The simplest genetic characters are those whose presence or absence depends on the genotype at a single locus. That is not to say that the character itself is programmed by only one pair of genes: expression of any human character is likely to depend on the action of a large number of genes and environmental factors. However, sometimes a particular genotype at one locus is both necessary and sufficient for the character to be expressed, given the normal range of human genetic and environmental backgrounds. Such monogenic characters are called Mendelian because their pattern of inheritance follows that established by Gregor Mendel.
Mendelian characters can be recognized by the characteristic pedigree patterns they give, as described in the next section. The best starting point for acquiring information on any such character, whether pathological or nonpathological, is the Online Mendelian Inheritance in Man (OMIM) database, https://www.ncbi.nlm.nih.gov/omim. OMIM contains about 24,000 entries, which may be sequenced genes, characters or diseases associated with known sequenced genes, or characters that are inherited in a Mendelian way but for which no gene has yet been identified. Some entries describe Mendelian sub sets of characters that are not in aggregate Mendelian—breast cancer, for example. Users need to be aware that in those cases the OMIM entry will therefore not give a balanced picture of the overall etiology. Each entry is a detailed review, usually historically ordered, of the genetics of a character or the history and function of a gene, with subsidiary clinical and other information, and a very useful list of references. Entries have accumulated text over many years with only patchy rewrites, so that the early part of an entry may not reflect current understanding. Where appropriate, throughout this book the OMIM reference number is quoted for each human character or gene when it is first described.
Most human genetic or partly genetic characters are not Mendelian. They are governed by genes at more than one locus. The more complex the pathway between a DNA sequence and an observable trait, the less likely it is that the trait will show a simple Mendelian pedigree pattern. Thus, DNA sequence variants are almost always inherited in a cleanly Mendelian manner. Disease states or other traits that reflect the biochemical action of a protein within a cellular or organismal context are less often entirely determined by alleles at a single genetic locus. The failure or malfunction of a developmental pathway that results in a birth defect is likely to involve a complex balance of factors. Thus, the common birth defects such as cleft palate, spina bifida, or congenital heart dis ease are rarely overall Mendelian, though there may be Mendelian subsets where major malfunction at a single locus derails an entire pathway. Behavioral traits such as IQ test performance or schizophrenia are still less likely to be Mendelian—but they may still be genetically determined to a greater or lesser extent.
Non-Mendelian characters may depend on two, three, or many genetic loci. We use multifactorial here as a catch-all term covering all these possibilities. More specifically, the genetic determination may involve a small number of loci (oligogenic) or many loci each of individually small effect (polygenic); or there may be a single major locus with a polygenic background—that is, the genotype at one locus has a major effect on the phenotype, but this effect is modified by the cumulative minor effects of genes at many other loci. In reality, characters form a continuous spectrum, from perfectly Mendelian through to truly polygenic (Figure1A). Superimposed on this there may be a greater or smaller effect of environmental factors. The overall etiology of a character could be represented by a point somewhere within the triangle of Figure 1B.
Fig1. Determinants of a phenotype. (A) ABO blood group depends (with rare exceptions) on the genotype at just one locus, the ABO locus at chromosome 9q34. Rhesus hemolytic disease of the newborn depends on the genotypes of mother and baby at the RHD locus at chromosome 1p36, but also on mother and baby being ABO compatible. Hirschsprung disease depends on the interaction of several genetic loci. Adult stature is determined by the cumulative small effects of many loci. (B) Nongenetic factors, collectively termed environmental, are important for many phenotypes, for example Hirschsprung disease and adult stature. The overall etiology of a character could be represented as a point somewhere within the triangle.
Mendelian characters are necessarily dichotomous: characters such as cystic fibrosis or extra fingers that you either have or do not have. Most human characteristics are not dichotomous. Think of the way you would describe a person so as to enable a friend to recognize them. Apart from sex (in most cases) and maybe hair and eye color, almost none of the characters you would describe are dichotomous. Most are continuous or quantitative characters such as height or weight—characters we all have, but to different degrees.
Such characters are necessarily non-Mendelian, but that is not to say that genes can have no role in determining them. The underlying loci are described as quantitative trait loci (QTLs). Dichotomous characters can also be non-Mendelian but wholly or partly genetically determined: they may tend to run in families, but the pedigrees do not fit any standard Mendelian pattern. The genetic factors may be described as susceptibility genes. QTLs and susceptibility genes are not different at the molecular level from Mendelian genes, just the characters concerned are determined in a more complex way. Variants in the same gene may be a Mendelian determinant of one phenotype and a QTL for another.
In a further layer of complication, a common human condition such as diabetes is likely to be very heterogeneous in its causation. Some cases may have a simple Mendelian cause, some might be entirely the result of environmental factors, while the majority of cases may be multifactorial. Such conditions are called complex.
