... Chapter 062. Principlesof
Human Genetics
(Part 12)
The Genetic Map
Given the size and complexity of the human genome, initial efforts aimed
at developing ... the identification of disease-causing genes by
positional cloning.
Recent insights into the structure of the normal human genome show that
certain blocks of DNA sequences, often containing numerous ...
corresponds to ~1 Mb of DNA (Fig. 62-3). Any polymorphic sequence variation
can be useful for mapping purposes. Examples of polymorphic markers include
variable number of tandem repeats (VNTRs),...
... fundamental principlesof genetics. The
pervasive nature of the role ofgenetics in medicine makes it imperative for
physicians and other health care professionals to become more informed about
genetics ... 64). The application of screening and prevention strategies will
Chapter 062. Principlesof
Human Genetics
(Part 13)
The Human DNA Sequence
The complete DNA sequence of each chromosome provides ... primary focus of the HGP was to obtain DNA
sequence for the entire human genome as well as model organisms. Although the
prospect of determining the complete sequence of the human genome seemed...
... Medicine > Chapter 62. PrinciplesofHuman
Genetics
Impact ofGenetics on Medical Practice
Impact ofGenetics on Medical Practice: Introduction
The beginning of the new millennium was ... distinct forms of Alzheimer's
disease, several of which lead to the formation of neurofibrillary tangles (Chap.
365). The identification of defective genes often leads to the detection of cellular ... and the generation of genetic and physical maps by the Human Genome Project
(HGP). The consequences of this wealth of knowledge for the practice of medicine
are profound. To date, the most...
...
information of
eukaryotic
genomes
Online
Mendelian
Inheritance in Man
http://www.ncbi.nlm.nih.gov/omim/ Online
compendium of
Mendelian
disorders and
human genes
causing genetic
disorders
Office ... and
Molecular Bases of
Inherited Disease
(OMMBID)
http:/ /genetics. accessmedicine.com Online
version of the
comprehensive text
on The Metabolic
and Molecular
Bases of Inherited
Disease, ... text
on The Metabolic
and Molecular
Bases of Inherited
Disease, 8e
Chapter 062. Principlesof
Human Genetics
(Part 1)
Table 62-1 Selected Databases Relevant for Genomics and Genetic...
... (or linked
genes) with the presence of a disease or genetic trait (see below).
Chapter 062. Principlesof
Human Genetics
(Part 4)
Figure 62-2
Flow of genetic information. Multiple extracellular ... regulation of gene expression
through the interaction of transcription factors with regulatory regions of genes.
RNA polymerase transcribes DNA into RNA that is processed to mRNA by
excision of intronic ... pairs of sister chromatids (2n →4n). The process of DNA synthesis
requires stringent fidelity in order to avoid transmitting errors to subsequent
generations of cells. Genetic abnormalities of...
... Chapter 062. Principlesof
Human Genetics
(Part 5)
Figure 62-3
Crossing-over and genetic recombination. During chiasma formation,
either of the two sister chromatids on ... 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 ... 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...
... deletion mutations of the β-
globin gene or larger deletions of the globin locus that can also result in
Chapter 062. Principlesof
Human Genetics
(Part 6)
The number of DNA sequences and ...
Figure 62-5
A. Examples of mutations. The coding strand is shown with the encoded
amino acid sequence. B. Chromatograms of sequence analyses after amplification
of genomic DNA by polymerase ... result in altered expression or splicing of genes. Examples are shown
in Fig. 62-5.
Figure 62-4
Point mutations causing β-thalassemia as example of allelic
heterogeneity. The β-globin gene...
...
Chapter 062. Principlesof
Human Genetics
(Part 7)
Transcriptional Activation and Repression
Every gene is controlled uniquely, whether in its spatial or temporal pattern
of expression ... representative of this group of
diseases; mutations in several different islet cell–specific transcription factors
cause various forms of MODY (Chap. 338).
Table 62-2 Selected Examples of Diseases ... factors account for ~30% of expressed genes. A growing number of
identified genetic diseases involve transcription factors (Table 62-2). The MODY
(maturity-onset diabetes of the young) disorders...
... are widely used in genetics and molecular
diagnostics, however, it is useful to review briefly some of the fundamental
principles of cloning and DNA sequencing.
Cloning of Genes
Cloning refers ... events.
Suppression of gene expression is as important as gene activation in the
control of cell differentiation and function. Some mechanisms of repression are the
corollary of activation. For ... expression of recombinant
proteins, and other recombinant DNA procedures.
The cloning of DNA involves the insertion of a DNA fragment into a
cloning vector, followed by the propagation of the...
... Chapter 062. Principlesof
Human Genetics
(Part 9)
Nucleic Acid Hybridization
Nucleic acid hybridization is a fundamental principle in molecular biology
that takes advantage of the fact ... expression pattern of large numbers of mRNA transcripts can be determined
by hybridization of RNA samples to cDNA or genomic microarrays. This method
has tremendous potential in the era of functional ... and permits
comprehensive analyses of gene expression profiles. As one example, microarrays
can be used to develop genetic fingerprints of different types of malignancies,
providing information...
... integration of
transgene
Transgenic
Pronuclear
injection of transgene
Variable copy numbers of
transgene
Chapter 062. Principlesof
Human Genetics
(Part 10)
Transgenic Mice as Models of Genetic ... are relevant to human physiology reflects
a surprising conservation of genetic pathways and gene function. Transgenic
mouse models have been particularly valuable, because many human and mouse ... be divided into two main approaches: (1)
expression of a gene by random insertion into the genome, and (2) deletion or
targeted mutagenesis of a gene by homologous recombination with the native...
... 062. Principlesof
Human Genetics
(Part 14)
Transmission of Genetic Disease
Origins and Types of Mutations
A mutation can be defined as any change in the primary nucleotide
sequence of ... an important cause of genetic
diversity as well as disease. Mutation rates are difficult to determine in humans
because many mutations are silent and because testing is often not adequate to ... at a rate of ~10
–10
/bp per cell division. Germline mutation rates
(as opposed to somatic mutations) are relevant in the transmission of genetic
disease. Because the population of oocytes...
... checkpoints. Mutations in the ATM gene give rise to defects in meiosis as
Chapter 062. Principlesof
Human Genetics
(Part 15)
Unequal Crossing-Over
Normally, DNA recombination in germ cells ... function is rescued by the
fusion of cells derived from two different forms of xeroderma pigmentosum.
Ataxia telangiectasia causes large telangiectatic lesions of the face,
cerebellar ataxia, ... effects of ultraviolet irradiation. More than 10 different
genes have been shown to cause the different forms of xeroderma pigmentosum.
This finding is consistent with the earlier classification of...
... the
∆F508 deletion of phenylalanine (F) in the CFTR gene are examples of allelic
variants of these genes that result in disease. Because each individual has two
copies of each chromosome (one ... with a loss of one X chromosomal locus.
that certain types of mutations (C →T or G →A) are relatively common, the
nature of the genetic code also results in overrepresentation of certain amino ... mutation (see below for discussion of anticipation). Trinucleotide
expansion was first recognized as a cause of the fragile X syndrome, one of the
most common causes of mental retardation. Other...
...
Chapter 062. Principlesof
Human Genetics
(Part 17)
Genotypes describe the specific alleles at a particular locus. For example,
there are three common alleles (E2, E3, E4) of the apolipoprotein ...
focuses on a panel of mutations that are particularly frequent (often taking the
ethnic background of the patient into account), but a negative result does not
exclude the presence of a mutation ...
the role of specific HLA allelic variants in susceptibility to these autoimmune
diseases. The recent characterization of common SNP haplotypes in four
populations from different parts of the...