Harrison's Internal Medicine Chapter 62. Principles of Human Genetics
Impact of Genetics on Medical Practice
Impact of Genetics on Medical Practice: Introduction
The beginning of the new millennium was marked by the announcement that the vast majority of the human genome had been sequenced. This milestone in the exploration of the human genome was preceded by numerous conceptual and technological advances.
(BQ) Part 1 book "Thompson & Thompson genetics in medicine" presents the following contents: Introduction to the human genome, human genetic diversity-mutation and polymorphism principles of clinical cytogenetics and genome analysis, the chromosomal and genomic basis of disease-disorders of the autosomes and sex chromosomes, genetic variation in populations,...
Inherited mitochondrial disorders are transmitted in a matrilineal fashion; all children from an affected mother will inherit the disease, but it will not be transmitted from an affected father to his children (Fig. 62-11D ). Alterations in the mtDNA affecting enzymes required for oxidative phosphorylation lead to reduction of ATP supply, generation of free radicals, and induction of apoptosis. Several syndromic disorders arising from mutations in the mitochondrial genome are known in humans and they affect both protein-coding and tRNA genes (Table 62-1 and Table 62-5).
Table 62-8 Genetic Approaches for Identifying Disease Genes
Classical linkage analysis
(parametric monogenic traits
large informative pedigrees
methods) Suitable for genome scan Difficult to obtain
sufficient statistical power for complex traits
Control not required
multifactorial disorders in isolated populations
methods (nonparametric identification methods) susceptibility genes
of sufficient nu...
Genetic linkage refers to the fact that genes are physically connected, or linked, to one another along the chromosomes. Two fundamental principles are essential for understanding the concept of linkage: (1) when two genes are close together on a chromosome, they are usually transmitted together, unless a recombination event separates them (Figs. 62-3, 62-8); and (2) the odds of a crossover, or recombination event, between two linked genes is proportional to the distance that separates them.
Table 62-1 Selected Databases Relevant for Genomics and Genetic Disorders
National Center Biotechnology Information (NCBI) for
Molecular biology information, public databases, computational
Extensive links to other
databases, genome resources, tutorials and
National Human Genome
information about the human genome sequence, genomes of other organisms, and research genomic ...
The Genetic Map
Given the size and complexity of the human genome, initial efforts aimed at developing genetic maps to provide orientation and to delimit where a gene of interest may be located. A genetic map describes the order of genes and defines the position of a gene relative to other loci on the same chromosome. It is constructed by assessing how frequently two markers are inherited together (i.e., linked) by association studies. Distances of the genetic map are expressed in recombination units, or centiMorgans (cM).
The Human DNA Sequence
The complete DNA sequence of each chromosome provides the highest resolution physical map. The 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 daunting several years ago, technical advances in DNA sequencing and bioinformatics led to the completion of a draft human sequence in June 2000, well in advance of the original goal year of 2003.
Transmission of Genetic Disease
Origins and Types of Mutations A mutation can be defined as any change in the primary nucleotide sequence of DNA regardless of its functional consequences. Some mutations may be lethal, others are less deleterious, and some may confer an evolutionary advantage. Mutations can occur in the germline (sperm or oocytes); these can be transmitted to progeny. Alternatively, mutations can occur during embryogenesis or in somatic tissues.
Complex Genetic Disorders
The expression of many common diseases such as cardiovascular disease, hypertension, diabetes, asthma, psychiatric disorders, and certain cancers is determined by a combination of genetic background, environmental factors, and lifestyle. A trait is called polygenic if multiple genes contribute to the phenotype or multifactorial if multiple genes are assumed to interact with environmental factors. Genetic models for these complex traits need to account for genetic heterogeneity and interactions with other genes and the environment.
In population genetics, the focus changes from alterations in an individual's genome to the distribution pattern of different genotypes in the population. In a case where there are only two alleles, A and a, the frequency of the genotypes will be p2 + 2pq + q2 = 1, with p2 corresponding to the frequency of AA, 2pq to the frequency of Aa, and q2 to aa. When the frequency of an allele is known, the frequency of the genotype can be calculated. Alternatively, one can determine an allele frequency, if the genotype frequency has been determined.
Allele frequencies vary...
DNA testing is performed by mutational analysis or linkage studies in individuals at risk for a genetic disorder known to be present in a family. Mass screening programs require tests of high sensitivity and specificity to be costeffective. Prerequisites for the success of genetic screening programs include the following: that the disorder is potentially serious; that it can be influenced at a presymptomatic stage by changes in behavior, diet, and/or pharmaceutical manipulations; and that the screening does not result in any harm or discrimination.
I wrote the first edition of this book more than
20 years ago, and the discoveries in genetics
since then have been phenomenal. The new
knowledge and applications of human genetics to
health and to society have made it even more necessary
that nurses "think genetically" in their practice
and, indeed in their lives. Genetic factors can
be responsible in some way for both direct and
indirect disease causation; for variation that determines
predisposition, susceptibility, and resistance
to disease and also for response to therapeutic
Flow of genetic information. Multiple extracellular signals activate intracellular signal cascades that result in altered 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 sequences. The mRNA is translated into a polypeptide chain to form the mature protein after undergoing posttranslational processing.
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.
Transcriptional Activation and Repression
Every gene is controlled uniquely, whether in its spatial or temporal pattern of expression or in its response to extracellular signals. It is estimated that transcription 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 representative of this group of diseases; mutations in several different islet cell–specific transcription factors cause various forms of MODY (Chap. 338).
Transgenic Mice as Models of Genetic Disease
Several organisms have been studied extensively as genetic models, including Mus musculus (mouse), Drosophila melanogaster (fruit fly), Caenorhabditis elegans (nematode), Saccharomyces cerevisiae (baker's yeast), and Escherichia coli (colonic bacterium). The ability to use these evolutionarily distant organisms as genetic models that are relevant to human physiology reflects a surprising conservation of genetic pathways and gene function.
Allelic Association, Linkage Disequilibrium, and Haplotypes
Allelic association refers to a situation in which the frequency of an allele is significantly increased or decreased in individuals affected by a particular disease in comparison to controls.
Linkage and association differ in several aspects. Genetic linkage is demonstrable in families or sibships. Association studies, on the other hand, compare a population of affected individuals with a control population.
More discrete sequence alterations rely heavily on the use of the PCR, which allows rapid gene amplification and analysis. Moreover, PCR makes it possible to perform genetic testing and mutational analysis with small amounts of DNA extracted from leukocytes or even from single cells, buccal cells, or hair roots. Screening for point mutations can be performed by numerous methods (Table 62-9); most are based on the recognition of mismatches between nucleic acid duplexes, electrophoretic separation of single- or double-stranded DNA, or sequencing of DNA fragments amplified by PCR.
Chapter 1 - Genetics: The study of biological information. This chapter includes contents: DNA - The fundamental information molecule of life, proteins: the functional molecules of life processes, complex systems and molecular interactions, molecular similarities of all life-forms, the modular construction of genomes, modern genetic techniques, human genetics.