Über die Autorin bzw. den Autor

STUART M. BROWN, PhD, is on the faculty of the New York University School of Medicine, where he is Associate Professor and Director of the Bioinfor-matics Core Facility and Director of the graduate Bioinformatics course.

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An up-to-date edition of the groundbreaking classic

Medical genomics is rapidly moving into mainstream medicine, with new and emerging technologies such as molecular genetic diagnostic tests and gene therapy having an unprecedented impact in clinical practice. Consequently, there is an urgent need for physicians and medical students to understand these developments and their evolving roles in the post-genomics era. This book fills that important need with a practical, comprehensive introduction to genomics with a focus on its impact on medical research and practice.

This valuable new edition has been thoroughly and meticulously updated and expanded to include the most exciting and up-to-the-minute topics in biomedical research, including all-new chapters on multilocus SNP genotyping (SNP chips), RNAi, ChIP-chip, and genomic tiling arrays. It also includes thoroughly revised coverage of topics from the previous edition, including molecular biology, biotechnology, genome databases, bioinformatics tools, human genetic variation, genetic testing, gene therapy, microarray and related gene expression technology, analysis of microarray data, pharmacogenomics and toxico-genomics, clinical research informatics, alternative splicing, cancer genomics, proteomics, consumer genomics, and genetic data privacy and ethics.

Covering concepts and techniques that are currently in use, as well as those on the cutting-edge of science, Essentials of Medical Genomics, Second Edition gives physicians and medical students everything they need to know about genomics and emerging technologies. Now 50% more comprehensive than the previous edition, and complemented with useful exercises and an appendix, this Second Edition is truly the most useful handbook available.

Aus dem Klappentext

An up-to-date edition of the groundbreaking classic

Medical genomics is rapidly moving into mainstream medicine, with new and emerging technologies such as molecular genetic diagnostic tests and gene therapy having an unprecedented impact in clinical practice. Consequently, there is an urgent need for physicians and medical students to understand these developments and their evolving roles in the post-genomics era. This book fills that important need with a practical, comprehensive introduction to genomics with a focus on its impact on medical research and practice.

This valuable new edition has been thoroughly and meticulously updated and expanded to include the most exciting and up-to-the-minute topics in biomedical research, including all-new chapters on multilocus SNP genotyping (SNP chips), RNAi, ChIP-chip, and genomic tiling arrays. It also includes thoroughly revised coverage of topics from the previous edition, including molecular biology, biotechnology, genome databases, bioinformatics tools, human genetic variation, genetic testing, gene therapy, microarray and related gene expression technology, analysis of microarray data, pharmacogenomics and toxico-genomics, clinical research informatics, alternative splicing, cancer genomics, proteomics, consumer genomics, and genetic data privacy and ethics.

Covering concepts and techniques that are currently in use, as well as those on the cutting-edge of science, Essentials of Medical Genomics, Second Edition gives physicians and medical students everything they need to know about genomics and emerging technologies. Now 50% more comprehensive than the previous edition, and complemented with useful exercises and an appendix, this Second Edition is truly the most useful handbook available.

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Essentials of Medical Genomics

John Wiley & Sons

Chapter One

The Human Genome Project is a bold undertaking to understand, at a fundamental level, all of the genetic information required to build and maintain a human being. The human genome is the complete information content of the human cell. This information is encoded in approximately 3.2 billion base pairs of DNA contained on 46 chromosomes (22 pairs of autosomes plus the two sex chromosomes-see Figure 1.1). The completion, in 2001, of the first draft of the human genome sequence was only the first phase of this project (Venter et al. 2001; Lander et al. 2001).

To use the metaphor of a book, the draft genome sequence gives biology all of the letters, in the correct order on the pages, but without the ability to recognize words, sentences, and punctuation, or even an understanding of the language in which the book is written. The task of making sense of all of this raw biological information falls, at least initially, to bioinformatics specialists who make use of computers to find the words and decode the language. The next step is to integrate all of this information into a new form of experimental biology, known as genomics, that can ask meaningful questions about what is happening in very complex systems where tens of thousands of different genes and proteins are interacting simultaneously.

The primary justification for the considerable amount of money spent on sequencing the human genome (from governments and private corporations) is that this information will lead to dramatic medical advances. In fact, the first wave of new drugs and medical technologies derived from genome information is currently making its way through clinical trials and into the healthcare system. However, to effectively utilize these new advances, medical professionals need to understand something about genes and genomes. Just as it is important for physicians to understand how to Gram-stain and evaluate a culture of bacteria, even if they never actually perform this test themselves in their medical practices, it is important to understand how DNA technologies work in order to appreciate their strengths, weaknesses, and peculiarities.

However, before we can discuss whole genomes and genomic technologies, it is necessary to understand the basics of how genes function to control biochemical processes within the cell (molecular biology) and how hereditary information is transmitted from one generation to the next (genetics).

The Principles of Inheritance

The principles of genetics were first described by the monk Gregor Mendel in 1866 in his observations of the inheritance of traits in garden peas ["Versuche ber Pflanzen-Hybriden" (Mendel 1866)]. Mendel described "differentiating characters" (differierende Merkmale) which may come in several forms. In his monastery garden, he made crosses between strains of garden peas that had different characters, each with two alternate forms that were easily observable, such as purple or white flower color, yellow or green seed color, smooth or wrinkled seed shape, and tall or short plant height. (These alternate forms are now known as alleles.) Then he studied the distribution of these forms in several generations of offspring from his crosses.

Mendel observed the same patterns of inheritance for each of these characters. Each strain, when bred with itself, showed no changes in any of the characters. In a cross between two strains that differ for a single character, such as pink versus white flowers, the first generation of hybrid offspring (the [F.sub.1]) all resembled one parent-all pink. Mendel called this the dominant form of the character. After self-pollinating the [F.sub.1] plants, the second-generation plants (the [F.sub.2]) showed a mixture of the two parental forms (see Figure 1.2). This is known as segregation. The recessive form that was not seen in the [F.sub.1]s (white flowers) was found in one-fourth (25%) of the [F.sub.2] plants.

Mendel also made crosses between strains of peas that differed for two or more traits. He found that each trait was assorted independently in the progeny-there was no connection between whether an [F.sub.2] plant had the dominant or recessive form for one character and which form it carried for another character (see Figure 1.3).

Mendel created a theoretical model ("Mendel's laws of genetics") to explain his results. He proposed that each individual has two copies of the hereditary material for each character, which may determine different forms of that character. These two copies separate and are subjected to independent assortment during the formation of gametes (sex cells). When a new individual is created by the fusion of two sex cells, the two copies from the two parents combine to produce a visible trait depending on which form is dominant and which is recessive. Mendel did not propose any physical explanation for how these traits were passed from parent to progeny; his characters were purely abstract units of heredity.

Modern genetics has completely embraced Mendel's model with some additional detail. There may be more than two different alleles for a gene in a given population, but each individual has only two, which may be the same (homozygous) or different (heterozygous). In some cases two different alleles combine to produce an intermediate form in heterozygous individuals, so that red and white flower alleles may combine to produce pink or type A and type B blood alleles, which in turn combine to produce the AB blood type.

Genes Are on Chromosomes

In 1902, Walter Sutton, a microscopist, proposed that Mendel's heritable characters resided on the chromosomes which he observed inside the cell nucleus (see Figure 1.4). Sutton observed that "the association of paternal and maternal chromosomes in pairs and their subsequent separation during cell division ... may constitute the physical basis of the Mendelian law of heredity" (Sutton 1903).

In 1909, the Danish botanist Wilhelm Johanssen coined the term "gene" to describe Mendel's heritable characters. In 1910, Thomas Hunt Morgan found that a trait for white eye color was located on the X chromosome of the fruitfly and was inherited together with a factor that determines sex (Morgan 1910). A number of subsequent studies by Morgan (1919) and others showed that each gene for a particular trait was located at a specific spot or locus on a chromosome in all individuals of a species. The chromosome was perceived as a linear organization of genes, like beads on a string. Throughout the early part of the twentieth century, a gene was considered to be a single, fundamental, indivisible unit of heredity, in much the same way as an atom was considered to be the fundamental unit of matter.

Each individual has two copies of each type of chromosome, having received one copy from each parent. The two copies of each chromosome in the parent are randomly divided into the sex cells (sperm and egg) in a process called segregation. It is possible to observe the segregation of chromosomes during meiosis using only a moderately powerful microscope. It is an aesthetically satisfying triumph of biology that this observed segregation of chromosomes in cells exactly corresponds to the segregation of traits that Mendel observed in his peas.

Recombination and Linkage

In the early twentieth...