Sinopsis
The completion of the human genome project has heralded a new era in biology. Undoubtedly, knowledge of the genetic blueprint will expedite the search for genes responsible for specific medical disorders, simplify the search for mammalian homologues of crucial genes in other biological systems and assist in the prediction of the variety of gene products found in each cell. It can also assist in determining the small but potentially significant genetic variations between individuals. However, sequence information alone is of limited value without a description of the function and, importantly, of the regulation of the gene products. Our bodies consist of hundreds of different cell types, each designed to perform a specific role that contributes to the overall functioning of the organism. Every one of these cells contains the same 20 000 to 30 000 genes that we are estimated to possess. The remarkable diversity in cell specialization is achieved through the tightly controlled expression and regulation of a precise subset of these genes in each cell lineage. Further regulation of these gene products is required in the response of our cells to physiological and environmental cues. Most impressive perhaps is how a tightly controlled program of gene expression guides the development of a fertilised oocyte into a full-grown adult organism. The human genome has been called our genetic blueprint, but it is the process of gene expression that truly brings the genome to life. In this chapter we aim to provide a general overview of the physical appearance of genes and the mechanisms of their expression.
The realization that certain traits are inherited from our ancestors must have been around for ages, but the study of these hereditary traits was first established by the Austrian monk Gregor Mendel. In his monastery in Brno, Czechoslovakia, he performed his famous experiments crossing pea plants and following a number of hereditary traits. He realised that many of these traits were under the control of two distinct factors, one
coming from the male parent and one from the female. He also noted that the traits he studied were not linked and thus must have resided on separate hereditary units, now known as chromosomes, and that some appearances of a trait could be dominant over others. In the early 1900s, with the rediscovery of Mendel’s work, the factors conveying hereditary traits were named ‘‘genes’’ by Wilhelm Johanssen. A large amount of
research since then has led to our current understanding about what constitutes a gene and how genes work.
Genes can be defined in two different ways: the gene as a ‘‘unit of inheritance’’, or the gene as a physical entity with a fixed position on the chromosome that can be mapped in relation to other genes (the genomic locus). While the latter is the more traditional view of a gene the former view is more suited to our current understanding of the genomic architecture of genes. A gene gives rise to a phenotype through its ability to generate an RNA (ribonucleic acid) or protein product. Thus the functional genetic unit must encompass not
only the DNA (deoxyribonucleic acid) that is transcribed into RNA, but also all of the surrounding DNA sequences that are involved in its transcription. Those regulatory sequences are called the cis-regulatory elements, and contain the binding sites for trans-acting transcription factors. Cis-regulatory elements can be grouped into different classes which will be discussed in more detail later. Recently it has become recognized
that cis-regulatory elements can be located anywhere on the chromosomal segment surrounding the gene from next to the promoter to many hundreds of kilobases away, either upstream or downstream. Notably, they can also be found in introns of neighboring genes or in the intergenic region beyond the next gene. Crucially, the concept of a gene as a functional genetic unit allows genes to overlap physically yet remain isolated from one another if they bind different sets of transcription factors (Dillon, 2003). As more genes are characterized in greater detail, it is becoming clear that overlap of functional genetic units is a widespread phenomenon.
Content
- Genes and their expression
- Epigenetic modification of chromatin
- Population genetics and disease
- Mapping common disease genes
- Population diversity, genomes and disease
- Study design in mapping complex disease traits
- Diseases of protein misfolding
- Aging and disease
- The MHC paradigm: genetic variation and complex disease
- Lessons from single gene disorders
- Common Medical Disorders
- Developmental disorders
- Genes, environment and cancer
- The polygenic basis of breast cancer
- TP53: A master gene in normal and tumor suppression
- Genetics of colorectal cancer
- Genetics of autoimmune disease
- Susceptibility to infectious diseases
- Inflammatory bowel diseases
- Genetic anemias
- Genetics of chronic disease: obesity
- Type 2 diabetes mellitus
- Genetics of coronary heart disease
- Genetics of hypertension
- Obstructive pulmonary disease
- Skeletal disorders
- The genetics of common skin diseases
- Molecular genetics of Alzheimer’s disease and other adult-onset dementias
- Major psychiatric disorders in adult life
- Speech and language disorders
- Common forms of visual handicap
- Genetic and environmental influences on hearing impairment
- Pharmacogenomics: clinical applications
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