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For some quantitative traits such as adult height or serum glucose concentration in normal individuals, it is difficult to distinguish the contributions of individual genes; this is because in general, phenotypes are the products of multiple genes acting in concert, and obviously influenced by the environment and chance. However, if one of the genes in the system is aberrant, a major departure from the “normal” or expected phenotype might arise. Whether the aberrant phenotype is serious (ie, a disease) or even recognized depends on the nature of the defective gene product and how resilient the system is to disruption. The latter point emphasizes the importance of homeostasis in both physiology and development—many pathogenic variants go unrecognized because the system can cope, even though tolerances for further perturbation might be narrowed.

In other words, most human characteristics and common diseases are polygenic, whereas many of the disordered phenotypes traditionally thought of as “genetic” are monogenic but still influenced by other loci in a person’s genome.

Phenotypes due to alterations at a single gene are also characterized as mendelian, after Gregor Mendel, the monk and part-time biologist who studied the reproducibility and recurrence of variation in garden peas. He showed that some traits were dominant to other traits, which he called recessive. The dominant traits required only one copy of a “factor” to be expressed, regardless of what the other copy was, whereas the recessive traits required two copies before expression occurred. In modern terms, the mendelian factors are genes, and the alternative copies of the gene are alleles. Let A be the common (normal) allele and let a be a mutant allele at a locus: If the same phenotype is present whether the genotype is A/a or a/a, the phenotype is dominant, whereas if the phenotype is present only when the genotype is a/a, it is recessive.

In medicine, it is important to keep two considerations in mind: First, dominance and recessiveness are attributes of the phenotype, not the gene; and second, the concepts of dominance and recessiveness depend on how the phenotype is defined. To illustrate both points, consider sickle cell disease. This condition occurs when a person inherits two alleles for betaS-globin, in which the normal glutamate at position 6 of the protein has been replaced by valine; the genotype for the beta-globin locus is HbS/HbS, compared with the normal HbA/HbA. When the genotype is HbS/HbA, the individual does not have sickle cell disease, so this condition satisfies the criteria for being a recessive phenotype. But consider the phenotype of sickled erythrocytes; red cells with the genotype HbS/HbS clearly sickle—but, if the oxygen tension is reduced, so do cells with the genotype HbS/HbA. Therefore, sickling is a dominant trait, and symptoms occasionally develop in heterozygous individuals when atmospheric oxygen is reduced, ...

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