In real life various complications often disguise a basic mendelian pattern. Figure 3.5 shows a number of common complications.

If a character is common in the population, there is a high chance that it may be brought into the pedigree independently by two or more people. A common recessive character like blood group O may be seen in successive generations because of repeated marriages of group O people with heterozygotes. This produces a pattern resembling dominant inheritance (Figure 3.5A). Thus the classic pedigree patterns are best seen with rare characters.

With dominant conditions, nonpenetrance is a frequent complication. The penetrance of a character, for a given genotype, is defined as the probability that a person who has the genotype will manifest the character. By definition, a dominant character is manifest in a heterozygous person, and so should show 100% penetrance. Nevertheless, many human characters, while generally showing dominant inheritance, occasionally skip a generation. In Figure 3.5B, II₂ has an affected parent and an affected child, and almost certainly carries the mutant gene, but is phenotypically normal. This would be described as a case of non-penetrance.

There is no mystery about nonpenetrance; indeed, 100% penetrance is the more surprising phenomenon. Very often the presence or absence of a character depends, in the main and in normal circumstances, on the genotype at one locus, but an unusual genetic background, a particular lifestyle or maybe just chance means that the occasional person may fail to manifest the character. Nonpenetrance is a major pitfall in genetic counseling. It would be an unwise counselor who, knowing the condition in Figure 3.5B was dominant and seeing III₇ was free of signs, told her that she had no risk of having affected children. One of the jobs of genetic counselors is to know the usual degree of penetrance of each dominant syndrome.

Frequently, of course, a character depends on many factors and does not show a mendelian pedigree pattern even if entirely genetic. There is a continuum of characters from fully penetrant mendelian to multifactorial (Section 3.4.2; Figure 3.10), with increasing influence of other genetic loci and/or the environment. No logical break separates imperfectly penetrant mendelian from multifactorial characters; it is a question of which is the most useful description to apply.

A particularly important case of reduced penetrance is seen with late-onset diseases. Genetic conditions are, of course, not necessarily congenital (present at birth). The genotype is fixed at conception, but the phenotype may not manifest until adult life. In such cases the penetrance is age-related. Huntington disease is a well-known example (Figure 3.6). Delayed onset might be caused by slow accumulation of a noxious substance, by slow tissue death or by inability to repair some form of environmental damage. Hereditary cancers are caused by a second mutation affecting a cell of a person who already carries one mutation in a tumor suppressor gene (Chapter 18). Depending on the disease, the penetrance may become 100% if the person lives long enough, or there may be people who carry the gene but who will never develop symptoms no matter how long they live. Age-of-onset curves such as Figure 3.6 are important tools in genetic counseling, because they enable the geneticist to estimate the chance that an at-risk but asymptomatic person will subsequently develop the disease.

Related to nonpenetrance is the variable expression frequently seen in dominant conditions. Figure 3.5C shows an example from a family with Waardenburg syndrome. Different family members show different features of the syndrome. The cause is the same as with nonpenetrance: other genes, environmental factors or pure chance have some influence on development of the symptoms. Nonpenetrance and variable expression are typically problems with dominant, rather than recessive, characters. Partly this reflects the difficulty of spotting nonpenetrant cases in a typical recessive pedigree. However, as a general rule, recessive conditions are less variable than dominant ones, probably because the phenotype of a heterozygote involves a balance between the effects of the two alleles, so that the outcome is likely to be more sensitive to outside influence than the phenotype of a homozygote. However, both nonpenetrance and variable expression are occasionally seen in recessive conditions.

These complications are much more conspicuous in humans than in plants or other animals, because laboratory animals and crop plants are far more genetically uniform than humans. What we see in human genetics is typical of a wild population. Nevertheless, mouse geneticists are familiar with the way expression of a mutant can change when it is bred onto a different genetic background, and understand its importance when studying mouse models of human diseases.

Anticipation describes the tendency of some variable dominant conditions to become more severe in successive generations. Until recently, most geneticists were skeptical that this ever really happened. The problem is that true anticipation is very easily mimicked by random variations in severity. A family comes to clinical attention when a severely affected child is born. Investigating the history, the geneticist notes that one of the parents is affected, but only mildly. This looks like anticipation, but may actually be just a bias of ascertainment. Had the parent been severely affected, he or she would most likely never have become a parent, and had the child been mildly affected, the family would not have come to notice. Given the lack of any plausible mechanism for anticipation, and the statistical problems of demonstrating it in the face of these biases, most geneticists were unwilling to consider anticipation seriously until molecular developments obliged them to do so.

Anticipation suddenly became respectable, even fashionable, with the discovery of unstable expanding trinucleotide repeats in Fragile-X syndrome (MIM 309550: mental retardation with various physical signs), and later in myotonic dystrophy (MIM 160900: a very variable multisystem disease with characteristic muscular dysfunction) and Huntington disease (see Box 16.7). Severity or age of onset of these diseases correlates with the repeat length, and the repeat length tends to grow as the gene is transmitted down the generations. Thus these conditions show true anticipation. Now once again we see claims for anticipation being made for many diseases, and it is important to bear in mind that the old objection about bias of ascertainment remains valid. To be credible, a claim of anticipation requires careful statistical backing, and not just anecdotal evidence.

Certain human characters are autosomal dominant and transmitted by parents of either sex, but they manifest only when inherited from a parent of one particular sex. For example there are families with autosomal dominant glomus tumors that are expressed only in people who inherit the gene from their father (Figure 3.5D), while Beckwith-Wiedemann syndrome (MIM 130650: exomphalos, macroglossia, overgrowth) is sometimes dominant but expressed only by people who inherit it from their mother (Figure 3.5E). These parental sex effects are evidence of imprinting, a poorly understood phenomenon whereby certain genes are somehow marked (imprinted) with their parental origin. The many questions that surround the mechanism and evolutionary purpose of imprinting are discussed in Chapter 7 and a particularly striking clinical example is described in Box 16.6.

For some X-linked dominant conditions, absence of the normal allele is lethal before birth. Thus affected males are not born, and we see a condition that affects only females, who pass it on to half their daughters but none of their sons (Figure 3.5F). There may be a history of miscarriages, but families are rarely big enough to prove that the number of sons is only half the number of daughters. An example is incontinentia pigmenti (MIM 308310: linear skin defects following defined patterns known as Blaschko's lines, often accompanied by neurological or skeletal problems).

Many cases of severe genetic disease are the result of fresh mutations, striking without warning in a family with no previous history of the disease. People with severe genetic diseases seldom reproduce, so they do not pass on their mutant genes. On the assumption that, averaged over time, new mutations exactly replace the disease genes lost through natural selection, there is a simple relationship (described in Section 3.3) between the rate at which natural selection is removing disadvantageous genes, the rate at which new mutation is creating them, and their frequency in the population. The general mechanisms that affect the population frequency of alleles are discussed in Section 9.2.3.

This mutation-selection dynamic has different effects on pedigrees, depending on the mode of inheritance. Autosomal recessive pedigrees are not significantly affected - any new mutations probably happened many generations ago, and we can safely assume that the parents of an affected child are both carriers. For dominant conditions however the turnover of disease genes is much faster, because they are constantly exposed to selection. A fully penetrant lethal dominant would necessarily always occur by fresh mutation, and the parents would never be affected (an example is thanatophoric dysplasia, MIM 187600: severe shortening of long bones and abnormal fusion of cranial sutures). People with nonlethal but severe dominant conditions often have unaffected parents and no previous family history of the condition. Serious X-linked recessives also show a significant proportion of fresh mutations, because the gene is exposed to natural selection whenever it is in a male.

When a normal couple with no relevant family history have a child with severe abnormalities (Figure 3.5H), deciding the mode of inheritance and recurrence risk can be very difficult: the problem might be autosomal recessive, autosomal dominant with a new mutation, X-linked recessive (if the child is male) or nongenetic. A further complication is introduced by germinal mosaicism (see below).

We have seen that in serious autosomal dominant and X-linked diseases, where affected people have few or no children, the disease genes are maintained in the population by recurrent mutation. A common assumption is that an entirely normal person produces a single mutant gamete. However, this is not necessarily what happens. Unless there is something special about the mutational process, such that it can happen only during gametogenesis, mutations may arise at any time during post-zygotic life. Post-zygotic mutations produce mosaics with two (or more) genetically distinct cell lines. The older literature on human mosaicism refers only to chromosomal mosaicism, because that was the only type of mosaicism that could be detected before DNA analysis was developed, but mosaicism for single gene mutations is at least as frequent and important.

Mosaicism can affect somatic and/or germ line tissues. Post-zygotic mutations are not merely frequent, they are inevitable. Human mutation rates are typically 10^-7 per gene per cell generation, and our bodies contain perhaps 10¹³ cells. It follows that every one of us must be a mosaic for innumerable genetic diseases. Indeed, as Professor John Edwards memorably remarked, a normal man may well produce the whole of the OMIM catalogue in every ejaculate. This should cause no anxiety. If a cell in your finger mutates to the Huntington disease genotype, or a cell in your ear picks up a cystic fibrosis mutation, there are absolutely no consequences for you or your family. Only if a somatic mutation results in the emergence of a substantial clone of mutant cells is there a risk to the whole organism. This can happen in two ways:

1. The mutation causes abnormal proliferation of a cell that would normally replicate little or not at all, thus generating a clone of mutant cells. This, of course, is how cancer happens, and this whole topic is discussed in detail in Chapter 18.
2. the mutation occurs in an early embryo, affecting a cell which is the progenitor of a significant fraction of the whole organism. In that case the mosaic individual may show clinical signs of disease.

Mutations occurring in a parent's germ line can cause de novo inherited disease in a child. When an early germ-line mutation has produced a person who harbors a large clone of mutant germ-line cells (germinal, or gonadal, mosaicism), a normal couple with no previous family history may produce more than one child with the same serious dominant disease. The pedigree mimicks recessive inheritance. Even if the correct mode of inheritance is realized, it is very difficult to calculate a recurrence risk to use in counseling the parents. Usually an empiric risk (Section 3.4.4) is quoted. Figure 3.7 shows an example of the uncertainty that mosaicism introduces into counseling, in this case in an X-linked disease.

Molecular studies can be a great help in these cases. Sometimes it is possible to demonstrate directly that a normal father is producing a proportion of mutant sperm (Figure 3.8). Direct testing of the germ line is not possible in women, but other accessible tissues such as fibroblasts or hair roots can be examined for evidence of mosaicism. A negative result on somatic tissues does not rule out germ line mosaicism, but a positive result, in conjunction with an affected child, proves it.

Mosaics are presumed (though rarely proved) to derive from a single fertilized egg. Chimeras on the other hand are the result of fusion of two zygotes into a single embryo (the reverse of twinning), or alternatively of limited colonization of one twin by cells from a nonidentical co-twin (Figure 3.9). Chimerism is proved by the presence in pooled tissue samples of too many parental alleles at several loci (if just one locus were involved, one would suspect mosaicism for a single mutation). Blood-grouping centers occasionally discover chimeras among normal donors, and some intersex patients turn out to be XX/XY chimeras. Strain et al. (1998) describe a remarkable case of a 46,XY/46,XX boy whose 46,XX cell line is parthenogenetic, derived by diploidization of a haploid maternal cell with no paternal contribution.