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146 Part IV: Molecular and Cellular Hematology Chapter 10: Genetic Principles and Molecular Biology 147

FROM GENES TO PROTEINS that affects an enzyme in one type of blood cell will also affect the same
DNA is formed and replicated in the cell nucleus, but protein synthesis enzyme in other blood cells, in liver, in brain, and in other tissues.
takes place in the cytoplasm. The DNA code is transported from nucleus
to cytoplasm, and subsequent protein is formed through two basic pro- MENDELIAN GENETICS
cesses: transcription and translation. These processes are mediated by Traits caused by single genes are called mendelian traits (after Gregor
RNA, which is chemically similar to DNA except that the sugar mole- Mendel). Each gene occupies a position along a chromosome known
cule is ribose rather than deoxyribose, and uracil rather than thymine is as a locus. The genes at a particular locus can take different forms (i.e.,
one of the four bases. The other bases of RNA, as in DNA, are adenine, they can be composed of different nucleotide sequences) called alleles.
cytosine, and guanine. Uracil is structurally similar to thymine, so it A locus that has two or more alleles that each occurs with an appre-
also can pair with adenine. Whereas DNA usually occurs as a double ciable frequency (classically defined as 1%) in a population is said to
strand, RNA usually occurs as a single strand. be polymorphic (or a polymorphism). Polymorphisms that involve a
In transcription, RNA is synthesized from a DNA template, form- single nucleotide are termed single nucleotide polymorphisms (SNPs),
ing messenger RNA (mRNA). RNA polymerase binds to a promoter site, while those that involve the presence or absence of larger pieces of DNA
a sequence of DNA that specifies the beginning of a gene. RNA poly- are termed copy number variants (CNVs). Sometimes genetic vari-
6,7
merase then separates a portion of the DNA, exposing unattached DNA ants, such as the alleles responsible for sickle cell disease, thalassemia,
bases. One DNA strand then provides the template for the sequence of or G6PD deficiency, reach polymorphic levels because the deleterious
mRNA nucleotides. effects that they may have are counterbalanced by beneficial effects on
The sequence of bases in the mRNA is thus complementary to the survival, such as increased resistance to malaria. They are known as
8
template strand, and except for the presence of uracil instead of thy- balanced polymorphisms. Short tandem repeats (STRs) are a special form
mine, the mRNA sequence is identical to the other DNA strand. Tran- of polymorphism consisting of differing numbers of repeating units
scription continues until a termination sequence is reached. Then the of one to six nucleotides, for example, ATATATATAT. Such sequences
RNA polymerase detaches from the DNA, and the transcribed mRNA are unstable in evolution of a species and tend to be very polymorphic.
is freed to move out of the nucleus and into the cytoplasm. Instead of only two possible genotypes, as in the case of most SNPs,
When the mRNA is first transcribed from the DNA template, it there may be 5, 10, or more different numbers of repeats at a given locus
reflects exactly the base sequence of the DNA. In eukaryotes, many in different individuals. As a result, STRs are very useful in genetic
RNA sequences are removed by nuclear enzymes, and the remain- mapping and in forensic analysis. In addition, an expanded number of
9
ing sequences are spliced together to form the functional mRNA that repeat copies of some STRs located within or near genes is an important
migrates to the cytoplasm. The excised sequences are called introns, and cause of inherited disease. 10
the sequences that are left to code for proteins are called exons. Because humans are diploid organisms, each chromosome is rep-
In translation, RNA directs the synthesis of a polypeptide, inter- resented twice, with one member of the chromosome pair contributed
acting with transfer RNA (tRNA), a cloverleaf-shaped strand of approx- by the father and one by the mother. At a given locus, an individual has
imately 80 nucleotides. The tRNA molecule has a site where an amino one allele whose origin is paternal and one whose origin is maternal.
acid attaches. The three-nucleotide sequence at the opposite side of the When the two alleles are identical, the individual is homozygous at that
cloverleaf is called the anticodon. It undergoes complementary base locus. When the alleles are not identical, the individual is heterozygous
pairing with an appropriate codon in the mRNA, which specifies the at that locus. The composition of genes at a given locus is known as the
sequence of amino acids through tRNA. genotype. The outward appearance of an individual, which is the result
The site of actual protein synthesis is in the ribosome, which con- of both genotype and environment, is the phenotype.
sists of roughly equal parts of protein and ribosomal RNA (rRNA).
During translation, the ribosome first binds to an initiation site on the
mRNA sequence and then binds to its surface, so that base pairing can DOMINANCE AND RECESSIVENESS
occur between tRNA and mRNA. The ribosome then moves along the In his experiments with garden peas, Gregor Mendel established that
mRNA sequence, processing each codon and translating an amino acid many traits can be either dominant or recessive. In dominant traits, such
by way of the interaction of mRNA and tRNA. as von Willebrand disease or porphyria cutanea tarda type II, one copy
The ribosome provides an enzyme that catalyzes the formation of a disease-causing allele is sufficient for disease causation, so heterozy-
of covalent peptide bonds between the adjacent amino acids, resulting gotes are typically affected. In recessive traits, such as β-thalassemia, two
in a growing polypeptide. When the ribosome arrives at a termination copies of the disease-causing allele must be present, so the affected indi-
signal on the mRNA sequence, translation and polypeptide forma- vidual is a homozygote. A carrier is an individual who has a disease gene
tion cease; the mRNA, ribosome, and polypeptide separate from one but is phenotypically normal. Many alleles for a recessive disease occur
another; and the polypeptide is released into the cytoplasm to perform in heterozygotes that carry one copy of the gene but do not express the
its required function. disease. When recessive alleles are lethal in the homozygous state, they
All cells receive the same complement of genes. Nonetheless, some are eliminated from the population when they occur in homozygotes.
proteins are tissue-specific. Several circumstances can account for this. By “hiding” in carriers, however, recessive genes for diseases are passed
Some enzymes that appear to perform the same function are encoded on to the next generation (the word “recessive” comes from the Latin
by different genes in different tissues. For example, the pyruvate kinase for “hidden”).
of leukocytes and that of erythrocytes are under separate genetic control
(Chap. 47). In other cases, alternative splicing of the primary mRNA
can produce different polypeptides, a phenomenon that is particularly GENE DUPLICATION
prominent with some of the red cell membrane proteins. Differences Crossing over during meiosis usually occurs with great precision.
in posttranslational processing, including proteolysis and glycosylation Homologous genes pair with each other, and although genes that
of the same polypeptide by different enzymes in different tissues, can were together on the chromosome before meiosis may now be on
lead to different final products. However, in most instances a mutation opposite chromosomes of the pair, each chromosome still contains a

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