The haploid genome of each human cell consists of 3.3 × 10⁹ bp of DNA subdivided into 23 chromosomes. The entire haploid genome contains sufficient DNA to code for nearly 1.5 million average-sized protein coding genes (ie, ~2200 bp of protein-coding DNA). However, early studies of mutation rates and of the complexities of the genomes of higher organ isms suggested that humans have significantly fewer than 100,000 proteins encoded by the ~1% of the human genome that is composed of exonic DNA. Indeed, current estimates based on sequencing of the human genome and the collection of mRNA species produced therefrom suggest there are about 25,000 protein-coding genes in humans. This implies that most genomic DNA is nonprotein coding—that is, its information is never translated into an amino acid sequence of a protein molecule. Certainly, some of the excess DNA sequences serve to regulate the expression of genes during development, differentiation, and adaptation to the environment, either by serving as binding sites for regulatory proteins or by encoding regulatory ncRNAs. Some excess clearly makes up the intervening sequences or introns that split the coding regions of genes, and another portion of the excess appears to be composed of many families of repeated sequences for which clear functions have yet to be defined, though some small RNAs transcribed from these repeats can modulate transcription, either directly by interacting with the transcription machinery or indirectly by affecting the activity of the chromatin template. Interestingly, the ENCODE Project Consortium has shown that most of the genomic sequence is indeed transcribed in at least some human cell types, albeit at a low level. A large fraction of such transcription appears to generate the lncRNAs . Further research will elucidate the role(s) played by such transcripts.

The DNA in an eukaryotic genome can be divided into two broad “sequence classes.” These are unique-sequence DNA, or nonrepetitive DNA and repetitive-sequence DNA. In the haploid genome, unique-sequence DNA generally includes the single copy genes that code for proteins. The repetitive DNA in the haploid genome includes sequences that vary in copy number from 2 to as many as 10⁷ copies per cell.

 More Than Half the DNA in Eukaryotic Organisms

Is in Unique or Nonrepetitive Sequences This estimation and genome-wide organization of repetitive sequence DNA was based on a variety of techniques, and most recently on direct genomic DNA sequencing. Similar techniques were used to determine the number of protein-encoding genes. In brewers’ yeast (Saccharomyces cerevisiae, a lower eukaryote), about two-thirds of its 6200 genes are expressed, but only approximately one-fifth are required for viability under laboratory growth conditions. In typical tissues in a higher eukaryote (eg, mammalian liver and kidney), between 10,000 and 15,000 genes are actively expressed. Different combinations of genes are expressed in each tissue of course, and how this is accomplished is one of the major unanswered questions in biology.

In Human DNA, at Least 30% of the Genome Consists of Repetitive Sequences

Repetitive-sequence DNA can be broadly classified as moderately repetitive or as highly repetitive. The highly repetitive sequences consist of 5 to 500 base pair lengths repeated many times in tandem. These sequences are often clustered in centromeres and telomeres of the chromosome and some are present in about 1 to 10 million copies per haploid genome.

The majority of these sequences are transcriptionally inactive and some of these sequences play a structural role in the chromosome.

The moderately repetitive sequences, which are defined as being present in numbers of less than 10⁶ copies per haploid genome, are not clustered but are interspersed with unique sequences. In many cases, these long interspersed repeats are transcribed by RNA polymerase II and the produced RNAs contain 5′-Cap structures  in distinguishable from those on mRNA. Depending on their length, mod erately repetitive sequences are classified as long interspersed nuclear elements (LINEs) or short interspersed nuclear elements (SINEs). Both types appear to be retroposons; that is, they arose from movement from one location to another (transposition) through an RNA intermediate by the action of reverse transcriptase that transcribes an RNA template into DNA. Mammalian genomes contain 20,000 to 50,000 copies of the 6 to 7 kbp LINEs. These represent species-specific families of repeat elements. SINEs are shorter (70-300 bp), and there may be more than 100,000 copies per genome. Of the SINEs in the human genome, one family, the Alu family, is present in about 500,000 copies per haploid genome and accounts for ~10% of the human genome. Members of the human Alu family and their closely related analogs in other animals can be transcribed as integral components of mRNA precursors or as discrete RNA molecules, including the well-studied 4.5S RNA and 7S RNA. These particular family members are highly con served within a species as well as between mammalian species. Components of the short-interspersed repeats, including the members of the Alu family, may be mobile elements, capable of jumping into and out of various sites within the genome. These transposition events can have disastrous results, as exemplified by the insertion of Alu sequences into a gene, which, when so mutated, causes neurofibromatosis. Additionally, Alu B1 and B2 SINE RNAs have been shown to regulate mRNA production at the levels of transcription and mRNA splicing.

Microsatellite Repeat Sequences

One category of repeat sequences exists as both dispersed and grouped tandem arrays. The sequences consist of 2 to 6 bp repeated up to 50 times. These microsatellite sequences most commonly are found as dinucleotide repeats of AC on one strand and TG on the opposite strand, but several other forms occur, including CG, AT, and CA. The AC repeat sequences occur at 50,000 to 100,000 locations in the genome. At any locus, the number of these repeats may vary on the two chromosomes, thus providing heterozygosity of the number of copies of a particular microsatellite number in an individual. This is a heritable trait, and because of their number and the ease of detecting them using the polymerase chain reaction (PCR), such repeats are useful in constructing genetic linkage maps. Most genes are associated with one or more microsatellite markers, so the relative position of genes on chromosomes can be assessed, as can the association of a gene with a disease. Using PCR, a large number of family members can be rapidly screened for a certain microsatellite polymorphism. The association of a specific polymorphism with a gene in affected family members—and the lack of this association in unaffected members—may be the first clue about the genetic basis of a disease.

Trinucleotide sequences that increase in number (micro satellite instability) can cause disease. The unstable (CGG)n repeat sequence (n = the number of repeats; in this case CGG) is associated with the fragile X syndrome. Other trinucleotide repeats that undergo dynamic mutation (usually an increase in repeat numbers) are associated with Huntington chorea (CAG), myotonic dystrophy (CTG), spinobulbar muscular atrophy (CAG), and Kennedy disease (CAG). The advent of next-generation, high-throughput DNA sequencing technologies has dramatically impacted both the speed, accuracy, and precision with which scientists and clinicians can analyze human genome structure. Some newly instituted clinical tests involve targeted genomic DNA sequencing prepared either from tissues or serum samples.

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مواضيع ذات صلة

DNA is organized into Chromosomes

Some Regions of Chromatin are “Active” & Others are “Inactive”

The Nucleosome Contains Histone & DNA

Histones Are the Most Abundant Chromatin Proteins

Specific Nucleases Digest Nucleic Acids

Directions for Future Research in Molecular Biology

The ras-fos-jun Pathway

Recessive Oncogenic Mutations, Tumor Suppressors

Small RNA

Ribosomal RNA

Messenger RNA

Identification of the src and sis Gene