A gene, the basic unit of heredity, is a segment of DNA containing all the information necessary to synthesize a polypeptide (protein) or a functional RNA molecule. Protein synthesis, folding, and tertiary and quaternary structure ultimately determine much of the body’s structure and function.
Humans have about 20,000 to 23,000 genes depending on how a gene is defined. Genes are contained in chromosomes in the cell nucleus and mitochondria. In humans, somatic (nongerm) cell nuclei normally have 46 chromosomes in 23 pairs. Each pair consists of one chromosome from the mother and one from the father. Twenty-two of the pairs, chromosome numbers 1 to 22, the autosomes, are normally homologous (identical in size, shape, and position and number of genes). The 23rd pair, the sex chromosomes (X and Y), determines a person’s sex as well as containing other functional genes. Women have 2 X chromosomes (which are homologous) in somatic cell nuclei; men have one X and one Y chromosome (which are heterologous).
The X chromosome carries genes responsible for many hereditary traits; the smaller Y chromosome carries genes that initiate male sex differentiation, as well as a few other genes. Because the X chromosome has many more genes than the Y chromosome, many X chromosome genes in males are not paired; in order to maintain a balance of genetic material between men and women, one of the X chromosomes in each cell of females is randomly inactivated early in fetal life (lyonization Lyon hypothesis (X-inactivation) Sex chromosome abnormalities may involve aneuploidy, partial deletions or duplications of sex chromosomes, or mosaicism. (See also Overview of Chromosomal Abnormalities.) Sex chromosome abnormalities... read more ). In some cells, the X from the mother is inactivated, and in others it is the X from the father. Once inactivation has taken place in a cell, all descendants of that cell have the same X inactivation. A karyotype illustrates the full set of chromosomes in a person’s cells.
Germ cells (egg and sperm) divide through meiosis, which reduces the number of chromosomes to 23—half the number in somatic cells. In meiosis, the genetic information inherited from a person’s mother and father is recombined through crossing over (exchange between homologous chromosomes). When an egg is fertilized by a sperm at conception, the normal number of 46 chromosomes is reconstituted.
Genes are arranged linearly along the DNA of chromosomes. Each gene has a specific location (locus), which is typically the same on each of the 2 homologous chromosomes. The genes that occupy the same locus on each chromosome of a pair (one inherited from the mother and one from the father) are called alleles. Each gene consists of a specific DNA sequence; 2 alleles may have slight differences or the same DNA sequences. Having a pair of identical alleles for a particular gene is homozygosity; having a pair of nonidentical alleles is heterozygosity. Some genes occur in multiple copies that may be next to each other or in different locations in the same or different chromosomes.
Structure of DNA
DNA (deoxyribonucleic acid) is the cell’s genetic material, contained in chromosomes within the cell nucleus and mitochondria.
Except for certain cells (for example, sperm and egg cells and red blood cells), the cell nucleus contains 23 pairs of chromosomes. A chromosome contains many genes. A gene is a segment of DNA that provides the code to construct a protein or RNA molecule.
The DNA molecule is a long, coiled double helix that resembles a spiral staircase. In it, two strands, composed of sugar (deoxyribose) and phosphate molecules, are connected by pairs of four molecules called bases, which form the steps of the staircase. In the steps, adenine is paired with thymine and guanine is paired with cytosine. Each pair of bases is held together by a hydrogen bond. A gene consists of a sequence of bases. Sequences of three bases code for an amino acid (amino acids are the building blocks of proteins) or other information.
Genes consist of DNA. The length of the gene determines the length of the protein or RNA synthesized from the gene code. DNA is a double helix in which nucleotides (bases) are paired:
Adenine (A) is paired with thymine (T)
Guanine (G) is paired with cytosine (C)
DNA is transcribed during protein synthesis, in which one strand of DNA is used as a template against which messenger RNA (mRNA) is synthesized. RNA has the same base pairs as DNA, except that uracil (U) replaces thymine (T). mRNA molecules travel from the nucleus to the cytoplasm and then to a ribosome, where protein synthesis occurs. Transfer RNA (tRNA) brings each amino acid back to the ribosome where it is added to the growing polypeptide chain in a sequence determined by the mRNA. As a chain of amino acids is assembled, it folds upon itself to create a complex 3-dimensional structure under the influence of nearby chaperone molecules.
The code in DNA is written in triplets containing 3 of the 4 possible nucleotides. Specific amino acids are coded by specific triplets termed codons. Because there are 4 nucleotides, the number of possible triplets is 43 (64). Because there are only 20 amino acids, there are redundant (extra) triplet combinations. Some triplets code for the same amino acids as other triplets. Other triplets may code for elements such as instructions to start or stop protein synthesis and the order in which to combine and assemble amino acids.
Genes consist of exons and introns. For protein-coding genes, exons code for amino acid components of the final protein. Introns contain other information that regulates the speed of protein production and the type of protein produced. Exons and introns together are transcribed onto mRNA, but the segments transcribed from introns are later spliced out. Many factors regulate transcription, including antisense RNA, which is synthesized from the DNA strand that is not transcribed into mRNA. In addition to DNA, chromosomes contain histones and other proteins that affect gene expression (which proteins and how many proteins are synthesized from a given gene).
Genotype refers to a specific genetic composition and sequence; it determines which proteins are coded for production.
Genome refers to the entire composition of a set of haploid chromosomes (single strand), including the genes they contain.
Phenotype refers to the entire physical, biochemical, and physiologic makeup of a person—ie, how the cell (and thus the body) functions. Phenotype is determined by a complex interaction of multiple factors including genotype, environmental factors, and the types and amounts of proteins actually synthesized, ie, how the genes are actually expressed. Specific genotypes may or may not correlate well with phenotype.
Expression refers to the process in which the information encoded in a gene is used to control the assembly of a molecule (usually protein or RNA). Gene expression depends on multiple factors such as whether a trait is dominant or recessive, the penetrance and expressivity of the gene (see Factors Affecting Gene Expression Factors Affecting Gene Expression Many factors can affect gene expression (and thus phenotypes). Some cause the expression of traits to deviate from the patterns predicted by Mendelian inheritance. (See also Overview of Genetics... read more ), degree of tissue differentiation (determined by tissue type and age), environmental factors, whether expression is sex-limited or subject to chromosomal inactivation or genomic imprinting, and other unknown factors.
Factors that affect gene expression without changing the genome sequence are epigenetic factors.
Knowledge of the many biochemical mechanisms that mediate gene expression is growing rapidly. One mechanism is variability in intron splicing (also called alternative splicing). During splicing, introns are spliced out and the remaining exons may be assembled in many combinations, resulting in many different mRNAs capable of coding for similar but different proteins. The number of proteins that can be synthesized by humans is > 100,000 even though the human genome has only about 20,000+ genes.
Other mechanisms mediating gene expression include DNA methylation and histone interactions involving methylation and acetylation. DNA methylation tends to silence gene expression. Histone proteins resemble spools around which DNA coils. Histone modifications such as acetylation or methylation can increase or decrease the expression of a particular gene. The strand of DNA that is not transcribed to form mRNA may also be used as a template for synthesis of RNA that controls transcription of the opposite strand.
Another important mechanism involves microRNAs (miRNAs). MiRNAs are short, hairpin-derived RNAs that repress target gene expression after transcription (hairpin refers to the shape the RNA sequences assume as they bind together). MiRNAs may be involved in regulation of as many as 60% of transcribed proteins.
Traits and Inheritance Patterns
A trait may be as simple as eye color or as complex as susceptibility to diabetes. Expression of a trait may involve one gene or many genes. Some single-gene defects Single-Gene Defects Genetic disorders determined by a single gene (Mendelian disorders) are easiest to analyze and the most well understood. If expression of a trait requires only one copy of a gene (one allele)... read more cause abnormalities in multiple tissues, an effect called pleiotropy. For example, osteogenesis imperfecta Osteogenesis Imperfecta Osteogenesis imperfecta is a hereditary collagen disorder causing diffuse abnormal fragility of bone and is sometimes accompanied by sensorineural hearing loss, blue sclerae, dentinogenesis... read more (a connective tissue disorder that often results from abnormalities in a single collagen gene) may cause fragile bones, deafness, blue-colored sclerae, dysplastic teeth, hypermobile joints, and heart valve abnormalities.
Construction of a family pedigree
The family pedigree (family tree) is used to diagram inheritance patterns. Pedigrees are commonly used in genetic counseling Prenatal Genetic Counseling Prenatal genetic counseling is provided for all prospective parents, ideally before conception, to assess risk factors for congenital disorders. Precautions to help prevent birth defects (eg... read more . The pedigree uses conventional symbols to represent family members and pertinent health information about them (see figure ). Some familial disorders with identical phenotypes have multiple patterns of inheritance.
Symbols for constructing a family pedigree
In the pedigree, symbols for each generation in the family are placed in a row and numbered with Roman numerals, starting with the older generation at the top and ending with the most recent at the bottom. Within each generation, people are numbered from left to right with Arabic numerals. Siblings are listed by age, with the oldest on the left. Thus, each member of the pedigree can be identified by 2 numbers (eg, II, 4). A spouse is also assigned an identifying number.
Phenotype is determined by a complex interaction of multiple factors including genotype, gene expression, and environmental factors.
Mechanisms regulating gene expression are being elucidated and include intron splicing, DNA methylation, histone modifications, microRNAs, and 3D genome organization.