The expression of genes within the human genome is controlled by a number of different mechanisms. Promoters, enhancers and silencers are segments of DNA that regulate the rate and amount of transcription, or expression, of nearby genes. Transcription is the process of synthesizing RNA as a messenger in order to implement the instructions encoded within DNA. Promoters are generally located immediately upstream from the first exon (coding segment of DNA) of a gene. Enhancers are genetic elements that increase transcription of associated genes. Silencers are genetic elements that suppress transcription of associated genes. Enhancers and silencers can be located some distance away from a promoter, may be upstream or downstream of the promoter on which they act, and can be effective even at considerable genetic distances.

Methylation is another mechanism of gene regulation. In methylation, portions of the DNA molecule, particularly regions of the DNA that control transcription are chemically modified through the action of enzymes called DNA methyltransferases. DNA methyltransferases attach a methyl group (CH₃) to the 5^th position carbon of cytosine bases, typically when cytosines occur in the context of C-G dinucleotides, sometimes referred to as CpG islands. Methylation of DNA usually results in the silencing or suppression of gene expression. Alternatively, a lack of methylation is usually associated with an active state of gene expression. Methylation is crucial for the regulation of gene expression and control of cellular growth throughout life, from embryonic development to adulthood. Methylation also is crucial for X-chromosome inactivation and imprinting.

Imprinting is a form of gene silencing whereby individual genes or groups of genes are methylated during gametogenesis to impart parent of origin effects on gene expression. For example, if a gene is maternally imprinted, (that is silenced in the maternal copy during female gametogenesis) only the paternal copy of the gene is expressed in the child. Paternal imprinting of genes also occurs. During gametogenesis, parental imprints are erased and reset in a manner consistent with whether the gametogenesis is occurring in a male or a female. A number of human genetic diseases occur because of mutations in imprinted genes or in the genetic control sequences responsible for setting, resetting or controlling imprinted regions. Such diseases include Angelman syndrome and Prader-Willi syndrome, which occur because of mutations in imprinted genes or errors in imprinting of genes on chromosome 15. These disorders also can be caused when errors in mitosis or meiosis produce a child who inherits both copies of his or her chromosome 15 from a single parent, resulting in inheritance of only imprinted copies of the genes involved and no active copy. This phenomenon is called uniparental disomy, or UPD.

Another type of genetic regulation is exerted at the level of RNA processing through a mechanism called alternative splicing. In alternative splicing, certain exons (coding segments of DNA) of a gene may be alternately included in the final mRNA product. In this way, inclusion of particular exons only in certain tissues or only at certain times during development permits cells to modify the performance characteristics of a particular protein, thereby altering the function or effect of a protein in a cell or tissue. As shown in the graphic, this precursor RNA is alternatively spliced into 3 different isoforms. Isoform 1 contains all 4 exons; isoform 2 contains only exons 1, 2, and 4; and, isoform 3 contains only exons 1 and 4.

Various factors, including DNA sequences, also contribute to the rate of production and stability of mRNAs. By controlling the rate at which new mRNAs are transcribed from a particular gene and the decay kinetics of a mRNA (the rate at which a mRNA is degraded within a cell), cells exert control over the amount of protein that is made from an mRNA, thereby influencing the level of particular proteins within cells and tissues. Different mRNAs have different decay kinetics, meaning that some are degraded very quickly and others are degraded much more slowly. For example, the mRNAs of many cellular growth factors and transcription factors are degraded very quickly, resulting in tight control of the temporal aspects of their cellular signaling properties. On the other hand, mRNAs that encode enzymes can be much longer lived.

During X-inactivation, most genes on one of the X chromosomes of a female are inactivated in a mechanism that provides dosage compensation to equalize the level of gene expression of most X-linked genes in females to that of males who have only one X chromosome. This process, often called Lyonization, results in the formation of a Barr body, the highly compacted, inactive X chromosome. In the photograph, Barr bodies are shown by arrows. The form of DNA in the inactive X-chromosome is called heterochromatin.

In human females, one X chromosome or the other is inactivated in each cell early in development. As a result, some human female cells have one X chromosome active, while the rest of the cells have the other X chromosome active. Typically, X-inactivation is random, or near random, meaning that roughly half of a female's cells express the genes of one X chromosome and the other half of her cells express genes from the other X chromosome. However, in some females, X-inactivation is not random, but skewed. In cases of nonrandom, or skewed X-inactivation, all or most cells of a female express X-linked genes from a single X chromosome. In reality, nonrandom X-inactivation may be less representative of the process of X-inactivation than of reduced survival of cells with a particular X chromosome inactivated, making it appear that X-inactivation was nonrandom.

In some cases, females who carry X-linked genetic diseases can be affected by those diseases, if X-inactivation is not random. For example, if a structural abnormality disrupts the pattern of X-inactivation, then most or all of a female's cells will express genes from a single X chromosome. If there are genes that are disrupted by the structural abnormality, and those genes cause a disorder, the female can show symptoms of the disorder. For many X-linked disorders, females will show mild to moderate symptoms. This milder manifestation of an X-linked disorder in females may be related, in part, to the fact that most females have, in addition to a large number of cells expressing the abnormal gene, a large number of cells expressing the normal gene. Symptoms remain milder than those seen in affected males who carry no normal copy of the gene because they carry only a single X chromosome.

Some genes on the inactive X chromosome escape inactivation and remain active in females. These genes are believed to be responsible for many traits of normal females. The lack of these genes in females missing all or parts of a second X chromosome, as occurs in many cases of Turner syndrome, are thought to be associated with many of the clinical features of the syndrome.

The RNA molecules made within eukaryotic cells must be processed before they can be used as messengers of the DNA code. Eukaryotic genes contain introns that must be removed. Introns are non-coding segments of DNA, of variable size, that separate the coding segments, or exons, of the genes of eukaryotic organisms. During RNA processing, the introns are removed from RNA molecules in a complex process called splicing. In addition, a methyl group called a 5' cap is attached to the 5' end of the RNA, and a polyA tail is added to the 3' end of the RNA in a process called polyadenylation. The resulting processed RNA is called a messenger RNA (mRNA). Processed mRNAs migrate from the nucleus (the site of their transcription and modification) to the cytoplasm for translation by ribosomes.

Prokaryotic genes typically do not contain introns, although there are some exceptions. As such, there is usually no splicing of RNA molecules in prokaryotic cells. Prokaryotic RNAs also are not capped or polyadenylated as are eukaryotic RNAs. Further, in prokaryotic cells, there is no nucleus to separate the processes of transcription and translation, so transcription and translation often occur simultaneously, with RNA molecules being translated into proteins as they are being transcribed from the prokaryotic DNA. A newly discovered branch of the tree of life is the domain Archaea. Members of the domain Archaea are prokaryotes, as are bacteria. However, some genes of members of the domain Archaea have introns and share other structural and functional similarities with eukaryotes (organisms with a cell nucleus surrounded by a membrane).

After processing, messenger RNA (mRNA) is transported from the nucleus of eukaryotic cells to the cytoplasm, where it comes into contact with ribosomes, the protein-making machinery of the cell. Ribosomes progress down the mRNA strand, in a 5’ to 3’ direction, creating a protein as they go. Ribosomes are complex structures made of protein and RNA, and can be found floating freely within the cytoplasm of eukaryotic cells or attached to the rough endoplasmic reticulum (RER).

Transfer RNA (tRNA) is the mediator for translation. tRNAs of eukaryotes are transcribed by an enzyme called RNA polymerase III. Like mRNAs, tRNAs undergo processing, but the processing of tRNAs is somewhat different from that of mRNA. tRNAs are cleaved from precursor RNAs and modified by the addition of nucleotides to their 3’ ends, and by methylation and other enzymatic modifications of certain ribonucleotides. The tRNA precursors of eukaryotes also contain an intron that must be removed by splicing.

tRNAs include an anti-codon loop, which contains a three-nucleotide long segment of RNA that binds to a complementary three-nucleotide long segment in an mRNA called a codon. tRNAs also have an attached amino acid. When a tRNA anti-codon associates, under the guidance of the ribosome, with its complementary mRNA codon, the amino acid attached to the tRNA is transferred from the tRNA to the growing protein molecule. As the ribosome moves down the mRNA molecule, additional tRNA molecules come in, bind to the codons embedded within the nucleotide sequence of the mRNA, and add amino acids to the growing protein, as specified by the nucleotide sequence of the mRNA and the gene from which it was transcribed.

Another class of RNAs, called ribosomal RNAs, are components of ribosomes. The ribosomal RNAs, rRNAs, of eukaryotes are transcribed by an enzyme called RNA polymerase I and also are processed before assembly into ribosomes.

Multifactorial disorders, which include common complex disorders, are characterized by the interaction of multiple genetic and/or environmental factors that influence the expression of a disorder. Although common complex disorders may not show a clear pattern of inheritance like Mendelian disorders do, there is typically a familial aggregation of the disorder. That is, close relatives of an affected individual may be at increased risk for the disorder, compared to the general population. Examples of multifactorial diseases include some forms of diabetes, high blood pressure, and obesity.

Disorders associated with a new mutation occur when a mutation happens prior to or during gametogenesis, or after fertilization. The mutation is found in the child but not in either parent. Timing of occurrence of the mutation is important to the tissue distribution of the mutated gene, the symptomatic expression of the disease, the risk for additional affected offspring of the parents, and the risk for future offspring of the affected individual. For example, if a mutation occurs in the gonadal tissues of an individual with a new mutation, there is an increased risk to future offspring of that person. An advanced paternal age effect is characteristic of some new mutation genetic diseases. Examples of diseases with a high new mutation rate include achondroplasia, Marfan syndrome, Waardenburg syndrome, and neurofibromatosis. These all are dominant disorders. Although recessive new mutations surely occur, it is far more likely that both parents of an individual affected by a recessive disorder are carriers of the recessive mutations.

Imprinting is a form of gene silencing whereby certain genes are methylated during gametogenesis (formation of egg and sperm) to impart parent of origin effects on gene expression. For example, if a gene is maternally imprinted (that is, silenced in the maternal copy during female gametogenesis), only the paternal copy of the gene is expressed in the child. Paternal imprinting of genes also occurs. During gametogenesis, parental imprints are erased and reset, in a manner consistent with whether the gametogenesis is occurring in a male or a female.

A number of human genetic diseases occur because of mutations in imprinted genes or in the control sequences responsible for setting, resetting or controlling imprinted regions. For example, if a person carries a mutation in an imprinted gene, the disease will be expressed only if the mutation is inherited from the parent whose gene is expressed. Imagine a mutation in a gene that is imprinted in the maternal genome. If a mutation in this gene is inherited from one's mother, the disease will not occur because it is the father's gene that is expressed. However, if the mutation is inherited from one's father, the disease will be evident.

Another source of abnormalities in imprinted genes involves the imprinting centers (DNA sequences) that control the establishment of an imprint and the switching of imprints in gametogenesis. Mutations in imprinting centers can result in disease because of failure to erase the grandparental imprint during gametogenesis. Examples of disorders associated with imprinted genes include Angelman syndrome and Prader-Willi syndrome. These disorders can also be caused when errors in meiosis result in a child who inherits both copies of his or her chromosome 15 from a single parent, resulting in inheritance of only imprinted copies of the gene. This phenomenon is called uniparental disomy, or UPD.

The appearance of a genetic disease at progressively earlier ages of onset and with increasing severity in successive generations of a family is called anticipation. The molecular genetic phenomenon behind anticipation is a length expansion of repetitive DNA sequences within a gene such as triplet (three nucleotide) repeats during transmission of the gene from generation to generation. These expansions cause increased severity of the disease with growing repeat length. Examples of diseases that show anticipation include myotonic dystrophy, Fragile X syndrome and Huntington disease.