Chapter 062. Principles of Human Genetics (Part 5)

Crossing-over and genetic recombination. During chiasma formation, either of the two sister chromatids on one chromosome pairs with one of the chromatids of the homologous chromosome. Genetic recombination occurs through crossing-over and results in recombinant and nonrecombinantchromosome segments in the gametes. Together with the random segregation of the maternal and paternal chromosomes, recombination contributes to genetic diversity and forms the basis of the concept of linkage.After the first meiotic division, which results in two daughter cells (2n), the two chromatids of each chromosome separate during a second meiotic division to yield four gametes with a haploid state (1n). When...
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Chapter 062. Principles of Human Genetics (Part 5) Chapter 062. Principles of Human Genetics (Part 5)Figure 62-3 Crossing-over and genetic recombination. During chiasma formation,either of the two sister chromatids on one chromosome pairs with one of thechromatids of the homologous chromosome. Genetic recombination occursthrough crossing-over and results in recombinant and nonrecombinantchromosome segments in the gametes. Together with the random segregation ofthe maternal and paternal chromosomes, recombination contributes to geneticdiversity and forms the basis of the concept of linkage. After the first meiotic division, which results in two daughter cells (2n), thetwo chromatids of each chromosome separate during a second meiotic division toyield four gametes with a haploid state (1n). When the egg is fertilized by sperm,the two haploid sets are combined, thereby restoring the diploid state (2n) in thezygote. Regulation of Gene Expression Mechanisms that regulate gene expression play a critical role in thefunction of genes. The transcription of genes is controlled primarily bytranscription factors that bind to DNA sequences in the regulatory regions ofgenes. As described below, mutations in transcription factors cause a significantnumber of genetic disorders. Gene expression is also influenced by epigeneticevents, such as X-inactivation and imprinting, processes in which DNAmethylation or histone modifications are associated with gene silencing. Severalgenetic disorders, such as Prader-Willi syndrome (neonatal hypotonia,developmental delay, obesity, short stature, and hypogonadism) and Albrighthereditary osteodystrophy (resistance to parathyroid hormone, short stature,brachydactyly, resistance to other hormones in certain subtypes), exhibit theconsequences of genomic imprinting. Most studies of gene expression havefocused on the regulatory DNA elements of genes that control transcription.However, it should be emphasized that gene expression requires a series of steps,including mRNA processing, protein translation, and posttranslationalmodifications, all of which are actively regulated (Fig. 62-2). The new field of functional genomics is based on the concept thatunderstanding alterations of gene expression under various physiologic andpathologic conditions provides insight into the underlying processes, and byrevealing certain gene expression profiles, this knowledge may be of diagnosticand therapeutic relevance. The large-scale study of expression profiles, whichtakes advantage of microarray technologies, is also referred to as transcriptomicsbecause the complement of mRNAs transcribed by the cellular genome is calledthe transcriptome. Structure of Genes A gene product is usually a protein but can occasionally consist of RNAthat is not translated (e.g., microRNAs). Exons refer to the portion of genes thatare eventually spliced together to form mRNA. Introns refer to the spacing regionsbetween the exons that are spliced out of precursor RNAs during RNA processing(Fig. 62-2). The gene locus also includes regions that are necessary to control itsexpression. The regulatory regions most commonly involve sequences upstream(5) of the transcription start site, although there are also examples of controlelements within introns or downstream of the coding regions of a gene. Theupstream regulatory regions are also referred to as the promoter. The minimalpromoter usually consists of a TATA box (which binds TATA-binding protein,TBP) and initiator sequences that enhance the formation of an active transcriptioncomplex. A gene may generate various transcripts through the use of alternativepromoters and/or alternative splicing of exons, mechanisms that contribute to theenormous diversity of proteins and their functions. Transcriptional terminationsignals reside downstream, or 3, of a gene. Specific sequences, such as theAAUAAA sequence at the 3 end of the mRNA, designate the site forpolyadenylation (poly-A tail), a process that influences mRNA transport to thecytoplasm, stability, and translation efficiency. A rigorous test of the regulatoryregion boundaries involves expressing a gene in a transgenic animal to determinewhether the isolated DNA flanking sequences are sufficient to recapitulate thenormal developmental, tissue-specific, and signal-responsive features of theendogenous gene. This has been accomplished for only a few genes; there aremany examples in which large genomic fragments only partially reconstitutenormal gene regulation in vivo, implying the presence of distant regulatorysequences. Genome-wide analyses of selected transcription factor binding sites,such as for the estrogen receptor, reveal that the majority ...