Harpers

322 / CHAPTER 36spersed repeats, including the members of the Alu family,may be mobile elements, capable of jumping intoand out of various sites within the genome (see below).This can have disastrous results, as exemplified by theinsertion of Alu sequences into a gene, which, when somutated, causes neurofibromatosis.Microsatellite Repeat SequencesOne category of repeat sequences exists as both dispersedand grouped tandem arrays. The sequences consistof 2–6 bp repeated up to 50 times. These microsatellitesequences most commonly are found asdinucleotide repeats of AC on one strand and TG onthe opposite strand, but several other forms occur, includingCG, AT, and CA. The AC repeat sequences areestimated to occur at 50,000–100,000 locations in thegenome. At any locus, the number of these repeats mayvary on the two chromosomes, thus providing heterozygosityof the number of copies of a particular microsatellitenumber in an individual. This is a heritabletrait, and, because of their number and the ease of detectingthem using the polymerase chain reaction(PCR) (Chapter 40), AC repeats are very useful in constructinggenetic linkage maps. Most genes are associatedwith one or more microsatellite markers, so the relativeposition of genes on chromosomes can beassessed, as can the association of a gene with a disease.Using PCR, a large number of family members can berapidly screened for a certain microsatellite polymorphism.The association of a specific polymorphismwith a gene in affected family members—and the lackof this association in unaffected members—may be thefirst clue about the genetic basis of a disease.Trinucleotide sequences that increase in number(microsatellite instability) can cause disease. The unstablep(CGG) n repeat sequence is associated with thefragile X syndrome. Other trinucleotide repeats thatundergo dynamic mutation (usually an increase) areassociated with Huntington’s chorea (CAG), myotonicdystrophy (CTG), spinobulbar muscular atrophy (CAG),and Kennedy’s disease (CAG).ONE PERCENT OF CELLULAR DNAIS IN MITOCHONDRIAThe majority of the peptides in mitochondria (about54 out of 67) are coded by nuclear genes. The rest arecoded by genes found in mitochondrial (mt) DNA.Human mitochondria contain two to ten copies of asmall circular double-stranded DNA molecule thatmakes up approximately 1% of total cellular DNA.This mtDNA codes for mt ribosomal and transferRNAs and for 13 proteins that play key roles in the respiratorychain. The linearized structural map of thehuman mitochondrial genes is shown in Figure 36–8.Some of the features of mtDNA are shown in Table36–3.An important feature of human mitochondrialmtDNA is that—because all mitochondria are contributedby the ovum during zygote formation—it istransmitted by maternal nonmendelian inheritance.kb2 4 6 8 10 12 14 16OHPH1PH2ATPase8 6ND3ND4LOH12S 16S ND1 ND2 CO1 CO2 CO3 ND4 ND5 CYT BPLOLFigure 36–8. Maps of human mitochondrial genes. The maps represent the heavy (upper strand) and light(lower map) strands of linearized mitochondrial (mt) DNA, showing the genes for the subunits of NADHcoenzymeQ oxidoreductase (ND1 through ND6), cytochrome c oxidase (CO1 through CO3), cytochrome b(CYT B), and ATP synthase (ATPase 8 and 6) and for the 12S and 16S ribosomal mt rRNAs. The transfer RNAs are denotedby small open boxes. The origin of heavy-strand (OH) and light-strand (OL) replication and the promotersfor the initiation of heavy-strand (PH1 and PH2) and light-strand (PL) transcription are indicated by arrows.(Reproduced, with permission, from Moraes CT et al: Mitochondrial DNA deletions in progressive external ophthalmoplegiaand Kearns-Sayre syndrome. N Engl J Med 1989;320:1293.)ND6