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

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).