucleic acid, ribonucleic acid (RNA), is involved in the actual synthesis of cellular enzymes and proteins. Cells contain several types of RNA: messenger RNA, transfer RNA, and ribosomal RNA. Messenger RNA (mRNA) contains the transcribed instructions for protein synthesis obtained from the DNA molecule and carries them into the cytoplasm.

The nuclei of all the cells in an organism contain the same accumulation of genes derived from the gametes of the two parents, genetic disorders are attributed to defects in mitochondrial DNA. Gene Structure The structure that stores the genetic information in the nucleus is a long, double-stranded, helical molecule of DNA. DNA is composed of nucleotides, which consist of phosphoric acid, a five-carbon sugar called deoxyribose, and one of four nitrogenous bases. Several hundred to almost one million base pairs can represent a gene; the size is proportional to the protein product it encodes. Of the two DNA strands, only one is used in transcribing the information for the cells polypeptide-building machinery. The genetic information of one strand is meaningful and is used as a template for transcription; the complementary code of the other strand does not make sense and is ignored. Genetic Code The four basesguanine, adenine, cytosine, and thymine (uracilis substituted for thymine in RNA) make up the alphabet of the genetic code. This triplet code is called a codon . An example is the nucleotide sequence GCU (guanine, cytosine, and uracil), which is the triplet RNA code for the amino acid alanine. Stop codes, which signal the end of a protein molecule, are also present. Gene Mutations Rarely, accidental errors in duplication of DNA occur. These errors are called mutations. Mutations result from the substitution of one base pair for another, the loss or addition of one or more base pairs, or rearrangements of base pairs. Many of these mutations occur spontaneously; others occur because of environmental agents, chemicals, and radiation.

CHROMOSOMES Most genetic information of a cell is organized, stored, and retrieved in small intracellular structures called chromosomes. Although the chromosomes are visible only in dividing cells, they retain their integrity between cell divisions. The chromosomes are arranged in pairs; one member of the pair is inherited from the father, the other from the mother. Each species has a characteristic number of chromosomes. In the human, 46 single or 23 pairs of chromosomes are present. Of the 23 pairs of human chromosomes, there are 22 pairs called autosomes that are alike in males and females. Each of the 22 pairs of autosomes has the same appearance in all individuals, and each has been given a numeric designation for classification purposes. The sex chromosomes make up the 23rd pair of chromosomes. Two sex chromosomes determine the sex of a person. All males have an X and Y chromosome (i.e., an X chromosome from the mother and a Y chromosome from the father); all females have two X chromosomes (i.e., one from each parent). Only one X chromosome in the female is active in controlling the expression of genetic traits; Chromosome Structure Cytogenetics is the study of the structure and numeric characteristics of the cells chromosomes. Chromosome studies can be done on any tissue or cell that grows and divides in culture. Lymphocytes from venous blood are frequently used for this purpose. After the cells have been cultured, a drug called colchicines is used to arrest mitosis in metaphase. In the metaphase spread, each chromosome takes the form of chromatids to form an X or wishbone pattern. Patterns of Inheritance Definitions Genetics has its own set of definitions. The genotype of a person is the genetic information stored in the base sequence triplet code. The phenotype refers to the recognizable traits, physical or biochemical, associated with a specific genotype. Expressivity refers to the manner in which the gene is expressed in the phenotype, which can range from mild to severe. Penetrance represents the ability of a gene to express its function. Seventy-five percent penetrance means 75% of persons of a particular genotype demonstrate a recognizable phenotype. Transmission of Genetic Information The transmission of information from one generation to the next is vested in genetic material transferred from each parent at the time of conception. Alleles are the alternate forms of a gene (one from each parent), and the locus is the position that they occupy on the chromosome. The genotype of a person represents the sum total of the genetic information in the cells and the phenotype the physical manifestations of that information. Penetrance is the percentage in a population with a particular genotype in which that genotype is phenotypically manifested, whereas expressivity is the manner in which the gene is expressed. Genetic Imprinting Besides autosomal and sex-linked genes and mitochondrial inheritance, it was found that certain genes exhibit a parent of origin type of transmission, in which the parental genomes do not always contribute equally in the development of an individual. 2

 An example of a disorder involving parenteral imprinting is uniparental disomy. This occurs when two chromosomes of the same number are inherited from one parent. Mendels Laws The main feature of inheritance is predictability: given certain conditions, the likelihood of the occurrence or recurrence of a specific trait is remarkably predictable. The units of inheritance are the genes, and the pattern of single-gene expression often can be predicted using Mendels laws of genetic transmission. Mendel discovered the basic pattern of inheritance by conducting carefully planned experiments with simple garden peas. Experimenting with several phenotypic traits in peas, Mendel proposed that inherited traits are transmitted from parents to offspring by means of independently inherited factors now known as genesand that these factors are transmitted as recessive and dominant traits. Mendel labeled dominant factors (his round peas) A and recessive factors (his wrinkled peas) a. Geneticists continue to use capital letters to designate dominant traits and lowercase letters to identify recessive traits. Persons in whom the two alleles of a given pair are the same (AA or aa) are called homozygotes. Heterozygotes have different alleles (Aa) at a gene locus. A recessive trait is one expressed only in a homozygous pairing; a dominant trait is one expressed in either a homozygous or a heterozygous pairing. All persons with a dominant allele (depending on the penetrance of the genes) Gene Therapy Two main approaches are used in gene therapy: transferred genes either replace defective genes or selectively inhibit deleterious genes. Cloned DNA sequences or ribosomes usually are the compounds used in gene therapy. However, the introduction of the cloned gene into the multicellular organism can influence only the few cells that get the gene. An answer to this problem would be the insertion of the gene into a sperm or ovum; after fertilization, the gene would be replicated in all of the differentiating cell types. DNA Fingerprinting DNA fingerprinting, which relies on recombinant DNA technologies and those of genetic mapping, is often used in forensic investigations.

Genetic and Congenital Disorders

Congenital defects, sometimes called birth defects, develop during prenatal life and usually are apparent at birth or shortly thereafter. Spina bifida and cleft lip, Birth defects, which affect more than 150,000 infants each year, are the leading cause of infant death.1 Birth defects may be caused by genetic factors (i.e., single-gene or multifactorial inheritance or chromosomal aberrations), or they may be caused by environmental factors that occurred during embryonic or fetal development (i.e., maternal disease, infections, or drugs taken during pregnancy). Genetic & Chromosomal Disorders Genetic disorders involve a permanent change (or mutation) in the genome. A genetic disorder can involve a single-gene trait, multifactorial inheritance, or a chromosome disorder.

Single-Gene Disorders 3

 Single-gene disorders are caused by a single defective or mutant gene. The defective gene may be present on an autosome or the X chromosome and it may affect only one member of an autosomal gene pair (matched with a normal gene) or both members of the pair. The genes on each chromosome are arranged in pairs and in strict order, with each gene occupying a specific location or locus. If the members of a gene pair are identical (i.e., code the exact same gene product), the person is homozygous, and if the two members are different, the person is heterozygous. If the trait is expressed in the heterozygote (one member of the gene pair codes for the trait), it is said to be dominant; if it is expressed only in the homozygote (both members of the gene pair code for the trait), it is recessive. Single-gene disorders are characterized by their patterns of transmission, which usually are obtained through a family genetic history. The patterns of inheritance depend on whether the phenotype is dominant or recessive, and whether the gene is located on an autosomal or sex chromosome Autosomal Dominant Disorders In autosomal dominant disorders, a single mutant allele from an affected parent is transmitted to an offspring regardless of sex. The affected parent has a 50% chance of transmitting the disorder to each offspring. The unaffected relatives of the parent or unaffected siblings of the offspring do not transmit the disorder. In many conditions, the age of onset is delayed, and the signs and symptoms of the disorder do not appear until later in life, as in Huntingtons chorea Autosomal Recessive Disorders Autosomal recessive disorders are manifested only when both members of the gene pair are affected. In this case, both parents may be unaffected but are carriers of the defective gene. Autosomal recessive disorders affect both sexes. The occurrence risk in each pregnancy is one in four for an affected child, two in four for a carrier child, and one in four for a normal (noncarrier, unaffected) homozygous child Phenylketonuria Phenylketonuria is a genetically inherited enzyme defect. It is characterized by a deficiency of phenylalanine hydroxylase, the enzyme needed for conversion of phenylalanine to tyrosine. As a result of this deficiency, toxic levels of phenylalanine accumulate in the blood. Like other inborn errors of metabolism, PKU is inherited as a recessive trait and is manifested only in the homozygote. Untreated, PKU results in severe mental retardation. Tay-Sachs Disease Tay-Sachs disease is a variant of a class of lysosomal storage diseases, known as gangliosidoses, in which substances (gangliosides) found in membranes of nervous tissue are deposited in neurons of the central nervous system and retina because of a failure of lysosomal degradation.4,5. The disease is particularly prevalent among eastern European (Ashkenazi) Jews. Infants with Tay-Sachs disease appear normal at birth but begin to manifest progressive weakness, muscle flaccidity, and decreased attentiveness at approximately 6 to10 months of age. This is followed by rapid deterioration of motor and mental function, often with development of generalized seizures. Retinal involvement leads to visual impairment and eventual blindness. Death usually occurs before 4 years of age. 4

X-Linked Disorders Sex-linked disorders are almost always associated with the X, or female, chromosome, and the inheritance pattern is predominantly recessive. Because of a normal paired gene, female heterozygotes rarely experience the effects of a defective gene. The common pattern of inheritance is one in which an unaffected mother carries one normal and one mutant allele on the X chromosome. This means that she has a 50% chance of transmitting the defective gene to her sons, and her daughters have a 50% chance of being carriers of the mutant gene. Fragile X Syndrome Fragile X syndrome is an X-linked disorder associated with a fragile site on the X chromosome where the chromatin fails to condense during mitosis. As with other X-linked disorders, fragile X syndrome affects males more often than females. The disorder, which affects approximately 1 in 1000 male infants, is the second most common cause of mental retardation, after Down syndrome. Affected males are mentally retarded and share a common physical phenotype that includes a long face with large mandible; large, everted ears; and large testicles (macroorchidism). Hyperextensible joints, a high-arched palate, and mitral valve prolapse, Multifactorial Inheritance Disorders Multifactorial inheritance disorders are caused by multiple genes and, in many cases, environmental factors. The exact number of genes contributing to multifactorial traits is not Multifactorial inheritance has been described as a threshold phenomenon in which the factors contributing to the trait might be compared with water filling a glass. Although multifactorial traits cannot be predicted with the same degree of accuracy as the mendelian single-gene mutations, characteristic patterns exist. First, multifactorial congenital malformations tend to involve a single organ or tissue derived from the same embryonic developmental field. Second, the risk of recurrence in future pregnancies is for the same or a similar defect. This means that parents of a child with a cleft palate defect have an increased risk of having another child with a cleft palate, but not with spina bifida. Third, the increased risk (compared with the general population) among first-degree relatives of the affected person is 2% to 7%, and among second-degree relatives, it is approximately one-half that amount. Chromosomal Disorders Chromosomal disorders form a major category of genetic disease, accounting for a large proportion of reproductive wastage (early gestational abortions), congenital malformations, and mental retardation. During cell division (i.e., mitosis) in nongerm cells, the chromosomes replicate so that each cell receives a full diploid number. Alterations in Chromosome Duplication Mosaicism is the presence in one individual of two or more cell lines characterized by distinctive karyotypes. This defect results from an accident during chromosomal duplication. Alterations in Chromosome Number A change in chromosome number is called aneuploidy. Among the causes of aneuploidy is failure of the chromosomes to separate during oogenesis or spermatogenesis. 5

 Monosomy refers to the presence of only one member of a chromosome pair. The defects associated with monosomy of the autosomes are severe and usually cause abortion. Monosomy of the X chromosome (45,X/O), or Turners syndrome, causes less severe defects. Polysomy, or the presence of more than two chromosomes to a set, occurs when a germ cell containing more than 23 chromosomes is involved in conception. This defect has been described for the autosomes and the sex chromosomes. Trisomies of chromosomes 8, 13, 18, and 21 are the more common forms of polysomy of the autosomes. Disorders Due to Environmental Influences The developing embryo is subject to many nongenetic influences. After conception, development is influenced by the environmental factors that the embryo shares with the mother. The physiologic status of the motherher hormone balance, her general state of health, her nutritional status, and the drugs she takes undoubtedly influences the development of the unborn child. For example, diabetes mellitus is associated with increased risk of congenital anomalies. Smoking is associated with lower than normal neonatal weight. Period of Vulnerability The embryos development is most easily disturbed during the period when differentiation and development of the organs are taking place. This time interval, which is often referred to as the period of organogenesis, extends from day 15 to day 60 after conception. Environmental influences during the first 2 weeks after fertilization may interfere with implantation and result in abortion or early resorption of the products of conception. Teratogenic Agents A teratogenic agent is an environmental agent that produces abnormalities during embryonic or fetal development. It is important to remember that, in this case, the environment is that of the embryo and fetus. Maternal disease or altered metabolic state also can affect the environment of the embryo or fetus. For discussion purposes, teratogenic agents have been divided into three groups: radiation, drugs and chemical substances, and infectious agents. Environmental agents can cause birth defects in three ways: by direct exposure of the pregnant woman and the embryo or fetus to the agent; through exposure of the soonto-be-pregnant woman with an agent that has a slow clearance rate such that a teratogenic dose is retained during early pregnancy; or as a result of mutagenic effects of an environmental agent that occur before pregnancy, causing permanent damage to a womans (or a mans) reproductive cells. Radiation Heavy doses of ionizing radiation have been shown to cause microcephaly, skeletal malformations, and mental retardation. There is no evidence that diagnostic levels of radiation cause congenital abnormalities. Radiation is teratogenic and mutagenic, and there is the possibility of effecting inheritable changes in genetic materials. Administration of therapeutic doses of radioactive iodine (131I) duringthe 13th week of gestation, the time when the fetal thyroid is beginning to concentrate iodine, has been shown to interfere with thyroid development. Chemicals and Drugs Environmental chemicals and drugs can cross the placenta and cause damage to the developing embryo and fetus. It has been estimated that only 2% to 3% of developmental defects have a known drug or environmental origin. 6

 They may produce cytotoxic (cell-killing), antimetabolic, or growth inhibiting properties. Often their effects depend on the time of exposure (in terms of embryonic and fetal development) and extent of exposure (dosage). The molecular weight of a drug also influences the rate of transfer and the amount of drug transferred across the placenta. Folic Acid Deficiency Although most birth defects are related to exposure to a teratogenic agent, deficiencies of nutrients and vitamins also may be a factor. Folic acid deficiency has been implicated in the development of neural tube defects (e.g., anencephaly, spina bifida, encephalocele). The Public Health Service recommends that all women of childbearing age should take 400 micrograms (g) of folic acid daily. It has been suggested that this recommendation may help to prevent as many as 50% of neural tube defects. Infectious Agents Many microorganisms cross the placenta and enter the fetal circulation, often producing multiple malformations. The acronym TORCH stands for toxoplasmosis, other, rubella (i.e., German measles), cytomegalovirus, and herpes, which are the agents most frequently implicated in fetal anomalies. The TORCH screening test examines the infants serum for the presence of antibodies to these agents. These infections tend to cause similar clinical manifestations, including microcephaly, hydrocephalus, defects of the eye, and hearing problems.