1. Mendelian inheritance in man After rediscovery of Mendel’s principles, an early task was to show that they were true for animals also, and especially for humans. In fact, human families, like the offspring of experimental organisms, show inheritance patterns both of the type discovered by Mendel (autosomal inheritance) and of sex linkage. In general, what in the hand of an experimental geneticist is simply a “mutant phenotype”, in the hand of a human geneticists becomes a disease or a condition of disability (often a severe disability).

2. Mendelian inheritance 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 require 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 genetic and environmental background of the organism. Such characters are called Mendelian.

3. Investigating Mendelian conditions in human Because controlled experimental crosses cannot be made with humans, geneticists must resort to scrutinizing records in the hope that informative matings have been made by chance. Such a scrutiny of records of matings is called pedigree analysis. A member of a family who first comes to the attention of a geneticist is called the proband. Usually the phenotype of the proband is exceptional in some way (for example, the proband might be a dwarf). The investigator then traces the history of the phenotype in the proband back through the history of the family and draws a family tree, or pedigree, by using standard symbols

4. Dominance and recessiveness Dominance and recessiveness are properties of characters, not genes. A character is dominant if it is manifest in the heterozygote and recessive if not. Thus alkaptonuria is recessive because only homozygotes for a defective enzyme manifest it, whereas heterozygotes show the normal phenotype. Most human dominant syndromes are known only in heterozygotes. Sometimes homozygotes have been described, born from matings of two heterozygous affected people, and often the homozygotes are much more severely affected. Examples are achondroplasia (short-limbed dwarfism) and Type 1 Waardenburg syndrome (deafness with pigmentary abnormalities). Nevertheless we describe achondroplasia and Waardenburg syndrome as dominant because these terms describe phenotypes seen in heterozygotes. Males are hemizygous for loci on the X and Y chromosomes, where they have only a single copy of each gene, so the question of dominance or recessiveness does not arise in males for X- or Y-linked characters.

5. The five basic Mendelian pedigree patterns Mendelian characters may be determined by loci on an autosome or on the X or Y sex chromosomes. Autosomal characters in both sexes and X-linked characters in females can be dominant or recessive. Thus there are five archetypal Mendelian pedigree patterns: Autosomal dominant Autosomal recessive X-linked recessive X-linked dominant Y-linked Only one important gene has been located on the human Y chromosome, the TDF gene, which codes for a testis-determining factor and plays a primary role in maleness. Even the X-linked dominant trait are rare. Therefore, in practice the important mendelian pedigree patterns are autosomal dominant, autosomal recessive and X-linked.

6. Autosomal Dominant Disorders In autosomal dominant disorders, the normal allele is recessive and the abnormal allele is dominant. An example of an autosomal dominant phenotype is achondroplasia, a type of dwarfism. In this case, people with normal stature are genotypically d/d, and the dwarf phenotype in principle could be D/d or D/D. However, it is believed that in D/D individuals the two "doses" of the D allele produce such a severe effect that this genotype is lethal. Therefore, all achondroplastics are heterozygotes. Diego Velásques: The Dwarf Sebastian de Morra (Museo del Prado, Madrid) A pedigree showing autosomal dominant inheritance

7. Autosomal dominant pedigree pattern In pedigree analysis, the main clues for identifying a dominant disorder are that the phenotype tends to appear in every generation of the pedigree and that affected fathers and mothers transmit the phenotype to both sons and daughters. It has been estimated that 1% of liveborn infants carry a gene for an autosomal dominant disease; in 20% of these cases (0.2% of livebirths) their disease is due to a new, or “sporadic” mutation that arose in the reproductive cells of one of their parents. More than 1,500 dominant diseases have been described in human Pedigree of a dominant phenotype determined by a dominant allele A . In this pedigree, all the genotypes have been deduced.

8. Autosomal Recessive Disorders The phenotype of a recessive disorder is determined by homozygosity for a recessive allele, and the unaffected phenotype is determined by the corresponding dominant allele. Although in some instances it may be misleading, the properties of dominance and recessiveness are thus transferred from traits to alleles. In general terms, recessive diseases are determined by alleles that we can call a, and the normal condition by A. Therefore, sufferers of the diseases are of genotype a/a, and unaffected people are either A/A or A/a. About 1,000 recessive diseases have been described in humans. Pedigree of a rare recessive phenotype determined by a recessive allele a . Gene symbols are normally not included in pedigree charts, but genotypes are inserted here for reference. Note that individuals II-1 and II-5 marry into the family; they are assumed to be normal because the heritable condition under scrutiny is rare. Note also that it is not possible to be certain of the genotype in some persons with normal phenotype; such persons are indicated by A/–

9. Autosomal recessive pedigree pattern Two key points that distinguish pedigrees segregating recessive conditions are that generally the disease appears in the progeny of unaffected parents and that the affected progeny include both males and females equally. When we know that both male and female phenotypic proportions are equal, we can assume that we are dealing with autosomal inheritance, not X-linked inheritance. The following typical pedigree illustrates the key point that affected children are born to unaffected parents:

10. Deducing genotypes from phenotypes in pedigrees From this pattern we can immediately deduce autosomal inheritance, with the recessive allele responsible for the rare phenotype (indicated by shading). Furthermore, we can deduce that the parents must both be heterozygotes, for example P/p. (Both must have a p allele because each contributed one to each affected child, and both must have a P allele because the people are phenotypically normal.) We can identify the genotypes of the children (in the order shown) as P/- , p/p, p/p, and P/- (“-” means either P or p). Hence, the pedigree can be rewritten as: Notice another interesting feature of pedigree analysis: even though Mendelian rules are at work, Mendelian ratios are rarely observed in single families because the sample sizes are too small. In the above example, we see a 1:1 phenotypic ratio in the progeny of what is clearly a monohybrid cross, in which we might expect a 3:1 ratio. If the couple were to have, say, 20 children, the ratio would undoubtedly be something like 15 unaffected and 5 affected children), but in a sample of four any ratio is possible and all ratios are commonly found.

11. Classical segregation analysis How can an investigator decide if a rare condition, may be showing a certain level of familial recurrence, can be the consequence of a single mutant gene, rather than being due to non-genetic causes? In case of simple dichotomous traits, classical segregation analysis may provide the answer. Segregation analysis is a statistical method of analyzing family data that tests whether an observed pattern of phenotypes in families is compatible with an explicit model of inheritance. In other words, it is the analysis of the ratios of offspring from a particular parental cross to test for conformity with the Mendelian theory. The starting point of segregation analysis is the collection of as may as possible families with the trait under consideration. Then, considering 1) the frequency of the mutant gene in the population, 2) the proportion of the marriages of each possible type in the population and 3) the Mendelian transmission probabilities in each of the marriage type, an expected number of affected individual can be calculated and compared with the observed number.

12. X-Linked Recessive Disorders Phenotypes with X-linked recessive inheritance typically show the following patterns in pedigrees: Many more males than females show the phenotype under study. This is because a female showing the phenotype can result only from a mating in which both the mother and the father bear the allele (for example, XA/Xa × Xa/Y), whereas a male with the phenotype can be produced when only the mother carries the allele. None of the offspring of an affected male are affected, but all his daughters must be heterozygous "carriers" because females must receive one of their X chromosomes from their fathers. Half the sons born to these carrier daughters are affected. Pedigree showing that X-linked recessive alleles expressed in males are then carried unexpressed by their daughters in the next generation, to be expressed again in their sons. Note that III-3 and III-4 cannot be distinguished phenotypically

13. Hemophilia The most famous cases of hemophilia are found in the pedigree of the interrelated royal families of Europe. The original hemophilia allele in the pedigree arose spontaneously (as a mutation) in the reproductive cells of Queen Victoria's parents or of Queen Victoria herself. Alexis, the son of the last czar of Russia, inherited the allele ultimately from Queen Victoria, who was the grandmother of his mother Alexandra.

14. X-linked dominant disorders These disorders have the following characteristics: 1. Affected males pass the condition to all their daughters but to none of their sons. 2. Affected heterozygous females married to unaffected males pass the condition to half their sons and daughters. There are few examples of X-linked dominant phenotypes in humans. One example is hypophosphatemia, a type of vitamin D-resistant rickets (bones become bent and distorted).

15. Complications to the basic Mendelian patterns (A) A common recessive, such as blood group O, can give the appearance of a dominant pattern. (B) Autosomal dominant inheritance with nonpenetrance in II2. (C) Autosomal dominant inheritance with variable expression. (D) Genetic imprinting: in this family autosomal dominant glomus tumors manifest only when the gene is inherited from the father. (E) Genetic imprinting: in this family autosomal dominant Beckwith-Wiedemann syndrome manifests only when the gene is inherited from the mother. (F) X-linked dominant incontinentia pigmenti. Affected males abort spontaneously (small squares). (G) An X-linked recessive pedigree where inbreeding gives an affected female and apparent male-to-male transmission. (H) A new autosomal dominant mutation, mimicking an autosomal or X-linked recessive pattern.

16. Impact of genetic diseases With improvements in hygiene and health care during the last century there has been a decline in the contribution of environmental factors to disease, in particular a decrease in illness due to infections and nutritional deficiency Monogenic diseases are responsible for a heavy loss of life. The global prevalence of all single gene diseases at birth is approximately 10/1000. In Canada, it has been estimated that taken together, monogenic diseases may account for upto 40% of the work of hospital based paediatric practice (Scriver, 1995). This has led to increased relative contribution of genetic disorders to morbidity and mortality: 2% of all neonates have a chromosomal abnormality or a single gene disorder. childhood Mendelian disorders account for 50% of blindness, 50% of deafness, 50% of all cases of severe mental retardation, 40-50% of childhood deaths The birth of a “normal” human being is almost a rare occurrence: A chromosomal abnormality is present in at least 50% of all recognized first trimester spontaneous abortions