The human genome contains some 3.2 billion DNA base pairs. Yet, within the genome there are only about 20,000 protein-encoding genes, constituting just 1.5% of the genome. These are the blueprints that instruct the assembly of the enzymes, structural elements, and signaling molecules within the 50 trillion cells that make up the human body. Although 20,000 underestimates the actual number of encoded proteins (many genes produce multiple RNA transcripts that translate to different protein isoforms), it is nevertheless startling to realize that worms, which are composed of fewer than 1000 cells and have 30-fold smaller genomes also have about 20,000 protein-encoding genes. Many of these proteins are recognizable homologs of molecules expressed in humans. What then separates humans from worms?

The answer is not completely known, but evidence suggests that much of the difference lies in the 98.5% of the human genome that does not encode proteins. The function of such long stretches of DNA (so-called genome “dark matter”) was mysterious for many years. However, over 85% of the human genome is ultimately transcribed; nearly 80% is devoted to regulation of gene expression. It follows that while proteins provide the building blocks and machinery required for assembling cells, tissues, and organisms, it is the noncoding regions of the genome that provide the critical “architectural planning.” Practically stated, the difference between worms and humans apparently lies more in the genomic “blueprints” than in the construction materials.

There are five major classes of functional non–protein coding sequences in the human genome (Fig. 1):

• Promoter and enhancer regions that provide binding sites for transcription factors. • Binding sites for factors that organize and maintain higher order chromatin structures.

• Noncoding regulatory RNAs. Over 60% of the genome is transcribed into RNAs that are never translated but regulate gene expression through a variety of mechanisms. The two best-studied varieties—micro-RNAs (miRNAs) and long noncoding RNAs (lncRNAs)—are described later.

• Mobile genetic elements (e.g., transposons) make up more than a third of the human genome. These “jumping genes” can move around the genome during evolution, resulting in variable copy number and positioning even among closely related species (e.g., humans and other primates). Although implicated in gene regulation and chromatin organization, the function of mobile genetic elements is not well established.

• Special structural regions of DNA, in particular, telomeres (chromosome ends) and centromeres (chromosome “tethers”). A major component of centromeres is so-called satellite DNA, consisting of large arrays—up to megabases in length—of repeating sequences (from 5 bp up to 5 kb). Although classically associated with spindle apparatus attachment, satellite DNA is also important in maintaining the dense, tightly packed organization of heterochromatin (discussed later).

Fig1. The organization of nuclear DNA. At the light microscopic level, the nuclear genetic material is organized into dispersed, transcriptionally active euchromatin and densely packed, transcriptionally inactive heterochromatin; chromatin can also be mechanically connected with the nuclear membrane, and membrane perturbation can thus influence transcription. Chromosomes (as shown) can be visualized only during mitosis. During mitosis, they are organized into paired chromatids connected at centromeres; the centromeres act as the locus for the formation of a kinetochore protein complex that regulates chromosome segregation at metaphase. The telomeres are repetitive nucleotide sequences that cap the termini of chromatids and permit repeated chromosomal replication without deterioration of genes near the ends. The chromatids are organized into short “P” (“petite”) and long “Q” (next letter in the alphabet) arms. The characteristic banding pattern of chromatids has been attributed to relative GC content (less GC content in bands relative to interbands), with genes tending to localize to interband regions. Individual chromatin fibers are comprised of a string of nucleosomes— DNA wound around octameric histone cores—with the nucleosomes connected via DNA linkers. Promoters are noncoding regions of DNA that initiate gene transcription; they are on the same strand and upstream of their associated gene. Enhancers can modulate gene expression over distances of 100 kb or more by looping back onto promoters and recruiting additional factors that drive the expression of pre–messenger RNA (mRNA) species. Intronic sequences are spliced out of the pre-mRNA to produce the final message that is translated into protein—without the 3′–untranslated region (UTR) and 5′-UTR. In addition to the enhancer, promoter, and UTR sequences, noncoding elements, including short repeats, regulatory factor binding regions, noncoding regulatory RNAs, and transposons, are distributed throughout the genome.

Many genetic variations (polymorphisms) associated with diseases are located in non–protein-coding regions of the genome. Thus variation in gene regulation may prove to be more important in disease causation than structural changes in specific proteins. Another surprise that emerged from genome sequencing is that any two humans are typically more than 99.5% DNA-identical (and are 99% sequence identical with chimpanzees)! Thus individual variation, including differential susceptibility to diseases and environmental stimuli, is encoded in less than 0.5% of our DNA (representing about 15 million bp).

The two most common forms of DNA variation in the human genome are single nucleotide polymorphisms (SNPs) and copy number variations (CNVs).

• SNPs are variants at single nucleotide positions and are almost always biallelic (only two choices exist at a given site within the population, such as A or T). Over 6 million human SNPs have been identified, with many showing wide variation in frequency in different populations.

 • SNPs occur across the genome—within exons, introns, intergenic regions, and coding regions.

• Roughly 1% of SNPs occur in coding regions, which is about what would be expected by chance, since coding regions comprise about 1.5% of the genome.

• SNPs located in noncoding regions can occur within genomic regulatory elements, thereby altering gene expression; in such instances, SNPs influence disease susceptibility directly.

• Some SNPs, termed “neutral” variants, are thought to have no effect on gene function or individual phenotype.

 • Even “neutral” SNPs may be useful markers if they happen to be coinherited with a disease-associated polymorphism as a result of physical proximity. In other words, the SNP and the causative genetic factor are in linkage disequilibrium.

• The effect of most SNPs on disease susceptibility is weak, and it remains to be seen if identification of such variants, alone or in combination, can be used to develop effective strategies to identify those at risk and, ultimately, prevent disease.

• CNVs are a form of genetic variation consisting of different numbers of large contiguous stretches of DNA; these can range from 1000 base pairs to millions of base pairs. CNVs can be biallelic and simply duplicated or, alternatively, deleted in some individuals. At other sites there are complex rearrangements of genomic material, with multiple variants in the human population.

 • CNVs are responsible for between 5 million and 24 million base pairs of sequence difference between any two individuals.

• Approximately 50% of CNVs involve gene-coding sequences; thus CNVs may underlie a large portion of human phenotypic diversity.

It is important to note that alterations in DNA sequence cannot by themselves explain the diversity of phenotypes in human populations; moreover, classic genetic inheritance cannot explain differing phenotypes in monozygotic twins. The answers to these conundrums probably lie in epigenetics— heritable changes in gene expression that are not caused by variations in DNA sequence.

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دراسة تكشف تأثير "تيك توك" وتطبيقات الفيديو على سلوك الأطفال

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أول قطار يعمل بالهيدروجين في أميركا يدخل الخدمة رسميًا

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روسيا: تطلق قمرين اصطناعيين بواسطة الصاروخ سويوز 2.1

ميزة ثورية.. أبل تدخل عالم قياس ضغط الدم

المزيد

مواضيع ذات صلة

Micro-RNA and Long Noncoding RNA

Histone Organization

DNA Synthesis Occurs During the S Phase of the Cell Cycle

Formation of Replication Bubbles

Initiation & Elongation of DNA Synthesis

The Exact Function of Much of the Mammalian Genome is Not Well Understood

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