Genetic Analysis of Complex Disease. Группа авторов

may exhibit reduced penetrance, in which a person carries a causative gene but does not exhibit any manifestations of the condition. On the other hand, variable expressivity refers to the range of features that may be observed in individuals with the same condition. Codominance, in which a trait is expressed from both alleles, has also been observed in certain traits, for example, in AB blood type.

Table 2.3 Hallmarks of Mendelian inheritance patterns of different types.

Inheritance pattern	Examples	Transmission features	Recurrence risk	Prevalence in population	Other critical features
Autosomal dominant	Marfan syndrome; neurofibromatosis; myotonic dystrophy	Transmitted from affected parent to affected offspring (vertical transmission) male‐to‐male possible transmission; de novo mutations may occur	For each offspring of affected parent, risk to child to inherit disease gene is 50%	p2 + 2pq	Reduced penetrance may be observed
Autosomal recessive	Sickle cell anemia; cystic fibrosis	Carrier parents generally unaffected	For carrier parents, risk for each subsequent child is 25%	q2	Consanguinity considered
X‐linked	Duchenne muscular dystrophy; fragile X syndrome; hemophilia	No male‐to‐male transmission; de novo mutations may rarely occur	50% of offspring of carrier female have trait (if male, affected, if female carrier); all female offspring of affected male are carriers	Females: q2; males: q	Females may show sub‐clinical, atypical, or fully penetrant features of the condition. Non‐random X inactivation may contribute to more severe female phenotype.
Y linked	Genes SRY and TDF, important in sex determination, are on the Y chromosome; no known diseases are located on Y	Exclusively male‐to‐male transmission	All sons of affected males are affected; no daughters of affected males are affected	Females: 0; males: q	Male‐determining genes are located just proximal to pseudoautosomal region on Y chromosome; faulty recombination in pseudoautosomal region can lead to errors in sex determination
Autosomal codominant	MN blood group; microsatellite repeat markers	Each allele confers measurable component to phenotype	Varies according to mating type	Genotypes expected to occur in Hardy–Weinberg proportions of p2, 2pq, and q2
Mitochondrial	Leber’s optic atrophy; KSS (Kearns–Sayre syndrome); MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke‐like episodes);	Exclusively maternal transmission through maternal mitochondria	All offspring of affected females are at risk to inherit mutation (may be affected or carrier). Proportion of affected offspring is variable based on maternal heteroplasmy. Offspring of affected male not at risk to inherit mutation.		Heteroplasmy may determine phenotypic severity. Majority of mitochondrial diseases are due to mutations in the nuclear genome rather than the mitochondrial genome and follow autosomal recessive inheritance pattern.

Figure 2.10 Pedigrees consistent with (a) autosomal dominant inheritance, (b) autosomal recessive inheritance, (c) X‐linked recessive inheritance, (d) X‐linked dominant inheritance, and (e) mitochondrial inheritance. Here and elsewhere squares indicate males, circles indicate females, open symbols indicate unaffected individuals, and solid symbols indicate affected individuals.

      X‐linked Inheritance

The majority of the genes located on the X chromosome do not have a complementary gene on the Y chromosome. Therefore, males are “hemizygous” at these loci because they have only a single copy of the gene. X‐linked conditions were historically described as “X‐linked dominant” or “X‐linked recessive.” In an X‐linked recessive condition, a single abnormal allele was sufficient to cause disease in a hemizygous male, while females needed two. On the other hand, in “X‐linked dominant” conditions, a single abnormal allele was sufficient to cause a condition in both males and females. Although these patterns of inheritance hold true for many conditions, female carriers may exhibit features of an X‐linked recessive condition, due to skewed X‐inactivation. For example, in Duchenne muscular dystrophy, approximately 25% of female carriers will exhibit some symptoms of the condition, ranging from muscle weakness to features as severe as seen in males (Hoogerwaard et al. 1999). This has led many researchers to argue that conditions with loci on the X‐chromosome should simply be termed, “X‐linked.”

      Mitochondrial Inheritance

      Mitochondrial inheritance is a non‐classical pattern of single gene inheritance that is observed in conditions in which the causative allele is located in the mitochondrial DNA (mtDNA). In humans, each mitochondrion has approximately 2–10 copies of the mtDNA, which contains 37 genes. A mutation in one of these genes may be present in all copies of the mtDNA in a cell (known as homoplasmy). Alternately, a cell may contain some mtDNA with the mutation and other mtDNA without the mutation, known as heteroplasmy. The degree of heteroplasmy may vary by tissue and can influence the severity of the disease and the risk to future offspring. Mitochondria are inherited from the mother and, therefore, are referred to as having “maternal inheritance.” The risk for an affected mother to pass on the genetic defect in the mtDNA can approach 100%.

      Y‐linked

      Alleles located on the Y chromosome are transmitted from affected males to all sons, and in each case, the son’s Y‐linked phenotype will be identical to that of the father; daughters of males with a Y‐linked trait will not inherit the trait, since they receive their father’s X chromosome. Very few expressed genes have been localized to the Y chromosome.

Genetic Changes Associated with Disease/ Trait Phenotypes

      Mutations Versus Polymorphisms

      Alterations in the genetic code can be neutral, beneficial, or deleterious. Neutral and beneficial changes contribute to the natural variation among individuals and are not considered to have a negative effect on the organism. Rare changes in the genetic code that lead to an abnormal trait or disease phenotype are typically termed a mutation (or a pathogenic variant). The pathology of a mutation can be the result of either a loss or gain of function of the gene product. Such changes can occur in a number of different ways as highlighted below. A polymorphism, on the other hand, is used to describe a genetic variation in which there are two or more possible alleles at a particular locus. A genetic variation