Chapter 062. Principles of Human Genetics (Part 5) pot

Regulation of Gene Expression Mechanisms that regulate gene expression play a critical role in the function of genes.. The transcription of genes is controlled primarily by transcriptio

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 the chromatids of the homologous chromosome Genetic recombination occurs through crossing-over and results in recombinant and nonrecombinant chromosome 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 the egg is fertilized by sperm, the two haploid sets are combined, thereby restoring the diploid state (2n) in the

zygote

Regulation of Gene Expression

Mechanisms that regulate gene expression play a critical role in the function of genes The transcription of genes is controlled primarily by

transcription factors that bind to DNA sequences in the regulatory regions of

genes As described below, mutations in transcription factors cause a significant

number of genetic disorders Gene expression is also influenced by epigenetic

events, such as X-inactivation and imprinting, processes in which DNA

methylation or histone modifications are associated with gene silencing Several

genetic disorders, such as Prader-Willi syndrome (neonatal hypotonia, developmental delay, obesity, short stature, and hypogonadism) and Albright hereditary osteodystrophy (resistance to parathyroid hormone, short stature, brachydactyly, resistance to other hormones in certain subtypes), exhibit the consequences of genomic imprinting Most studies of gene expression have focused 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 posttranslational modifications, all of which are actively regulated (Fig 62-2)

The new field of functional genomics is based on the concept that

understanding alterations of gene expression under various physiologic and pathologic conditions provides insight into the underlying processes, and by revealing certain gene expression profiles, this knowledge may be of diagnostic and therapeutic relevance The large-scale study of expression profiles, which

takes advantage of microarray technologies, is also referred to as transcriptomics

because the complement of mRNAs transcribed by the cellular genome is called

the transcriptome

Structure of Genes

A gene product is usually a protein but can occasionally consist of RNA

that is not translated (e.g., microRNAs) Exons refer to the portion of genes that

are eventually spliced together to form mRNA Introns refer to the spacing regions

between 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 its expression The regulatory regions most commonly involve sequences upstream (5') of the transcription start site, although there are also examples of control elements within introns or downstream of the coding regions of a gene The

upstream regulatory regions are also referred to as the promoter The minimal

promoter usually consists of a TATA box (which binds TATA-binding protein, TBP) and initiator sequences that enhance the formation of an active transcription complex A gene may generate various transcripts through the use of alternative promoters and/or alternative splicing of exons, mechanisms that contribute to the enormous diversity of proteins and their functions Transcriptional termination signals reside downstream, or 3', of a gene Specific sequences, such as the AAUAAA sequence at the 3' end of the mRNA, designate the site for polyadenylation (poly-A tail), a process that influences mRNA transport to the cytoplasm, stability, and translation efficiency A rigorous test of the regulatory region boundaries involves expressing a gene in a transgenic animal to determine whether the isolated DNA flanking sequences are sufficient to recapitulate the normal developmental, tissue-specific, and signal-responsive features of the endogenous gene This has been accomplished for only a few genes; there are

many examples in which large genomic fragments only partially reconstitute normal gene regulation in vivo, implying the presence of distant regulatory sequences Genome-wide analyses of selected transcription factor binding sites, such as for the estrogen receptor, reveal that the majority of regulatory sites are very distant from the transcription start sites of genes A detailed understanding of mechanisms that regulate genes is also relevant for gene therapy strategies that require normal gene regulation (Chap 65)