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Clinical findings of FSHD patients. Myopathic face with evident weakness of the orbicularis oris and oculi (a and b). Wasting of pectoral, shoulder girdle and humeral muscles and typical hypertrophied appearance due to the anterior rotation and elevation of the shoulders (c). Winging of the scapula (d).
A continuum of genetic complexity. As described in the text, this continuum can be considered among disorders ranging from single gene, to major gene, to complex trait, and can also be considered in the context of individual subjects within a single phenotype such as Hirschsprung disease, hypertension, or coronary atherosclerosis. The arrows in the lower portion of the figure depict the relative effects of the germline alleles at different loci (in proportion to size of the arrow) in causing the phenotype or disease susceptibility. The raindrops depict the contributions of factors other than germline genotype such as environmental differences (diet, smoking, drug exposure), stochastic factors (random X inactivation or immunoglobulin rearrangements), and somatic mutation.
Perspectives on the amount of DNA, number of genes, and genetic distance in the human genome. The arrows in the lowest panel indicate hypothetical transcripts, with vertical lines indicating exons within genes.
Prototypical eukaryotic gene. In schematic form, a cellular gene is depicted in which exons or coding regions (boxes) are separated by intervening sequences (introns). Introns begin with the dinucleotide GT and end with AG. A short motif of AATAA (or modified versions) direct endonucleolytic cleavage and polyadenylation of nascent RNAs. Promoter elements, shown as empty parentheses, lie upstream from the start of the gene and are often multiple in nature. Common promoter elements include motifs such as TATA and CCAAT (TATA and CAT boxes) and GGCGGG (the Spl nuclear factor binding site). Additional sequences, known as enhancers, augment transcription and can lie either before, within, or downstream from the gene. After transcription, the RNA is processed to yield mature mRNA, which is translated to yield protein.
The eukaryotic nuclear genetic code. A, The RNA codons appear in boldface type; the complementary DNA codons are in italics. A = adenine; C = cytosine; G = guanine; T = thymine; U = uridine (replaces thymine in RNA). In RNA, adenine is complementary to thymine of DNA; uridine is complementary to adenine of DNA; cytosine is complementary to guanine and vice versa. “Stop” = peptide chain termination. The three-letter and single-letter abbreviations for the amino acids are as follows: Ala (A) = alanine; Arg (R) = arginine; Asn (N) = asparagine; Asp (D) = aspartic acid; Cys (C) = cysteine; Gln (Q) = glutamine; Glu (E) = glutamic acid; Gly (G) = glycine; His (H) = histidine; Ile (I) = isoleucine; Leu (L) = leucine; Lys (K) = lysine; Met (M) = methionine; Phe (F) = phenylalanine; Pro (P) = proline; Ser (S) = serine; Thr (T) = threonine; Trp (W) = tryptophan; Tyr (Y) = tyrosine; Val (V) = valine. B, The outermost complete circle represents the amino acid in single letter code or a stop codon (*); the DNA sense strand for the triplet codon for each amino acid is given on the radial, starting with the first base of the codon in the center. Differences in the mitochondrial genetic code are shown in the outermost boxes.
Point mutations in β-thalassemia. The β-globin gene is shown with numbered hatched areas representing the coding regions of exons. Boxed open areas between the exons are introns, and boxed open areas at the 5′ and 3′ ends of the gene are untranslated regions that appear in the messenger RNA. The various types of mutations are depicted by different symbols. (From Kazazian and Boehm.39 Used by permission.)
DNA sequence specificity and nuclease activity for three restriction endonucleases. HaeIII leaves a blunt end while the other enzymes leave single-stranded ends.
Procedures for Southern and northern blot analysis.
Polymerase chain reaction for amplification of DNA. The target DNA is shown as a solid line in cycle 1. Newly synthesized DNA is indicated by dotted lines in each cycle. Primer oligonucleotides are indicated by solid rectangles. Each DNA strand is marked with an arrow indicating 5′ to 3′ orientation.
Protein truncation testing. PCR is performed starting with genomic DNA or RT-PCR is performed using mRNA. Sequences for transcription and translation (TT) are introduced at the 5′-end of the coding segments. Mutations leading to truncation of a protein are detected by gel analysis.
Denaturing high performance liquid chromatography (DHPLC). Exon 9 of the E6-AP ubiquitin-protein ligase gene was amplified as described elsewhere,53 and DHPLC detects an abnormal pattern of a 2997 T→A mutation causing Angelman syndrome. The analysis was performed using the WAVE equipment of Transgenomic, Inc., Omaha, NE. (Figure courtesy of Dr. Dani Bercovich.)
Use of DNA chips for molecular analysis. Large numbers of unique oligonucleotides are arrayed on a solid support and analyzed as indicated. See Southern54 for detailed discussion.
Example of restriction fragment length polymorphism (RFLP) in human DNA using Southern blotting. The solid blocks indicate segments of DNA used as probe. Parents are heterozygous and children are homozygous for the RFLP. Symbols above the arrows indicate cutting (+) or noncutting (−) by the restriction endonuclease. The “2” above the open triangle depicts a 2-kb insertion/deletion polymorphism. Numbers indicate DNA length in kilobases.
Depiction of a short tandem repeat (STR) polymorphism for a dinucleotide (GT)n repeat. Each repeat is separated by a vertical line. Sites for two primers for PCR are indicated by arrows. Four alleles of 24, 21, 18, and 15 GT repeats are indicated. Inheritance of the alleles in a family as detected by PCR is shown below.
Depiction of meiotic crossing over and linkage analysis. The upper panel shows two copies of one chromosome (one in solid line and one in dashed line) from an individual before (above) and after (below) meiotic crossing over. The individual is heterozygous for a disease locus with a normal allele (open square) and a disease allele (filled square) and is heterozygous for four DNA markers with alleles A/B, F/G, K/L, and R/S at 0, 1, 10, and >50 cM from the disease locus, respectively. The lower panel depicts analysis in a family for an autosomal dominant disorder. The DNA marker with K/L alleles at 10 cM from the disease locus on chromosome 4 and another DNA marker with Y/Z alleles on chromosome 7 are depicted. The chromosomes 4 and 7 for each parent are shown and the genotypes given for each family member. The disease phenotype is inherited from the father with the L allele for the DNA marker except for the last child who represents a crossover of the type shown in the upper panel. See text for discussion.
A positional cloning strategy. DNA markers at sites A and B are found to flank a disease gene. Overlapping DNA clones are isolated for the region, and the disease gene is identified within the region.
Depiction of estimated roles of modifier genes and nongenetic factors in influencing the phenotypes for “monogenic” disorders. Extensive variation is due to allelic heterogeneity, and the intent is to indicate crude estimates of the contributions that might occur in addition to allelic variation.
A trypsin G-banded normal human female karyotype. (Courtesy of David H. Ledbetter.)
Rank order (abscissa is percentage of phenotypes involving system) for the involvement of a particular anatomic/functional system by Mendelian disease in humans (see Costa et al.93 for likelihood that more than one system is involved). Skin, hair, and nails are shown both individually and as a group-designated integument. Mus Skel = musculoskeletal; NS = nervous system. (From Costa et al.93 Used by permission.)
Pedigree pattern for an autosomal dominant trait. Note the vertical pattern of inheritance; compare new mutation and inherited pedigrees.