Genetica per Scienze Naturali a.a. 04-05 prof S. Presciuttini 1. Mendelian inheritance in man After...

Genetica per Scienze Naturalia.a. 04-05 prof S. Presciuttini

1. Mendelian inheritance in man After rediscovery of Mendel’s principles, an early task was After rediscovery of Mendel’s principles, an early task was

to show that they were true for animals also, and especially to show that they were true for animals also, and especially for humans.for humans.

In fact, human families, like the offspring of experimental In fact, human families, like the offspring of experimental organisms, show inheritance patterns both of the type organisms, show inheritance patterns both of the type discovered by Mendel (autosomal inheritance) and of sex discovered by Mendel (autosomal inheritance) and of sex linkage.linkage.

In general, what in the hand of an experimental geneticist is In general, what in the hand of an experimental geneticist is simply a “mutant phenotype”, in the hand of a human simply a “mutant phenotype”, in the hand of a human geneticists becomes a disease or a condition of disability geneticists becomes a disease or a condition of disability (often a severe disability).(often a severe disability).


2. Mendelian inheritance

The simplest genetic characters are those whose presence or absence 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 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 - character itself is programmed by only one pair of genes - expression of any human character is likely to require a large expression of any human character is likely to require a large number of genes and environmental factors.number of genes and environmental factors.

However, sometimes a particular genotype at one locus is However, sometimes a particular genotype at one locus is both both necessary and sufficientnecessary and sufficient for the character to be expressed, given for the character to be expressed, given the normal genetic and environmental background of the organism. the normal genetic and environmental background of the organism. Such characters are called Such characters are called MendelianMendelian..


3. Investigating Mendelian conditions in human

A member of a family who first comes to the A member of a family who first comes to the attention of a geneticist is called the proband. attention of a geneticist is called the proband. Usually the phenotype of the proband is Usually the phenotype of the proband is exceptional in some way (for example, the exceptional in some way (for example, the proband might be a dwarf).proband might be a dwarf).

The investigator then traces the history of the The investigator then traces the history of the phenotype in the proband back through the phenotype in the proband back through the history of the family and draws a family tree, history of the family and draws a family tree, or pedigree, by using standard symbolsor pedigree, by using standard symbols

Because controlled experimental crosses cannot be made with humans, geneticists must 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 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. chance. Such a scrutiny of records of matings is called pedigree analysis.


4. Dominance and recessiveness Dominance and recessiveness are properties of characters, not genes. A Dominance and recessiveness are properties of characters, not genes. A

character is character is dominantdominant if it is manifest in the heterozygote and if it is manifest in the heterozygote and recessiverecessive if if not. Thus alkaptonuria is recessive because only homozygotes for a not. Thus alkaptonuria is recessive because only homozygotes for a defective enzyme manifest it, whereas heterozygotes show the normal defective enzyme manifest it, whereas heterozygotes show the normal phenotype.phenotype.

Most human dominant syndromes are known only in heterozygotes. Most human dominant syndromes are known only in heterozygotes. Sometimes homozygotes have been described, born from matings of two Sometimes homozygotes have been described, born from matings of two heterozygous affected people, and often the homozygotes are much more heterozygous affected people, and often the homozygotes are much more severely affected. Examples are achondroplasia (short-limbed dwarfism) and severely affected. Examples are achondroplasia (short-limbed dwarfism) and Type 1 Waardenburg syndrome (deafness with pigmentary abnormalities). Type 1 Waardenburg syndrome (deafness with pigmentary abnormalities). Nevertheless we describe achondroplasia and Waardenburg syndrome as Nevertheless we describe achondroplasia and Waardenburg syndrome as dominant because these terms describe phenotypes seen in heterozygotes.dominant because these terms describe phenotypes seen in heterozygotes.

Males are Males are hemizygoushemizygous for loci on the X and Y chromosomes, where they for loci on the X and Y chromosomes, where they have only a single copy of each gene, so the question of dominance or 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.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 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 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 characters in females can be dominant or recessive. Thus there are five archetypal Mendelian pedigree patterns: archetypal Mendelian pedigree patterns: 1.1. Autosomal dominantAutosomal dominant

2.2. Autosomal recessiveAutosomal recessive

3.3. X-linked recessiveX-linked recessive

4.4. X-linked dominantX-linked dominant

5.5. Y-linkedY-linked

Only one important gene has been located on the human Y chromosome, 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 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.primary role in maleness. Even the X-linked dominant trait are rare.

Therefore, Therefore, in practice the important mendelian pedigree patterns are in practice the important mendelian pedigree patterns are autosomal dominant, autosomal recessive and X-linked. autosomal dominant, autosomal recessive and X-linked.


6. Autosomal Dominant Disorders In autosomal dominant disorders, the normal allele In autosomal dominant disorders, the normal allele

is recessive and the abnormal allele is dominant. is recessive and the abnormal allele is dominant. An example of an autosomal dominant phenotype An example of an autosomal dominant phenotype is achondroplasia, a type of dwarfism. In this case, is achondroplasia, a type of dwarfism. In this case, people with normal stature are genotypically people with normal stature are genotypically d/dd/d, , and the dwarf phenotype in principle could be and the dwarf phenotype in principle could be D/dD/d or or D/DD/D. However, it is believed that in . However, it is believed that in D/DD/D individuals the two "doses" of the individuals the two "doses" of the DD allele produce allele produce such a severe effect that this genotype is lethal. such a severe effect that this genotype is lethal. Therefore, all achondroplastics are heterozygotes. Therefore, all achondroplastics are heterozygotes.

Diego VelDiego Veláásques: sques: The Dwarf The Dwarf Sebastian de MorraSebastian de Morra (Museo (Museo del Prado, Madrid)del Prado, Madrid)A pedigree showing A pedigree showing

autosomal dominant autosomal dominant inheritanceinheritance


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 humanMore than 1,500 dominant diseases have been described in human

Pedigree of a dominant phenotype Pedigree of a dominant phenotype determined by a dominant allele determined by a dominant allele A A . In . In this pedigree, all the genotypes have this pedigree, all the genotypes have been deduced. been deduced.


8. Autosomal Recessive Disorders The phenotype of a recessive disorder is determined by homozygosity for a The phenotype of a recessive disorder is determined by homozygosity for a

recessive allele, and the unaffected phenotype is determined by the recessive allele, and the unaffected phenotype is determined by the corresponding dominant allele. Although in some instances it may be corresponding dominant allele. Although in some instances it may be misleading, the properties of dominance and recessiveness are thus misleading, the properties of dominance and recessiveness are thus transferred from traits to alleles.transferred from traits to alleles.

In general terms, recessive diseases In general terms, recessive diseases are determined by alleles that we can are determined by alleles that we can call call aa, and the normal condition by , and the normal condition by AA. Therefore, sufferers of the diseases are . Therefore, sufferers of the diseases are of genotype of genotype a/aa/a, and unaffected people are either , and unaffected people are either A/AA/A or or A/aA/a..

About 1,000 recessive diseases have been described in humans.About 1,000 recessive diseases have been described in humans.

Pedigree of a rare recessive phenotype determined by a Pedigree of a rare recessive phenotype determined by a recessive allele recessive allele a a . Gene symbols are normally not included in . Gene symbols are normally not included in pedigree charts, but genotypes are inserted here for reference. pedigree charts, but genotypes are inserted here for reference. Note that individuals II-1 and II-5 marry into the family; they Note that individuals II-1 and II-5 marry into the family; they are assumed to be normal because the heritable condition under are assumed to be normal because the heritable condition under scrutiny is rare. Note also that it is not possible to be certain of scrutiny is rare. Note also that it is not possible to be certain of the genotype in some persons with normal phenotype; such the genotype in some persons with normal phenotype; such persons are indicated by A/– persons are indicated by A/–


9. Autosomal recessive pedigree pattern Two key points that distinguish pedigrees segregating recessive Two key points that distinguish pedigrees segregating recessive

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

recessive allele responsible for the recessive allele responsible for the rarerare phenotype (indicated by shading). phenotype (indicated by shading). Furthermore, we can deduce that the parents must both be heterozygotes, for Furthermore, we can deduce that the parents must both be heterozygotes, for example example P/pP/p. (Both must have a . (Both must have a pp allele because each contributed one to each allele because each contributed one to each affected child, and both must have a affected child, and both must have a PP allele because the people are phenotypically allele because the people are phenotypically normal.) We can identify the genotypes of the children (in the order shown) as normal.) We can identify the genotypes of the children (in the order shown) as P/-P/- , , p/pp/p, , p/pp/p, and , and P/- P/- (“-” means either(“-” means either P P oror p p). Hence, the pedigree can be rewritten). Hence, the pedigree can be rewritten as: as:

Notice another interesting feature of pedigree analysis: even though Mendelian Notice another interesting feature of pedigree analysis: even though Mendelian rules are at work, Mendelian ratios are rarely observed in single families because 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 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 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 3:1 ratio. If the couple were to have, say, 20 children, the ratio would undoubtedly be something like 15 unaffected and 5 be something like 15 unaffected and 5 affected affected children), but in a sample of four children), but in a sample of four any ratio is possible and all ratios are commonly found.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 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, level of familial recurrence, can be the consequence of a single mutant gene, rather than being due to non-genetic causes?rather than being due to non-genetic causes?

In case of simple dichotomous traits, classical segregation analysis may provide In case of simple dichotomous traits, classical segregation analysis may provide the answer. Segregation analysis is a statistical method of analyzing family data the answer. Segregation analysis is a statistical method of analyzing family data that tests whether an observed pattern of phenotypes in families is compatible 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 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 ratios of offspring from a particular parental cross to test for conformity with the Mendelian theory. the Mendelian theory.

The starting point of segregation analysis is the collection of as may as possible 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 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 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 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 in each of the marriage type, an expected number of affected individual can be calculated and compared with the observed number. calculated and compared with the observed number.


12. X-Linked Recessive Disorders Phenotypes with X-linked recessive inheritance typically show the Phenotypes with X-linked recessive inheritance typically show the

following patterns in pedigrees:following patterns in pedigrees: Many more males than females show the phenotype under study. This is 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 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, Xboth the mother and the father bear the allele (for example, XAA/X/Xaa × X × Xaa/Y), /Y), whereas a male with the phenotype can be produced when only the mother whereas a male with the phenotype can be produced when only the mother carries the allele.carries the allele.

None of the offspring of an affected male are affected, but all his daughters 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 must be heterozygous "carriers" because females must receive one of their X chromosomes from their fathers. Half the sons born to these carrier daughters chromosomes from their fathers. Half the sons born to these carrier daughters are affected. are affected.

Pedigree showing that X-linked recessive alleles expressed Pedigree showing that X-linked recessive alleles expressed in males are then carried unexpressed by their daughters in in males are then carried unexpressed by their daughters in the next generation, to be expressed again in their sons. the next generation, to be expressed again in their sons. Note that III-3 and III-4 cannot be distinguished Note that III-3 and III-4 cannot be distinguished phenotypicallyphenotypically


13. Hemophilia

The most famous cases of hemophilia are found in the pedigree of the interrelated royal families 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 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 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 the last czar of Russia, inherited the allele ultimately from Queen Victoria, who was the grandmother of his mother Alexandra.grandmother of his mother Alexandra.


14. X-linked dominant disorders These disorders have the following characteristics: These disorders have the following characteristics:

1. Affected males pass the condition to all their daughters but to none of their 1. Affected males pass the condition to all their daughters but to none of their sons. sons.

2. Affected heterozygous females married to unaffected males pass the 2. Affected heterozygous females married to unaffected males pass the condition to half their sons and daughters. condition to half their sons and daughters.

There are few examples of X-linked There are few examples of X-linked dominant phenotypes in humans. One dominant phenotypes in humans. One example is hypophosphatemia, a type of example is hypophosphatemia, a type of vitamin D-resistant rickets (bones become vitamin D-resistant rickets (bones become bent and distorted).bent and distorted).


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


16. Impact of genetic diseases With improvements in hygiene and health care during the last century there has 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 been a decline in the contribution of environmental factors to disease, in particular a decrease in illness due to infections and nutritional deficiencydecrease in illness due to infections and nutritional deficiency

Monogenic diseases are responsible for a heavy loss of life. The global prevalence 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 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 estimated that taken together, monogenic diseases may account for upto 40% of the work of hospital based paediatric practice (Scriver, 1995).work of hospital based paediatric practice (Scriver, 1995).

This has led to increased relative contribution of genetic disorders to morbidity and This has led to increased relative contribution of genetic disorders to morbidity and mortality:mortality:

2% of all neonates have a chromosomal abnormality or a single gene disorder.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 childhood Mendelian disorders account for 50% of blindness, 50% of deafness, 50% of

all cases of severe mental retardation, 40-50% of childhood deathsall cases of severe mental retardation, 40-50% of childhood deaths The birth of a “normal” human being is almost a rare occurrence: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 A chromosomal abnormality is present in at least 50% of all recognized first trimester spontaneous abortionsspontaneous abortions

Genetica per Scienze Naturali a.a. 04-05 prof S. Presciuttini 1. Mendelian inheritance in man After...

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