Almost every human trait and disease has a genetic component, whether inherited orinfluenced by behavioral factors such as exercise. Genetic components can also modifythe bodys response to environmental factors such as toxins. Understanding theunderlying concepts of human genetics and the role of genes, behavior, and theenvironment is important for appropriately collecting and applying genetic and genomicinformation and technologies during clinical care. It is important in improving diseasediagnosis and treatment as well. This chapter provides fundamental information aboutbasic genetics concepts, including cell structure, the molecular and biochemical basisof disease, major types of genetic disease, laws of inheritance, and the impact ofgenetic variation.
Cells are the fundamental structural and functional units of every known livingorganism. Instructions needed to direct activities are contained within a DNA(deoxyribonucleic acid) sequence. DNA from all organisms is made up of the samechemical units (bases) called adenine, thymine, guanine, and cytosine, abbreviatedas A, T, G, and C. In complementary DNA strands, A matches with T, and C with G, toform base pairs. The human genome (total composition of genetic material within acell) is packaged into larger units known as chromosomesphysically separatemolecules that range in length from about 50 to 250 million base pairs. Human cellscontain two sets of chromosomes, one set inherited from each parent. Each cellnormally contains 23 pairs of chromosomes, which consist of 22 autosomes (numbered 1through 22) and one pair of sex chromosomes (XX or XY). However, sperm and ovanormally contain half as much genetic material: only one copy of eachchromosome.
Each chromosome contains many genes, the basic physical and functional units ofheredity. Genes are specific sequences of bases that encode instructions for how tomake proteins. The DNA sequence is the particular side-by-side arrangement of basesalong the DNA strand (e.g., ATTCCGGA). Each gene has a unique DNA sequence. Genescomprise only about 29 percent of the human genome; the remainder consists ofnon-coding regions, whose functions may include providing chromosomal structuralintegrity and regulating where, when, and in what quantity proteins are made. Thehuman genome is estimated to contain 20,000 to 25,000 genes.
Although each cell contains a full complement of DNA, cells use genes selectively.For example, the genes active in a liver cell differ from the genes active in abrain cell because each cell performs different functions and, therefore, requiresdifferent proteins. Different genes can also be activated during development or inresponse to environmental stimuli such as an infection or stress.
Many, if not most, diseases are caused or influenced by genetics. Genes, through theproteins they encode, determine how efficiently foods and chemicals are metabolized,how effectively toxins are detoxified, and how vigorously infections are targeted.Genetic diseases can be categorized into three major groups: single-gene,chromosomal, and multifactorial.
Changes in the DNA sequence of single genes, also known as mutations, cause thousandsof diseases. A gene can mutate in many ways, resulting in an altered protein productthat is unable to perform its normal function. The most common gene mutationinvolves a change or misspelling in a single base in the DNA.Other mutations include the loss (deletion) or gain (duplication or insertion) of asingle or multiple base(s). The altered protein product may still retain some normalfunction, but at a reduced capacity. In other cases, the protein may be totallydisabled by the mutation or gain an entirely new, but damaging, function. Theoutcome of a particular mutation depends not only on how it alters aproteins function, but also on how vital that particular protein is tosurvival. Other mutations, called polymorphisms, are natural variations in DNAsequence that have no adverse effects and are simply differences amongindividuals.
In addition to mutations in single genes, genetic diseases can be caused by largermutations in chromosomes. Chromosomal abnormalities may result from either the totalnumber of chromosomes differing from the usual amount or the physical structure of achromosome differing from the usual structure. The most common type of chromosomalabnormality is known as aneuploidy, an abnormal number of chromosomes due to anextra or missing chromosome. A usual karyotype (complete chromosome set) contains 46chromosomes including an XX (female) or an XY (male) sex chromosome pair. Structuralchromosomal abnormalities include deletions, duplications, insertions, inversions,or translocations of a chromosome segment. (See Appendix F for more information aboutchromosomal abnormalities.)
Multifactorial diseases are caused by a complex combination of genetic, behavioral,and environmental factors. Examples of these conditions include spina bifida,diabetes, and heart disease. Although multifactorial diseases can recur in families,some mutations such as cancer can be acquired throughout an individualslifetime. All genes work in the context of environment and behavior. Alterations inbehavior or the environment such as diet, exercise, exposure to toxic agents, ormedications can all influence genetic traits.
The basic laws of inheritance are useful in understanding patterns of diseasetransmission. Single-gene diseases are usually inherited in one of several patterns,depending on the location of the gene (e.g., chromosomes 1-22 or X and Y) andwhether one or two normal copies of the gene are needed for normal protein activity.Five basic modes of inheritance for single-gene diseases exist: autosomal dominant,autosomal recessive, X-linked dominant, X-linked recessive, and mitochondria. (Seediagram on following page.)
All individuals are 99.9 percent the same genetically. The differences in thesequence of DNA among individuals, or genetic variation, explain some of thedifferences among people such as physical traits and higher or lower risk forcertain diseases. Mutations and polymorphisms are forms of genetic variation. Whilemutations are generally associated with disease and are relatively rare,polymorphisms are more frequent and their clinical significance is not asstraightforward. Single nucleotide polymorphisms (SNPs, pronouncedsnips) are DNA sequence variations that occur when a singlenucleotide is altered. SNPs occur every 100 to 300 bases along the 3 billion-basehuman genome. A single individual may carry millions of SNPs.
Although some genetic variations may cause or modify disease risk, other changes mayresult in no increased risk or a neutral presentation. For example, genetic variantsin a single gene account for the different blood types: A, B, AB, and O.Understanding the clinical significance of genetic variation is a complicatedprocess because of our limited knowledge of which genes are involved in a disease orcondition and the multiple gene-gene and gene-behavior-environment interactionslikely to be involved in complex, chronic diseases. New technologies are enablingfaster and more accurate detection of genetic variants in hundreds or thousands ofgenes in a single process.
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GENETICS 101 - Understanding Genetics - NCBI Bookshelf
