In this slide set, we will explore the structures and functions of genomes, including the genomes of eukaryotes, prokaryotes and viruses. We also will explore the human genome in depth and learn how changes in the structure or number of chromosomes in the human genome lead to certain genetic disorders.

Illustration:
The image on this slide is a photograph of the model of the DNA molecule built by Drs. James Watson and Francis Crick in 1953. Drs. Watson and Crick used this model to depict their proposed structure for the DNA double helix. The hypothesized structure was derived from X-ray diffraction data produced by Drs. Maurice Wilkins and Rosalind Franklin. The model was constructed from metal scraps obtained from a machine shop.

Drs. Watson and Crick published their proposed DNA structure in the journal, Nature, on April 2, 1953 (Volume 171, page 737). For their work, Drs. Watson, Crick and Wilkins were awarded the Nobel Prize in Physiology or Medicine in 1962. Dr. Franklin died before 1962. Since Nobel Prizes are awarded only to living individuals, she could not be honored.

Each chromosome of a living cell is a DNA double helix. The atoms that make up DNA are organized into two primary molecular components: bases and pentose sugars with attached phosphate groups. The bases are the key informational components of DNA, the letters of the DNA alphabet. The bases of DNA include adenine (A), cytosine (C), guanine (G), and thymine (T). Each base consists of a nitrogen-containing component called an amine. The side groups attached to the amines differ among the bases. The pentose sugars and phosphate groups serve as the links that connect the bases in a string, or strand, of DNA. When DNA strands form a double-stranded molecule, two strands of DNA are joined together through hydrogen bonds that form between the bases. In the double-stranded DNA molecule, an A base always pairs with a T base and a C base always pairs with a G base. Once joined, the bases are referred to as base pairs.

Embedded within the DNA sequence of each chromosome are the organism’s genes. The chromosome can be thought of as the DNA scaffolding within which the genes reside. An organism’s set of chromosomes is called its genome. Genes are interspersed unevenly along the lengths of most eukaryotic chromosomes. Across the human genome, for example, there are gene-rich regions and gene-poor regions.

The genomes of most eukaryotes are fairly large and often complex. In addition to genes themselves, most eukaryotic genomes also contain a variety of non-coding structural and regulatory elements and introns. Some of the genetic material also serves as a fossil record, a history book written in biological terms and handed down from generation to generation.

In addition to the DNA inside the cell nucleus, eukaryotic cells have separate genetic material in certain organelles such as mitochondria and, in plants, chloroplasts. In general, organelles, prokaryotes and viruses have greater biological constraints than nuclei on the tolerable sizes of their genomes because of the small genome size that can be incorporated into the organelle, bacterial cell, or viral capsid. As such, the genes of mitochondria, bacteria and viruses typically lack many of the complex non-coding elements commonly found in the nuclear genes of eukaryotes.

The genes within an organism's genome are generally not evenly distributed along the length of that organism's DNA. The genes of mitochondria, bacteria and viruses often are immediately adjacent to one another, and frequently overlap. In eukaryotes, there are gene-rich and gene-poor regions within the genome where non-coding spacer regions span the distance between gene-rich areas. Within the gene-rich areas, overlapping genes are common. Overlapping genes are different genes whose nucleotide sequences overlap along a segment of DNA. The nucleotide sequence of overlapping genes is read by RNA polymerases in two or more reading frames or from opposite strands of the DNA molecule, thereby encoding different proteins within the same segment of DNA. Overlapping genes are found throughout nature, from bacteria and viruses to mammals, including humans.

Viruses are not cells. They are genetic material encased in a protein coat, called a viral capsid. Some complex viruses also surround themselves with a viral envelope or membrane made up of lipids and glycoproteins. The genetic and biological characteristics of viruses vary widely.

Like bacterial genomes, the genomes of viruses are very small and typically do not contain introns (non-coding sections of DNA). However, despite their small sizes, the genomes of viruses can be quite complex in that the genes of viruses often overlap or lie immediately adjacent to one another. Like bacteria, some viruses encode multicistronic RNA molecules, which are RNA molecules that contain the coding sequences of more than one protein, usually arranged in sequential manner along the length of the RNA. A multicistronic RNA molecule encodes several proteins but is transcribed in a single RNA molecule. When the RNA is translated, one long polypeptide is made that is actually several proteins joined end-to-end. The polypeptide is processed by enzymatic cleavage to liberate the individual proteins from the larger polypeptide.

In addition, many viruses demonstrate temporal regulation of transcription. For example, early and late genes are expressed at different times during the course of a viral infection of a cell.

There are two domains of prokaryotes: bacteria and archaea. Members of these groups do not have a cell nucleus or organelles bounded by membranes. Although there are exceptions, bacterial genomes do not typically have introns. On the other hand, the genes of organisms in the domain Archaea are sometimes a bit more complex and can have introns and other structural and regulatory elements similar to those found in eukaryotes. Prokaryotic genome sizes can vary widely. Some may be as small as a a few hundred thousand base pairs or as large as several million base pairs.

Like the extensive diversity in life forms within the eukaryote domain, the genomes of eukaryotes also vary greatly in size and composition. For example, the yeast Saccharomyces cerevisiae genome is ~12.5 million base pairs in size, while the fern Psilotum nudum genome is ~250 billion base pairs in size. Further, most eukaryotic genomes encode complex genetic elements that preserve and maintain the structure of the genome, and regulate the transcription (expression) of eukaryotic genes.

Genomes of eukaryotes contain regions known as introns. 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, the genetic material of eukaryotes is organized into one or more linear structures called chromosomes.

Mitochondria are the power plants of cells: they provide cells with the chemical energy needed to perform the metabolic tasks associated with life. It is widely believed that mitochondria are the remnants of ancient energy-producing symbiotic bacterial cells that were assimilated into eukaryotic cells. Similarly, chloroplasts in green plants are believed to be remnants of photosynthetic bacteria.

The mitochondrial chromosome encodes 13 proteins, 2 rRNAs and 22 tRNAs. Mitochondria obtain many of their proteins from genes encoded in the nuclear genomes of cells. Nuclear encoded proteins are imported into the mitochondria after translation. 

The haploid human genome consists of 23 different chromosomes. The diploid human genome consists of 23 pairs of chromosomes. One of each pair of chromosomes is inherited from each parent. For example, each of us carries two copies of chromosome 1: one from our mother, the other from our father. The first 22 pairs of human chromosomes are called autosomes. The 23^rd pair of human chromosomes determine gender. Human females carry two X chromosomes: one inherited from the mother, one from the father. Human males carry one X chromosome and one Y chromosome. Males inherit their X chromosome from their mothers and their Y chromosome from their fathers.

In addition to the nucleus, the mitochondria of human cells also carry one or more copies of a small, circular DNA molecule. The mitochondrial chromosomes are inherited through the egg. Sperm do not contribute mitochondria to embryos. As a result, genetic diseases caused by mutations in genes on the mitochondrial chromosome are passed through the maternal lineage, from mothers to all their children. Children of fathers affected by mitochondrially transmitted genetic disorders are not at risk for inheriting the diseases. However, because mitochondria also import proteins encoded by nuclear genes, the inheritance of diseases of the mitochondria do not always follow this pattern. Examples of mitochondrially transmitted genetic diseases include MERFF (myoclonic epilepsy with ragged red [muscle] fibers), LHON (Leber hereditary optic neuropathy), a form of dementia called MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes), MIDD (maternally inherited diabetes and deafness) syndrome, and genetic susceptibility to aminoglycoside ototoxicity (aminoglycosides are a group of antibiotics that include gentamicin, streptomycin, tobramycin, kanamycin, neomycin, amikacin, and others). In general, observable effects of mitochondrial mutations are believed to be a reflection of how sensitive particular tissues (central nervous system, skeletal muscles, heart, kidney, and liver) are to energy metabolism.

The haploid human genome (23 chromosomes) contains ~3 billion base pairs of DNA. The diploid human genome (23 pairs of chromosomes) contains ~6 billion base pairs of DNA.

Only 1.5-3% of the human genome codes for proteins. It is believed that much of the rest of the human genome serves regulatory and structural functions. The exact number of genes carried by humans is not yet known, but is likely to be somewhere between 35,000 and 100,000.

Humans are more than 99% identical to each other at the DNA level. Only identical twins possess identical genomic DNA. It is the <1% variability in our DNA that makes each of us unique. In recent years, the variability in human DNA has been used as a fossil record to study human history and trace the migration of humans out of Africa as we spread across and populated the Earth. What we have learned from our DNA is clear: every human on the planet today is related to every other human. We all are descended from the same trunk of the human family tree: brothers and sisters separated only by time and geography.

The photograph in this slide is of twin stacks containing a total of eighty-nine Houston telephone books, spiraled to mimic the shape of the DNA double helix. Together the two stacks of telephone books contain approximately the same number of characters as the haploid human genome (23 chromosomes) contains base pairs.

If the DNA contained within a single human cell were laid out lengthwise, with each chromosome arranged end to end, the DNA would be 5.8 feet, or almost two meters, long. However, it would be very thin, only ~24 angstroms wide. It would take 26 million DNA molecules arranged side by side to measure 1 inch wide.

To fit into the microscopic nucleus of a human cell, the length of DNA must be packaged very precisely. In the first level of packaging, the DNA double helix is wound tightly around proteins called histones. Histones are made up of eight component proteins and often are referred to as histone octamers. The packaging of DNA around histones gives DNA a beads-on-a-string appearance. Histone-packaged DNA results in a 10 nanometer (nm) fiber: remember, the native DNA double helix is only 24 angstroms wide, so this 100 angstrom, or 10 nm, fiber is four times wider, and quite a bit shorter than the native double helix would be.

The histone-packaged DNA is further wound into 30 nm fibers. These fibers are then packaged into loops of DNA believed to be anchored to the cytoskeleton within the nucleus of the cell. DNA that is completely packaged is referred to as chromatin.