Medical Genetics - V. M. Zaporozhan 2005

Introduction to Medical Genetics
Molecular Foundations of Heredity
Human Genome

The Genome is the complete genetic system of a Cell, which determines The Nature of an Organism's ontogenetic development and the hereditary transmission of all its Structural and functional traits.

The Modern concept of the genome refers to the totality of all nuclear and Mitochondrial DNA of an organism (or cell). The amount of DNA in a genome is measured in Base Pairs (bp) or kilobase pairs (kbp). The Human Genome consists of 3.2×10⁹ bp and, from a contemporary perspective, contains about 30,000 genes, which is significantly fewer than previously estimated (about 100,000).

It is believed that protein-coding DNA sequences account for only 2% of the genome. RNA-coding regions make up about 20%, while the majority consists of non-coding DNA (Table 1.3).

Most eukaryotic protein-coding genes belong to unique sequences that appear only once in the genome. Mutations in these genes lead to monogenic hereditary disorders. Some protein-coding genes are repeated from several to several hundred times. Certain genes form multigene families and superfamilies. These are groups of genes that originated from a common ancestral Gene, share a similar exon-intron Organization, and encode functionally related Proteins. Examples of gene families include genes for Globins, IMMUNOGLOBULINS, interferons, Collagen, and histone proteins. Gene superfamilies are formed by the GENES OF THE Major Histocompatibility Complex (MHC) and cytochrome Enzymes.

Non-coding DNA sequences may be associated with structural genes (introns, regulatory regions) or represent independent sequences.

Table 1.3. Structural and functional elements of DNA

Independent sequences include:

1. Spacers — intergenic regions that perform a structural role.

2. Pseudogenes — inactive copies of cellular genes that are unable to be transcribed or produce functionally inactive proteins. They are formed either As a result of mutation (pseudogenes) or through reverse METABOLISM/31.html">Transcription (i.e., DNA Synthesis using an RNA template) of mature Messenger RNA followed by the Integration of the resulting DNA into the genome (processed pseudogenes). Processed pseudogenes lack a promoter region and therefore are not transcribed.

3. Repeats originating from mobile (transposable) genetic elements. These include transposons, or "jumping genes" (about 3% of the human genome), which encode information for their own transposition to another site via the enzyme transposase using a cut-and-paste mechanism; retrovirus analogs, or retrotransposons (8% of the genome); and short and long interspersed elements (SINEs and LINEs) formed through reverse transcription. SINEs (short interspersed elements) are fragments 100–300 bp long, numbering about 1.5 million copies (13% of the human genome). LINEs (long interspersed elements) are fragments 5–8 kbp long, occurring in approximately 850,000 copies per genome (21% of the human genome). Both SINEs and LINEs belong to interspersed (or dispersed) repeats.

Mobile elements can insert into any region of DNA. In doing so, they can inactivate a gene or alter a coding sequence, which is one of the mechanisms underlying Hereditary diseases. Mobile elements are also an important evolutionary factor, as they enable the rapid generation of new genes or novel regulatory elements. For example, 47 genes derived from common transposons have been identified in the human genome.

4. Simple sequence repeats arranged consecutively in a tandem array, known as satellite DNA. Depending on the size of the repeating unit, satellite DNA (alpha-satellite DNA, beta-satellite DNA), minisatellite DNA, and microsatellite DNA are distinguished. Satellite DNA forms blocks ranging from several million base pairs to larger and is located primarily in the centromeric regions of Chromosomes. Minisatellite DNA forms blocks ranging from 100 to 20,000 bp, with a repeating unit size of 14 to 500 bp. Microsatellite DNA is represented by sequences up to several hundred NUCLEOTIDES long, with a repeating unit size of 1–13 bp (most commonly 2–4 bp). The number of repeats in minisatellites and microsatellites exhibits high individuality, allowing their analysis to be used in forensic practice for personal identification and paternity testing. Satellite DNA accounts for about 3% of the human genome.

The presence in the genome of a large amount of DNA that does not code for Amino acid sequences or RNA explains the so-called C-value paradox — the discrepancy between the amount of DNA per cell and the organism's complexity. The function of silent DNA has not yet been fully established. It is believed to be involved in the Introduction/30.html">Regulation of Gene Expression, enhance the accuracy of homologous pairing and recombination during Meiosis, facilitate DNA Replication, or carry a fundamentally different, yet undeciphered code.

According to their copy number in the genome, all human DNA sequences can be divided into 3 groups.

1. Unique sequences, which are represented by single copies per genome. They account for 45% of all DNA and can function either as structural genes or as silent sequences.

2. Moderately repetitive sequences with a repeat frequency ranging from 2 to 10⁴ per genome. These include genes encoding certain proteins (immunoglobulins, Histones, and non-histone chromosomal proteins), as well as tRNA and rRNA genes, and DNA regions performing regulatory Functions (promoters, terminators, etc.). The presence of multiple gene copies is due to the high demand for their products (histones, rRNA, tRNA, etc.) and serves as protection against potential mutations.

3. Highly repetitive sequences — with a repeat frequency up to 10⁶. An example is the satellite DNA fraction.