Chromosomes (Molecular Biology)

Chromosomes are the nucleoprotein complexes that provide the structural framework for the expression of genes and mediate the transfer of genetic information from generation to generation. The nuclei, mitochondria, and chloroplasts of all cells, both eukaryotes and prokaryotes, plus viruses, all contain chromosomes. These various chromosomes can vary greatly in size, from very large (see Polytene Chromosome, Lampbrush Chromosomes) to very small (see Double Minute Chromosome; Minichromosome). All chromosomes contain DNA, which can be packaged by different proteins to assemble a nucleoprotein complex. The DNA in the chromosomes of a eukaryotic cell nucleus is packed with small basic proteins known as histones. The most striking property of every chromosome within the eukaryotic cell nucleus is the length of each molecule of DNA incorporated and folded into it. The human genome of 3 x 109 bp would extend over a meter if unraveled and straightened, yet it is compacted into a nucleus only 10-5 m in diameter. It is an astonishing feat of engineering to organize such a long linear DNA molecule within ordered structures that can reversibly fold and unfold within the chromosome.

The basic architectural matrix of the chromosomes found within eukaryotic cell nuclei is chromatin. All of the DNA in the nucleus of a somatic cell is packaged into chromatin by the histone proteins, together with other DNA-binding proteins. In specialized germ cells, such as sperm, protamines can replace the histones as the primary means of packaging DNA. There is considerable specialization in the type of chromatin assembled in different regions of a chromosome, depending on its functional requirements. Chromatin containing genes that are being expressed in a cell is called euchromatin. A large chromosomal region that contains inactive genes is assembled into facultative heterochromatin. Specialized chromosomal structures that contain very few genes but have other essential architectural roles in the chromosome are assembled into constitutive heterochromatin. The centromere is an essential structure containing constitutive heterochromatin that mediates segregation of the chromosomes. The molecular motors that drive this process are found within the kinetochore that is attached to the centromeric heterochromatin. Other heterochromatic domains are at the ends of chromosomes in specialized structures known as telomeres. Within the telomere are many reiterated terminal repeat sequences resulting from the activity of the enzyme telomerase. The telomere protects the end of the chromosome from degradation, fusion, and progressive loss of DNA during chromosomal duplication.

The position of the centromere relative to the rest of the chromosome provides an important reference point for describing different types of chromosomes. Chromosomes can be metacentric, with a centromere near the middle of the chromosome, or acrocentric, when it is near the end of the chromosome, or even potentially telocentric, when it is at the very tip. Most eukaryotic chromosomes are monocentric, having a single centromere, but some are holocentric and have multiple centromeric domains. Holocentric chromosomes have specialized mechanisms for segregating chromosomes during cell division that differ from those found in most plant and animal cells.

In animal cells, the presence of multiple centromeres in a single chromosome is often the product of chromosomal rearrangements. Such events usually occur as a result of chromosomal damage and can involve duplications, inversions, and translocations. A dicentric chromosome contains two centromeres following one of these rearrangements, whereas an acentric chromosome lacks a centromere entirely. Isochromosomes might also be formed, where a chromosome contains multiple identical chromosomal arms. All of these rearrangements lead to major problems for segregating chromosomes during the cell division of meiosis and mitosis. Chromosomal damage can be very useful in mapping the positions of genes relative to each other by methodologies that apply somatic cell genetics (see Radiation Hybrid).

Each diploid cell receives two sex chromosomes, either two X-chromosomes in females or one X-and one Y-Chromosome in males, plus two copies of each of the other chromosomes, known as autosomes. Each pair of autosomes consists of two homologous chromosomes, one from the father and one from the mother in humans. Immediately after mitotic division, each chromosome consists of a single DNA molecule. This single molecule of DNA is assembled into a chromatid, which duplicates during the S-phase of the cell cycle to form two sister chromatids. Then these sister chromatids are segregated to the two daughter cells at mitosis. In meiosis, haploid germ cells are created. This involves segregating of homologous chromosomes at the first meiotic division before the sister chromatids are segregated at the second meiotic division. Because homologous chromosomal regions are aligned during meiosis, chromosomal rearrangements can lead to major problems in segregating homologous chromosomal material. This can lead to multivalent chromosomes, whereas a normal meiosis would produce only bivalent chromosomes.

For organisms that undergo sexual reproduction, special sex chromosomes exist. In humans, these are known as the X- and Y-chromosomes. Female cells contain two X-chromosomes, whereas male cells contain a single X-chromosome and a Y-chromosome. Mary Lyon proposed that gene expression from the two X-chromosomes in a female cell should be the same as that from the single X-chromosome in a male cell (see Lyon Hypothesis). This is accomplished by silencing one of the two X-chromosomes in a female cell (see X-Chromosome Inactivation; Random X-Inactivation). The silenced X-chromosome is converted to a Barr body made up of facultative heterochromatin. X-and Y-chromosomes share some limited regions of homology that mediate their pairing and subsequent segregation during meiosis.

An important aspect of chromosomal biology involves mapping individual genes on chromosomes, which facilitates diagnosing particular diseases. A wealth of mapping procedures exist. These make up the field of cytogenetics, which is based on visualizing chromosomes. Mapping procedures involve using particular stains for the DNA and protein components of the chromosome (see C-Banding; G Banding). In recent times, these methodologies have been supplemented with high-resolution denaturation mapping techniques. Then all of the stained chromosomes of a particular cell that make up the karyotype can be displayed formally as an ideogram.

At a more refined level, structure at the level of chromosome and chromatin also determines the functions of particular genes. It has long been known from visualizating the large polytene chromosomes that individual chromosomal domains exist. Individual domains like the Balbiani rings contain chromatin that reversibly changes structure to reflect different functional states. Balbiani rings appear as puffs when they are being transcribed. Other regions of the polytene chromosome, known as interbands, contain the regulatory DNA sequences that control the appearance of puffs. Chromosomal rearrangements can lead to positioning genes next to large domains of constitutive heterochromatin. Placing a gene next to the chromocenter in Drosophila, where the centromeres fuse together, represses expression of the gene. This position effect indicates that structurally specialized domains of chromosomes exist and presents a major problem for biotechnology and gene therapy in expressing foreign DNA in target cells.

Nucleases like DNase I have been very useful in mapping regulatory DNA in the chromosome. The locus control regions, enhancers, and promoters that control gene expression exist as sites that are hypersensitive to digestion by DNase I. These elements often control the expression of clusters of contiguous genes that have related functions in the cell. Sites with extreme DNase I sensitivity are also found at the regulatory elements controlling the initiation of DNA replication at the origin of replication. The terminally redundant regulatory elements of retroviruses are also assembled into nucleoprotein complexes that retain accessibility to DNase I.

Chromosomes are fascinating structures around which much of modern medicine and biotechnology revolves. They also provide the foundation for considering basic molecular mechanisms that control gene expression and for considering the forces that facilitate evolution. Genes require a chromosomal environment to be maintained throughout the generations and within which to realize their full regulatory potential.

Next post:

Previous post: