The Human Genome


The human genome has approximately 20,000 genes that encode the wide variety of proteins found in the human body. Reproductive or germline cells contain 1 copy (N) of this genetic complement and are haploid , whereas somatic (nongermline) cells contain 2 complete copies (2N) and are diploid . Genes are organized into long segments of deoxyribonucleic acid ( DNA ), which, during cell division, are compacted into intricate structures together with proteins to form chromosomes. Each somatic cell has 46 chromosomes: 22 pairs of autosomes , or nonsex chromosomes, and 1 pair of sex chromosomes (XY in a male, XX in a female). Germ cells (ova or sperm) contain 22 autosomes and 1 sex chromosome, for a total of 23. At fertilization, the full diploid chromosome complement of 46 is again realized in the embryo.

Most of the genetic material is contained in the cell's nucleus. The mitochondria (the cell's energy-producing organelles) contain their own unique genome. The mitochondrial chromosome consists of a double-stranded circular piece of DNA, which contains 16,568 base pairs (bp) of DNA and is present in multiple copies per cell. The proteins that occupy the mitochondria are produced either in the mitochondria, using information contained in the mitochondrial genome, or are produced outside of the mitochondria, using information contained in the nuclear genome, and then transported into the organelle. Sperm do not usually contribute mitochondria to the developing embryo, so all mitochondria are maternally derived, and a child's mitochondrial genetic makeup derives exclusively from the child's biological mother (see Chapter 106 ).

Fundamentals of Molecular Genetics

DNA consists of a pair of chains of a sugar-phosphate backbone linked by pyrimidine and purine bases to form a double helix ( Fig. 96.1 ). The sugar in DNA is deoxyribose. The pyrimidines are cytosine (C) and thymine (T); the purines are guanine (G) and adenine (A). The bases are linked by hydrogen bonds such that A always pairs with T and G with C. Each strand of the double helix has polarity, with a free phosphate at one end (5′) and an unbonded hydroxyl on the sugar at the other end (3′). The 2 strands are oriented in opposite polarity in the double helix.

Fig. 96.1, DNA double helix, with sugar-phosphate backbone and nitrogenous bases.

The replication of DNA follows the pairing of bases in the parent DNA strand. The original 2 strands unwind by breaking the hydrogen bonds between base pairs. Free nucleotides, consisting of a base attached to a sugar-phosphate chain, form new hydrogen bonds with their complementary bases on the parent strand; new phosphodiester bonds are created by enzymes called DNA polymerases. Replication of chromosomes begins simultaneously at multiple sites, forming replication bubbles that expand bidirectionally until the entire DNA molecule (chromosome) is replicated. Errors in DNA replication, or mutations induced by environmental mutagens such as irradiation or chemicals, are detected and potentially corrected by DNA repair systems.

The central tenet of molecular genetics is that information encoded in DNA, predominantly located in the cell nucleus, is transcribed into messenger ribonucleic acid ( mRNA ), which is then transported to the cytoplasm, where it is translated into protein. A prototypical gene consists of a regulatory region, segments called exons that encode the amino acid sequence of a protein, and intervening segments called introns ( Fig. 96.2 ).

Fig. 96.2, Flow of information from DNA to RNA to protein for a hypothetical gene with 3 exons and 2 introns.

Transcription is initiated by attachment of ribonucleic acid ( RNA ) polymerase to the promoter site upstream of the beginning of the coding sequence. Specific proteins bind to the region to repress or activate transcription by opening up the chromatin , which is a complex of DNA and histone proteins. It is the action of these regulatory proteins ( transcription factors ) that determines, in large part, when a gene is turned on or off. Some genes are also turned on and off by methylation of cytosine bases that are adjacent to guanine bases ( cytosine-phosphate-guanine bases, CpGs ). Methylation is an example of an epigenetic change, meaning a change that can affect gene expression, and possibly the characteristics of a cell or organism, but that does not involve a change in the underlying genetic sequence. Gene regulation is flexible and responsive, with genes being turned on or off during development and in response to internal and external environmental conditions and stimuli.

Transcription proceeds through the entire length of the gene in a 5′ to 3′ direction to form an mRNA transcript whose sequence is complementary to that of one of the DNA strands. RNA, like DNA, is a sugar-phosphate chain with pyrimidines and purines. In RNA the sugar is ribose, and uracil replaces the thymine found in DNA. A “cap” consisting of 7-methylguanosine is added to the 5′ end of the RNA in a 5′-5′ bond and, for most transcripts, several hundred adenine bases are enzymatically added to the 3′ end after transcription.

mRNA processing occurs in the nucleus and consists of excision of the introns and splicing together of the exons. Specific sequences at the start and end of introns mark the sites where the splicing machinery will act on the transcript. In some cases, there may be tissue-specific patterns to splicing, so that the same primary transcript can produce multiple distinct proteins.

The processed transcript is next exported to the cytoplasm, where it binds to ribosomes, which are complexes of protein and ribosomal RNA ( rRNA ). The genetic code is then read in triplets of bases, each triplet corresponding with a specific amino acid or providing a signal that terminates translation . The triplet codons are recognized by transfer RNAs ( tRNAs ) that include complementary anticodons and bind the corresponding amino acid, delivering it to the growing peptide. New amino acids are enzymatically attached to the peptide. Each time an amino acid is added, the ribosome moves 1 triplet codon step along the mRNA. Eventually a stop codon is reached, at which point translation ends and the peptide is released. In some proteins, there are posttranslational modifications , such as attachment of sugars ( glycosylation ); the protein is then delivered to its destination within or outside the cell by trafficking mechanisms that recognize portions of the peptide.

Another mechanism of genetic regulation is noncoding RNAs, which are RNAs transcribed from DNA but not translated into proteins. Noncoding RNAs function in mediating splicing, the processing of coding RNAs in the nucleus, and the translation of coding mRNAs in ribosomes. The roles of large noncoding RNAs (>200 bp) and short noncoding RNAs (<200 bp) extend beyond these processes to impact a diverse set of biologic functions, including the regulation of gene expression. For example, micro RNAs ( miRNAs ) are a class of small RNAs that control gene expression in the cell by directly targeting specific sets of coding RNAs by direct RNA–RNA binding. This RNA–RNA interaction can lead to degradation of the target-coding RNA or inhibition of translation of the protein specified by that coding RNA. miRNAs, in general, target and regulate several hundred mRNAs.

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