9
Molecular Genetics of Disease
and the Human Genome Project
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Fig. 1. The 23 chromosomes in the human genome. There are 22 autosomes (chromosomes 1 to 22) and two sex chromosomes (X and Y). Females inherit 22
autosomes and one X chromosome from each parent (46;XX). Males inherit 22 autosomes from each parent, an X chromosome from the mother and a Y
chromosome from the father (46;XY). Metacentric chromosomes have a centromere (where spindle fiber binds during cell division) in the middle. Acrocentric
chromosomes (chromosomes 13, 14, 15, 21, and 22) have their centromere near the end. The lighter bands of the chromosomes represent regions that have
a higher GC-nucleotide content and more genes than the darker bands. Housekeeping genes tend to be located within the light bands and tissue-specific
genes in the dark bands. The distribution of genes between chromosomes is also not uniform. For example, chromosome 21 is relatively gene-poor, while
chromosome 19 is extremely gene-rich.
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Table 1
Components of the Human Genome
• The genome is the total genetic material in a cell.
• The nuclear genome is comprised of 46 chromosomes, which come as 23 pairs; one of each pair
comes from either parent.
• Mitochondrial DNA is also part of the genome. It is always inherited from the mother and is found
in the cytoplasm.
• Chromosomes are made of deoxyribonucleic acid (DNA).
• DNA is made of four chemical units (nucleotides) called adenine (A), guanine (G), cytosine (C),
and thymine (T).
• The genome is comprised of about 3 billion A, C, G, and Ts.
• Genes are the portions of DNA that encode functional RNA molecules or proteins.
• There are approx 30,000–40,000 genes in the genome.
• Proteins provide the structure for the cell and are involved in biochemical reactions (enzymes).
Fig. 2. Anatomy of a gene. Information flows from DNA to RNA (transcription) to protein (translation).
Fig. 3. Patterns of inheritance for autosomal recessive, autosomal dominant and X-linked disorders.
Recessive alleles are indicated by ‘a’ and dominant alleles by ‘A’. Males only have one X chromosome, therefore only one allele is shown for X-linked inheritance.
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Table 2
Gene Expression
Transcription
RNA processing
Capping
Splicing
Polyadenylation
Transport
Translation
Housekeeping genes
Tissue-specific genes
The synthesis of a single-strand RNA molecule from a DNA template
in the cell nucleus.
This process is controlled by the interactions between proteins and
DNA sequences near each gene.
Addition of a modified nucleotide chain to the 5' end of a growing
mRNA chain. This is required for the normal processing, stability,
and translation of mRNA.
The process of removing introns and joining exons into a mature
mRNA molecule.
Addition of 20 – 200 adenosine residues (poly A tail) to the 3' end of
the RNA transcript.
The fully processed RNA is taken to the cytoplasm where translation
takes place.
The synthesis of a protein from its mRNA template.
Expressed in all cell types because their products provide basic
functions in cells.
Expressed in only certain cell-types because their products have
specific functions.
Table 3
Types of Mutations and Their Effects
Missense mutations
Nonsense mutations
Silent mutations
Splice-site mutations
Insertions
Duplications
Translocations
Inversions
Trinucleotide repeats
Deletions
Deletion of:
A gene
An exon
An intron
Promoter
Splice-site
Many genes
Single-nucleotide changes resulting in the substition of an amino
acid in the protein.
Single-nucleotide changes that create one of the three termination codons (TAA, TGA, or TAG) resulting in a shortened,
dysfunctional protein.
Have no detectable phenotypic effect.
Altered sequences at the ends of introns (5' donor or 3' acceptor)
during RNA processing, that affect gene splicing and function.
Addition of extra DNA sequences of varying sizes.
Doubling of DNA sequences.
Interchange of segments of DNA between two different chromosomes.
Occur when a region of DNA inverts its orientation with respect
to the rest of the chromosome.
Expansion of triplet repeat sequences.
Loss of part of a DNA sequence (could be loss of a single nucleotide or millions of nucleotides).
Effects:
No protein product
Truncated protein
Usually no phenotypic change
Gene nonfunctional
Protein nonfunctional
Chromosomal abnormalities and usually a heterogeneous
phenotype
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Fig. 4. Different mutations in the same gene (e.g., CFTR in cystic fibrosis) can produce different clinical outcomes. The clinical symptoms (severe/
mild) correlate to the pancreatic function of the patients. Adapted from Zielenski and Tsui (1995).
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Fig. 5. DNA sequencing. Four different fluorescently tagged dyes (red for thymines, green for adenines,
blue for cytosines, and black for guanines) represent the four nucleotides.
Fig. 6. Disease gene identification by positional cloning using mapping and DNA sequencing
techniques.
Fig. 7. Timeline of the Human Genome Project (HGP). A historical summary of some of the
enabling technologies (on the left) and the achievements (on the right) leading up to and including
the HGP are shown. The formal international HGP began in 1990. Other aspects of the HGP are the
study of model organisms, analysis of genome variation, and the development of bioinformatics.
Establishing training and public education programs, as well as the study of the ethical, legal, and
social issues of genetics research in society, are also important priorities.
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